Enclomiphene Citrate Capsule 6.25 mg Each – 60 count

Semaglutide / Cyanocobalamin Injection 1/0.5 mg/mL 2.5 mL – 5 Week Supply

Semaglutide / Cyanocobalamin Injection (2.5 mL)

1/0.5 MG/ML, 5/0.5 MG/ML

Semaglutide
Semaglutide is a synthetic glucagon-like peptide-1 receptor agonist (GLP-1 RA) that belongs to a class of antidiabetic agents called incretin mimetics. Incretins are endogenous compounds, including glucagon-like peptide-1 (GLP-1), that improve glycemic control once released into the circulation via the gut. Semaglutide subcutaneous injection and oral tablets are used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Semaglutide oral tablets demonstrated CV safety by meeting the primary endpoint of non-inferiority for the composite MACE endpoint; the proportion of patients who experienced at least one MACE was 3.8% with semaglutide oral tablets and 4.8% with placebo.^[1] However, semaglutide oral tablets are not approved for the reduction of CV events. As with other agents in this class, semaglutide has a boxed warning regarding rodent thyroid C-cell tumor findings and the uncertain relevance to humans. First-line T2DM therapy depends on comorbidities, patient-centered treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification. Therapy with a GLP-1 RA or sodium-glucose cotransporter 2 inhibitor (SGLT2 inhibitor) that has proven CV benefit is recommended for initial therapy, with or without metformin based on glycemic needs, in patients with indicators of high-risk or established CV disease. Among the GLP-1 RAs, evidence of CV benefit is strongest for liraglutide, favorable for semaglutide, and less certain for exenatide; there is no evidence of CV benefit with lixisenatide. GLP-1 RAs have high glucose-lowering efficacy, but with variation within the drug class. Evidence suggests that the effect may be greatest for semaglutide once weekly, followed by dulaglutide and liraglutide, closely followed by exenatide once weekly, and then exenatide twice daily and lixisenatide. GLP-1 RAs improve CV outcomes, as well as secondary outcomes such as progression of renal disease, in patients with established CV disease or chronic kidney disease (CKD); these factors make GLP-1 RAs an alternative initial treatment option, with or without metformin based on glycemic needs, in T2DM patients with indicators of high-risk or established heart failure (HF) or CKD who cannot tolerate an SGLT2 inhibitor. In patients with T2DM who do not have atherosclerotic cardiovascular disease (ASCVD)/indicators of high-risk, HF, or CKD and who need to minimize hypoglycemia and/or promote weight loss, GLP-1 RAs are generally recommended as a second or third-line option as add-on to metformin therapy. For patients requiring an injectable medication, GLP-1 RAs are preferred to insulin due to similar or even better efficacy in A1C reduction, lower risk of hypoglycemia, and reductions in body weight.^[2]^[3]^[4]^[5] A separate product, semaglutide subcutaneous injection, is indicated as an adjunct to lifestyle modifications for weight loss and chronic weight management in obese (BMI 30 kg/m2 or greater) or overweight adults (BMI 27 kg/m2 or greater) with at least 1 weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Four clinical trials for weight management were conducted pre-approval. Depending on the clinical trial, more treated participants lost 5% up to 15% of their initial body weight vs. those taking placebo. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be offered as chronic treatment along with lifestyle modifications to patients with obesity when the potential benefits outweigh the risks. Short-term pharmacotherapy has not been shown to produce longer-term health benefits and cannot be generally recommended. A generalized hierarchy for medication preferences that would apply to all overweight patients cannot currently be scientifically justified. Individualized weight loss pharmacotherapy is recommended, based upon factors such as the specific characteristics of each weight loss medication, the presence of weight-related complications, and the medical history of the patient.^[6]

Cyanocobalamin
Cyanocobalamin is a vitamin of the B-complex family, commonly known as cobalamins (corrinoids). It is a synthetic or man-made form of vitamin B12 that is available as both a prescription and over-the-counter (OTC) medication. Cobalamins exist in several other chemical forms, including hydroxocobalamin, methylcobalamin, and adenosylcobalamin.^[7]^[8] Cyanocobalamin is the most common form of cobalamins used in nutritional supplements and fortified foods. It contains a cyano (cyanide) group in its structure, which makes it more stable than other forms of vitamin B12 as the cyanide stabilizes the molecule from deterioration. Hydroxocobalamin, however, is the most biologically active form of Vitamin B12; hence, it is more preferable than cyanocobalamin for the treatment of vitamin B12 deficiency.^[7]^[8]^[9]^[10]

Cyanocobalamin does not naturally exist in foods owing to the presence of cyanide, which is absent in the natural form of the vitamin. The chemical structure of cyanocobalamin contains the rare mineral cobalt (4.34%), which binds the cyano group and is located in the center of a corrin ring.^[11] The commercial manufacturing of the vitamin is done through bacterial fermentation. Compared to other forms of vitamin B12, it is easier to crystallize and more air-stable.^[9] Cyanocobalamin is usually obtained as a dark red, amorphous or crystalline powder, orthorhombic needles, or red crystals. The anhydrous form of the compound is highly hygroscopic. It may absorb up to 12% of water if exposed to air. Cyanocobalamin is sparingly soluble in alcohol and water (1 in 80 of water), but insoluble in chloroform, acetone, and ether. The coenzymes of this vitamin are highly unstable in light.^[12]

Cyanocobalamin is available in several dosage forms including the tablet, nasal spray, and injection. The US-FDA initially approved the drug in 1942.^[13] However, the compound became widely available for routine use in the treatment of B12 deficiency in the early 1950s.^[14]

The lack of vitamin B12 may result from any of the following conditions:

Addisonian (pernicious) anemia — this condition causes autoantibody formation against parietal cells, which results in a lack of IF essential for absorption of vitamin B12 from the intestine

Malabsorption — impaired absorption of vitamin B12

Gastrointestinal pathology, dysfunction, or surgery — these include atrophic gastritis, celiac disease, small bowel bacterial overgrowth, pancreatic insufficiency, Helicobacter pylori infection, gastric carcinoma, and total or partial gastrectomy

Diphyllobothrium latum and related species (the fish tapeworm) infestation — these parasites compete with vitamin B12 for intestinal absorption; this leads to a malabsorption of the vitamin

Certain medications use — long term metformin use and chronic acid-reducing drugs decrease the absorption of vitamin B12 from food particles

Malignancy of the pancreas or bowel

Folic acid deficiency

Semaglutide
Semaglutide an incretin mimetic; specifically, semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist with 94% sequence homology to human GLP-1. Semaglutide binds and activates the GLP-1 receptor. GLP-1 is an important, gut-derived, glucose homeostasis regulator that is released after the oral ingestion of carbohydrates or fats. In patients with Type 2 diabetes, GLP-1 concentrations are decreased in response to an oral glucose load. GLP-1 enhances insulin secretion; it increases glucose-dependent insulin synthesis and in vivo secretion of insulin from pancreatic beta cells in the presence of elevated glucose. In addition to increases in insulin secretion and synthesis, GLP-1 suppresses glucagon secretion, slows gastric emptying, reduces food intake, and promotes beta-cell proliferation.^[15] The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation; semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Therefore, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase.

Cyanocobalamin
Cyanocobalamin is a vital compound for cell division and growth, hematopoiesis, and nucleoprotein and myelin synthesis. This vitamin also has an important role in protein synthesis, neural metabolism, DNA and RNA production, as well as fat and carbohydrate metabolism. Several cells appear to have the greatest demand for cyanocobalamin, particularly those that undergo rapid division such as bone marrow and epithelial cells.^[11]^[13]

Cyanocobalamin binds itself to plasma proteins in the systemic circulation. It attaches with specific cobalamin binding proteins, called transcobalamin I and II, to enter into the tissues. In cells, this vitamin functions as a cofactor for two vital enzymatic reactions: (1) methionine synthase, i.e. the regeneration of methionine from homocysteine and (2) methylmalonyl-CoA mutase, i.e. the isomerization of methylmalonyl-CoA to succinyl-CoA. Both these methylation reactions are vital for growth and cell reproduction.^[16]^[17]

Methionine, a sulfur-containing, essential amino acid, is a precursor of S-adenosylmethionine, a cofactor for one-carbon metabolism and the final methyl donor for the methylation of DNA, RNA, proteins, and phospholipids.^[18] The methionine synthase plays a paramount role in the synthesis of nitrogenous bases (purines and pyrimidines) involved in the formation of DNA. The lack of adequate cobalamin in the body hinders the regeneration of tetrahydrofolate, which eventually leads to megaloblastic anemia due to the functional folate deficiency.^[16]^[17] On the other hand, the methylmalonyl-CoA mutase helps to metabolize odd chain fatty acids and branch chain amino acids.^[11] Cobalamin is also thought to keep the body’s level of sulfhydryl (SH) groups in reduced form. SH groups activate many enzyme systems involved in protein synthesis as well as fat and carbohydrate metabolism. If there is a lack of cobalamin in the body, methylmalonyl CoA accumulates, which presumably leads to the neurological manifestations of B12 deficiency.^[10]^[13]^[16]^[19]

The replenishment with parenteral cyanocobalamin causes a rapid and complete improvement of megaloblastic anemia and gastrointestinal symptoms caused by vitamin B12 deficiency. The parenteral administration also halts the progression of neurological damage associated with B12 deficiency, but the complete improvement of the condition may depend on the severity and extent of the deficiency.^[19]^[20]

Semaglutide
Semaglutide is contraindicated in patients with a history of angioedema, anaphylaxis, or other serious hypersensitivity reaction to semaglutide. There is a risk of serious hypersensitivity reactions with semaglutide. Serious hypersensitivity reactions have also been reported during postmarketing use with other GLP-1 receptor agonists. Use caution in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists because it is unknown whether such patients will be predisposed to serious reactions with semaglutide. If a serious hypersensitivity reaction is suspected, discontinue semaglutide. Treat promptly per standard of care, and monitor until signs and symptoms resolve.

Semaglutide is contraindicated in patients with a personal or family history of certain types of thyroid cancer, specifically thyroid C-cell tumors such as medullary thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Semaglutide has been shown to cause dose-dependent and treatment duration-dependent malignant thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. A statistically significant increase in cancer was observed in rats receiving semaglutide at all dose levels (greater than 2X human exposure). It is unknown whether semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. In clinical trials, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and were diagnosed after thyroidectomy, which was prompted by finding on protocol-specified screening with serum calcitonin or thyroid ultrasound. Patients should be counseled on the potential risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with semaglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

Semaglutide should not be used for the treatment of type 1 diabetes mellitus.

Hypoglycemia should be monitored for by the patient and clinician when semaglutide treatment is initiated and continued for type 2 diabetes mellitus (T2DM) and when used for weight reduction and maintenance. In a clinical trial of semaglutide injection for weight loss in patients with T2DM and a BMI of 27 kg/m2 or more, hypoglycemia (defined as a plasma glucose less than 54 mg/dL) was reported in 6.2% of semaglutide-treated patients versus 2.5% of placebo-treated patients. One episode of severe hypoglycemia (requiring the assistance of another person) was reported in one semaglutide-treated patient versus no placebo-treated patients. In clinical trials of semaglutide injection for T2DM, hypoglycemia was increased when semaglutide was used in combination with a sulfonylurea; patients receiving semaglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Although specific dose recommendations are not available, the clinician should consider a dose reduction of the sulfonylurea or insulin when used in combination with semaglutide. In addition, when semaglutide is used in combination with insulin detemir, the dose of insulin should be evaluated; in patients at increased risk of hypoglycemia consider reducing the dose of insulin at initiation of semaglutide, followed by careful titration. Adequate blood glucose monitoring should be continued and followed. Patient and family education regarding hypoglycemia management is crucial; the patient and patient’s family should be instructed on how to recognize and manage the symptoms of hypoglycemia. Early warning signs of hypoglycemia may be less obvious in patients with hypoglycemia unawareness which can be due to a long history of diabetes (where deficiencies in the release or response to counter regulatory hormones exist), with autonomic neuropathy, intensified diabetes control, or taking beta-blockers, guanethidine, or reserpine. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or other carbohydrate to treat hypoglycemic episodes. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia in a patient is an indication for the modification of treatment regimens, including setting higher glycemic goals.^[4] Semaglutide may have particular benefits when used in patients with T2DM who are overweight. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications should be considered as an adjunct to lifestyle therapy in all patients with T2DM as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure.^[6]

Semaglutide has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. After initiation and dose increases, patients should be observed carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue semaglutide; if pancreatitis is confirmed, do not resume semaglutide. Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including semaglutide. The FDA and the EMA have stated that after review of published and unpublished reports, the current data do not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Continue to consider precautions related to pancreatic risk until more data are available.^[21] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, obese patients receiving incretin-based therapies for weight loss should be monitored for the development of pancreatitis. Incretin-based therapies should be avoided in patients with prior or current pancreatitis; otherwise, there are insufficient data to recommend withholding them for weight loss due to concerns of pancreatitis.^[6]

Use semaglutide with caution in patients with known gallbladder disease or a history of cholelithiasis. If cholelithiasis or cholecystitis are suspected in a patient taking semaglutide, gallbladder studies are indicated. Acute gallbladder disease events, such as cholecystitis or cholelithiasis, have been reported in clinical studies. In clinical trials of semaglutide injection for type 2 diabetes mellitus (T2DM), cholelithiasis was reported in 1.5% and 0.4% of patients-treated with semaglutide 0.5 mg and 1 mg subcutaneous injection, respectively. Cholelithiasis was not reported in placebo-treated patients. In clinical trials of semaglutide tablets for T2DM, cholelithiasis was reported in 1% of patients-treated with semaglutide 7 mg tablets. Cholelithiasis was not reported in patients receiving the 14 mg tablets or placebo-treated patients. In clinical trials of semaglutide injection for weight management, cholelithiasis was reported in 1.6% of semaglutide-treated patients compared with 0.7% of placebo-treated patients. Cholecystitis was reported in 0.6% and 0.2% of patients, respectively. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in semaglutide-treated patients than in placebo-treated patients, even after accounting for the degree of weight loss. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, close monitoring for cholelithiasis is recommended during weight loss therapy, regardless of modality. In high-risk patients, use semaglutide with caution. Effective preventative measures for patients at risk for cholelithiasis include a slower rate of weight loss, increasing/including some dietary fat in the diet (assuming the patient has been on a very low-calorie diet containing little or no fat), or administration of ursodeoxycholic acid.^[6]

During semaglutide therapy, patients with a history of diabetic retinopathy should be closely monitored. Inform patients to contact their care team if changes in vision are experienced during treatment. There is an increased risk for diabetic retinopathy complications in patients with a history of diabetic retinopathy at baseline compared to patients without a known history of diabetic retinopathy. In a 2-year trial involving patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with semaglutide 0.5 and 1 mg once weekly injections (3%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). In a pooled analysis of glycemic control trials with oral semaglutide, diabetic retinopathy complications occurred in 4.2% of T2DM patients receiving semaglutide and 3.8% with comparator. In a trial of semaglutide injection in patients with T2DM and BMI of 27 kg/m2 or more, diabetic retinopathy was reported by 4% of semaglutide-treated patients vs. 2.7% of placebo-treated patients. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied.

Use caution during treatment with semaglutide in patients with renal impairment or end-stage renal disease (renal failure); however, no dose adjustments are needed based on renal function. Use caution and monitor renal function when initiating or increasing doses of semaglutide in patients with renal impairment or any patients who report severe gastrointestinal reactions during use. There have been postmarketing reports of renal impairment, acute kidney injury, and worsening of chronic renal failure, which sometimes has required hemodialysis, in patients treated with GLP-1 receptor agonists. Some of these events have been reported in patients without known underlying renal disease. In many of these cases, altered renal function has been reversed with supportive treatment and discontinuation of potentially causative agents. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration.

Suicidal behavior and ideation have been reported in clinical trials with other incretin mimetics indicated for weight management. Therefore, when semaglutide is used for weight management, administer with caution in patients with depression and avoid use in patients with a history of suicide attempts or active suicidal ideation; monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in moods or behaviors. Discontinue semaglutide in patients who develop suicidal thoughts or behaviors. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all patients undergoing weight loss therapy should be monitored for mood disorders, depression, and suicidal ideation. Caution is recommended in patients with a psychotic disorder (e.g., schizophrenia due to insufficient data. Patients receiving an antipsychotic should be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; these guidelines suggest that metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.^[6]

Semaglutide for the treatment of obesity or weight management should not be used during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus. According to the American Association of Clinical Endocrinologists the and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy; these guidelines recommend contraception requirements for patients of childbearing potential; those receiving semaglutide for weight reduction should use adequate contraception and discontinue semaglutide if pregnancy occurs.^[6] There are no adequate data or clinical studies of semaglutide use for the treatment of type 2 diabetes mellitus (T2DM) in pregnant women to inform a drug-associated risk for adverse developmental outcomes; use in pregnancy only if the potential benefit justifies the potential risk to the fetus. Rat studies have noted embryofetal mortality, structural abnormalities, and alterations to growth at maternal exposures below the maximum recommended human dose (MRHD) based on exposure AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at below the MRHD (rabbit) and 5-fold or greater the MRHD (monkey). Poorly controlled diabetes during pregnancy also increases fetal risk. In addition, salcaprozate sodium (SNAC), an absorption enhancer in oral semaglutide tablets, crosses the placenta, and reaches fetal tissues in rats. In a pre- and postnatal development study of SNAC exposure, an increase in gestation length, an increase in the number of stillbirths, and a decrease in pup viability were observed. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in pregnant women with diabetes mellitus and gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.^[4]

Semaglutide may be associated with reproductive risk and preconceptual planning is recommended; females of childbearing potential should discontinue semaglutide at least 2 months before a planned pregnancy due to the drug’s long washout period.

Use injectable semaglutide with caution during lactation; oral semaglutide therapy is not recommended during breastfeeding. There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats and was detected at levels 3- to 12- fold lower than in maternal rat plasma. Salcaprozate sodium (SNAC) (an absorption enhancer in oral semaglutide tablets) and/or its metabolites concentrated in the milk of lactating rats. There are no data on the presence of SNAC in human milk. Since the activity of UGT2B7, an enzyme involved in SNAC clearance, is lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC from breastfeeding and because semaglutide injection can be considered for use during lactation, advise patients that breastfeeding is not recommended during treatment with oral semaglutide tablets. If semaglutide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breastfeeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected.^[22]Also, while the manufacturers of metformin recommend against breastfeeding while taking the drug, data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies.^[23]^[24]^[25] Tolbutamide is usually considered compatible with breastfeeding.^[26] Glyburide may also be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide.^[27] If any oral hypoglycemics are used during breastfeeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.^[28]

Semaglutide has been studied in adults 65 years of age or older during clinical trials; safety and efficacy were not different in geriatric adults versus younger adults. In general, however, geriatric adults are especially at risk for hypoglycemic episodes. The specific reasons identified include intensive insulin therapy, decreased renal function, severe liver disease, alcohol ingestion, defective counter regulatory hormone release, missing meals/fasting, and gastroparesis. Because hypoglycemic events may be difficult to recognize in some elderly patients, antidiabetic agent regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals.^[4] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function.^[29]

Cyanocobalamin
Cyanocobalamin is contraindicated in those with hypersensitivity to cobalt moiety or cobalamin molecule due to the risk of anaphylaxis.^[30]

Warnings:
The use of cyanocobalamin is warned in patients with early Leber’s disease as there have been reports of severe and swift optic atrophy with its administration. Appropriate caution should be exercised while treating severe megaloblastic anemia with cyanocobalamin as intense treatment may lead to hypokalemia and sudden death. Cautious use of parenteral cyanocobalamin is also recommended in patients with renal impairment, including premature neonates, because of the possibility of greater aluminum accumulation, which may cause central nervous system and bone toxicity. Formulations of cyanocobalamin injection containing benzyl alcohol as a preservative should also be avoided in premature neonates and those with hypersensitivity due to its association with ‘gasping syndrome.^[31]^[32]^[33]

Monitoring:
A history of the patient’s allergies/hypersensitivity should be obtained before administering cyanocobalamin injection. If the patient is suspected to be sensitive to cobalt or other components of cobalamin, an intradermal test dose is recommended.^[19]^[31]

Several laboratory tests should be performed prior to treatment with cyanocobalamin, including serum vitamin B12, folate, iron, hematocrit, and reticulocyte count. All these parameters need to be normal before initiating the treatment. Serum levels of vitamin B12 and peripheral blood counts should be monitored in one month. For hematocrit and reticulocyte counts, recommendations are to repeat these tests daily from the 5th to 7th days of treatment and then frequently until the hematocrit returns to a normal range.^[16]^[32]^[34]

Both serum potassium concentrations and the platelet count need to be monitored carefully after parenteral administration of cyanocobalamin. This is because hypokalemia and thrombocytosis could occur due to the increase in erythrocyte metabolism following vitamin B12 therapy. Potassium replacement therapy should be administered if necessary.^[19]^[31]
Patients with pernicious anemia are three times more likely to have gastric carcinoma compared to general population; thus, appropriate tests need to be carried out to rule out this condition if suspected.^[32]

Therapeutic response to cyanocobalamin may decrease due to elderly age, infection, renal insufficiency, diabetes mellitus, marrow suppressants use (e.g. chloramphenicol), and concurrent iron or folic acid deficiency.^[19]^[35] Therefore, these factors should be taken into consideration and regular monitoring should be performed in these conditions while treating vitamin B12 deficiency with cyanocobalamin.

Semaglutide
In monotherapy trials with semaglutide injection for type 2 diabetes mellitus (T2DM), severe hypoglycemia (requiring the assistance of another person) was not reported in either the treatment group or the placebo group. Documented symptomatic hypoglycemia (glucose of 70 mg/dL or less) was reported in 1.6% to 3.8% of patients receiving semaglutide injection vs. 0% of patients receiving placebo. Severe or blood glucose confirmed symptomatic hypoglycemia (glucose of 56 mg/dL or less) was not reported in any of the patients receiving semaglutide monotherapy compared to 1.6% of patients receiving placebo. In trials where semaglutide was added on to basal insulin with or without metformin, severe hypoglycemia (requiring the assistance of another person) was reported in 1.5% of semaglutide-treated patients. Documented symptomatic hypoglycemia (glucose of 70 mg/dL or less) was reported in 16.7% to 29.8% of patients receiving semaglutide, and severe or blood glucose confirmed symptomatic hypoglycemia (glucose of 56 mg/dL or less) was reported in 8.3% to 10.7% of patients receiving semaglutide. Hypoglycemia was more frequent when semaglutide was used in combination with a sulfonylurea; severe hypoglycemia occurred in 0.8% and 1.2% of patients when semaglutide 0.5 mg and 1 mg, respectively, was given with a sulfonylurea; with documented symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when semaglutide 0.5 mg and 1 mg, respectively. Severe or blood glucose confirmed symptomatic hypoglycemia (glucose of 56 mg/dL or less) occurred in 6.5% and 10.4% of patients when semaglutide 0.5 mg and 1 mg, respectively, when coadministered with a sulfonylurea. In monotherapy trials with semaglutide oral tablets for T2DM, severe hypoglycemia (requiring the assistance of another person) was reported in 1% of patients receiving the 7 mg tablets and 0% of patients receiving the 14 mg tablets or placebo. A blood glucose level of 54 mg/dL or less occurred in 1% of patients receiving placebo and 0% of the semaglutide oral treatment groups. In trials where semaglutide tablets was added on to metformin and/or sulfonylurea, basal insulin alone, or metformin in combination with basal insulin in patients with moderate renal impairment, severe hypoglycemia was not reported in any of the patients in the trial. In contrast, blood glucose level of 54 mg/dL or less occurred in 6% of patients receiving the 14 mg tablets, 3% of patients receiving placebo, and 0% of patients receiving the 7 mg tablets. In trials with semaglutide was added on to insulin with or without metformin, severe hypoglycemia was reported in 1% of patients receiving the 14 mg tablets, 1% of patients receiving placebo, and 0% of the patients receiving the 7 mg tablets. A blood glucose level of 54 mg/dL or less was reported in 26% of patients receiving the 7 mg tablets, 30% of patients receiving the 14 mg tablets, and 32% with placebo. In a trial of patients with T2DM and a BMI of 27 kg/m2 or greater being treated with semaglutide injection for weight loss, clinically significant hypoglycemia (plasma glucose less than 54 mg/dL) was reported in 6.2% of semaglutide-treated patients versus 2.5% of placebo-treated patients. A higher rate of clinically significant hypoglycemic episodes was reported with the semaglutide 2.4 mg/week dose versus the 1 mg/week dose (10.7 vs. 7.2 episodes per 100 patient-years of exposure, respectively); the rate in the placebo-treated group was 3.2 episodes per 100 patient years of exposure. In addition, one episode of severe hypoglycemia requiring intravenous glucose was reported in a semaglutide-treated patient. The risk of hypoglycemia was increased when semaglutide was used with a sulfonylurea.

As with other GLP-1 analogs, gastrointestinal (GI) events are the most commonly reported adverse effects with semaglutide. More patients receiving semaglutide discontinued treatment due to GI adverse reactions than patients receiving placebo during all clinical trials. The following adverse effects were reported in patients receiving semaglutide injection or oral tablets across all clinical trials and at incidences higher than with placebo: nausea (11% to 44%), vomiting (5% to 24%), diarrhea (8.5% to 30%), abdominal pain (5.7% to 20%), abdominal distention (2% to 7%), constipation (3.1% to 24%), dyspepsia (0.6% to 9%), decreased appetite (6% to 9%), eructation (0.6% to 7%), flatulence (0.4% to 6%), gastroesophageal reflux disease (1.5% to 5%), gastroenteritis (4% to 6%), and gastritis (0.4% to 4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. Appendicitis was reported in 10 (0.5%) semaglutide-treated patients vs. 2 (0.2%) placebo-treated patients during clinical trials of semaglutide injection used for weight management. In the trial with semaglutide 1 mg and 2 mg injection for type 2 diabetes mellitus, GI events occurred more frequently among patients receiving semaglutide 2 mg injection (34%) compared to semaglutide 1 mg injection (30.8%).

Acute gallbladder disease events, such as cholecystitis or cholelithiasis, have been reported in clinical studies with semaglutide. In clinical trials of semaglutide injection for type 2 diabetes mellitus (T2DM), cholelithiasis was reported in 1.5% and 0.4% of patients-treated with semaglutide 0.5 mg and 1 mg subcutaneous injection, respectively. Cholelithiasis was not reported in placebo-treated patients. In clinical trials of oral semaglutide for T2DM, cholelithiasis was reported in 1% of patients-treated with semaglutide 7 mg PO. Cholelithiasis was not reported in patients receiving the 14 mg PO or placebo-treated patients. In clinical trials of semaglutide injection for weight management, cholelithiasis was reported in 1.6% of semaglutide-treated patients compared with 0.7% of placebo-treated patients. Cholecystitis was reported in 0.6% of semaglutide-treated patients (vs. 0.2%, placebo). Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in semaglutide-treated patients than in placebo-treated patients, even after accounting for the degree of weight loss. Cholecystectomy has been reported during postmarketing use.

In placebo-controlled trials of semaglutide injection for type 2 diabetes mellitus, fatigue, dysgeusia, and dizziness were reported in greater than 0.4% of semaglutide-treated patients. In placebo-controlled trials of semaglutide injection for weight management, headache (14%), fatigue (11%), and dizziness (8%) were reported in treated patients.

In placebo-controlled trials for type 2 diabetes mellitus, an injection site reaction (e.g., injection-site discomfort, erythema) was reported in 0.2% of patients receiving semaglutide. In clinical trials, 1.4% of patients treated with semaglutide injection for weight management experienced injection site reactions (including injection site pruritus, erythema, inflammation, induration, and irritation) vs. 1% with placebo.

Antibody formation against semaglutide has been reported. In clinical trials with semaglutide injection for type 2 diabetes mellitus (T2DM), 32 (1%) of patients receiving semaglutide tested positive for anti-semaglutide antibodies. Of these 32 semaglutide-treated patients that developed anti-semaglutide antibodies, 19 patients (0.6% of the overall population) developed antibodies cross-reacting with native GLP-1. In clinical trials with semaglutide oral tablets for T2DM, 14 (0.5%) of patients developed anti-semaglutide antibodies. Of the 14 semaglutide-treated patients that developed anti-semaglutide antibodies, 7 patients (0.2% of the overall population) developed antibodies cross-reacting with native GLP-1. In clinical trials with semaglutide injection for weight management, 50 (2.9%) of patients receiving semaglutide tested positive for anti-semaglutide antibodies. Of these 50 semaglutide-treated patients that developed anti-semaglutide antibodies, 28 patients (1.6% of the overall population) developed antibodies cross-reacting with native GLP-1. The in vitro neutralizing activity of the antibodies is uncertain at this time. The incidence of antibodies to semaglutide cannot be directly compared with the incidence of antibodies of other products.

There have been postmarketing reports of acute renal failure (unspecified) and worsening of chronic renal failure, which sometimes has required hemodialysis in patients treated with GLP-1 receptor agonists. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced gastrointestinal reactions such as nausea, vomiting, diarrhea, or dehydration. In clinical trials of semaglutide injection for weight management, acute kidney injury occurred in 7 patients (0.4 cases per 100 patient-years) receiving semaglutide vs. 4 patients (0.2 cases per 100 patient-years) receiving placebo. The risk of renal adverse reactions was increased in patients with a history of renal impairment (the weight management trials included 65 patients with a history of moderate or severe renal impairment at baseline), and occurred more frequently during dose titration. Monitor renal function when initiating or escalating doses of semaglutide in patients reporting severe adverse GI reactions.

In clinical trials of semaglutide for type 2 diabetes mellitus, patients exposed to semaglutide subcutaneous injection reported increases in amylase (hyperamylasemia) and lipase, and had a mean increase from baseline in amylase of 13% and lipase of 22%. These changes were not observed in placebo-treated patients. In trials with semaglutide oral tablets, patients exposed to semaglutide 7 mg and 14 mg oral tablets had a mean increase from baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%, respectively. These changes were not observed in placebo-treated patients. In clinical trials of semaglutide injection for weight management, patients treated with semaglutide had a mean increase from baseline in amylase of 16% and lipase of 39%. These changes were not observed in the placebo group. There have been reports of acute pancreatitis in patients taking semaglutide during premarketing trials. In glycemic control trials with semaglutide injection, acute pancreatitis was reported in 7 semaglutide-treated patients (0.3 cases per 100 patient-years) versus 3 in comparator-treated patients (0.2 cases per 100 patient-years). One case of chronic pancreatitis was confirmed in a semaglutide-treated patient. In a 2-year trial, acute pancreatitis was reported in 8 semaglutide-treated patients (0.27 cases per 100 patient-years) and 10 placebo-treated patients (0.33 cases per 100 patient-years), both on a background of standard of care. In trials of patients receiving oral semaglutide, pancreatitis was reported as a serious adverse event in 6 patients (0.1 events per 100 patient-years) receiving semaglutide versus 1 in comparator-treated patients (less than 0.1 events per 100 patient-years). In clinical trials of semaglutide injection for weight management, acute pancreatitis was confirmed by adjudication in 4 semaglutide-treated patients (0.2 cases per 100 patient-years) versus 1 in placebo-treated patients (less than 0.1 cases per 100 patient-years). One additional case of acute pancreatitis was confirmed in a patient treated with semaglutide in another clinical trial. The FDA and the EMA have stated that after review of published and unpublished reports, the current data do not support an increased risk of pancreatitis and pancreatic cancer in patients receiving incretin mimetics. The agencies have not reached any new conclusions about safety risks of the incretin mimetics, although they have expressed that the totality of the data that have been reviewed provides reassurance. Continue to consider precautions related to pancreatic risk until more data are available.^[21] After treatment initiation and dose increases, patients should be observed carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). Semaglutide has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis.

Hypersensitivity reactions, including anaphylaxis, anaphylactoid reactions, angioedema, rash, and urticaria, have been reported postmarketing with use of semaglutide.

Sinus tachycardia was observed during clinical studies of semaglutide injection for weight management; mean increases in resting heart rate of 1 to 4 beats per minute (bpm) were seen with routine clinical monitoring in semaglutide-treated patients vs. placebo. More patients treated with semaglutide than with placebo had maximum changes from baseline at any visit of 10 to 19 bpm (41% vs. 34%, respectively) and 20 bpm or more (26% vs. 16%, respectively). In placebo-controlled trials for type 2 diabetes mellitus (T2DM), semaglutide injection 0.5 and 1 mg resulted in a mean increase in heart rate of 2 to 3 bpm. There was a mean decrease in heart rate of 0.3 bpm in placebo-treated patients. In placebo-controlled trials of oral semaglutide for T2DM, semaglutide 7 and 14 mg resulted in a mean increase in heart rate of 2 to 3 bpm. There was no change in heart rate in placebo-treated patients. Heart rate should be monitored at regular intervals consistent with usual clinical practice in patients taking semaglutide and patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during semaglutide treatment. For patients who experience a sustained increase in resting heart rate while taking semaglutide, the drug should be discontinued. Adverse reactions related to hypotension (hypotension, orthostatic hypotension, and decreased blood pressure) were reported in 1.3% of semaglutide-treated patients versus 0.4% of placebo-treated patients during clinical trials of the semaglutide injection for weight management. Syncope was reported in 0.8% and 0.2% of patients, respectively. Some reactions were related to gastrointestinal adverse reactions and volume loss associated with semaglutide. Hypotension and orthostatic hypotension were more frequently seen in patients on concomitant antihypertensive therapy.

Hair loss (alopecia) was reported in 3% of patients receiving semaglutide injection for weight management during clinical trials vs. 1% of patients receiving placebo.

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. In a 2-year trial involving patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk, more events of diabetic retinopathy complications occurred in the patients treated with semaglutide injection (3%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was greater among patients with a history of diabetic retinopathy at baseline (semaglutide 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide 0.7%, placebo 0.4%). In a pooled analysis of glycemic control trials with oral semaglutide for T2DM, diabetic retinopathy complications occurred in 4.2% of patients receiving semaglutide vs. 3.8% with comparator. In a trial of patients with T2DM and BMI 27 kg/m2 or more receiving semaglutide injection for weight management, retinal disorders were reported by 6.9% of patients treated with semaglutide 2.4 mg/week, 6.2% of patients treated with semaglutide 1 mg/week, and 4.2% of patients treated with placebo. The majority of events were reported as diabetic retinopathy (4%, 2.7%, and 2.7%, respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively). The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy during treatment.

Semaglutide may be associated with the development of a new primary malignancy. Nonclinical studies in rodents of clinically relevant doses of GLP-1 receptor agonists showed dose-related and treatment-duration-dependent increases in the incidence of thyroid C-cell tumors (adenomas and carcinomas). It is unknown whether GLP-1 receptor agonists are associated with thyroid C-cell tumors, including MTC in humans. Patients should be counseled on the risk and symptoms of thyroid tumors (e.g. symptoms may include a mass in the neck, dysphagia, dyspnea or persistent hoarseness). Although routine monitoring of serum calcitonin is of uncertain value in patients treated with semaglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

Cyanocobalamin
Vitamin B12 is known to be non-toxic even in high doses. The reported adverse reactions following parenteral administration of vitamin B12 include:

Generalized: Anaphylaxis and death

Cardiovascular: Pulmonary edema and congestive cardiac/heart failure during early treatment; peripheral vascular thrombosis

Hematological: Polycythemia vera (a rare type of blood cancer)

Gastrointestinal: Mild, transient diarrhea

Dermatological: Itching; transitory exanthema (widespread skin rash)

Miscellaneous: Feeling of swelling of entire body

Semaglutide
Semaglutide for the treatment of obesity or weight management should not be used during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm due to the potential hazard of maternal weight loss to the fetus. According to the American Association of Clinical Endocrinologists the and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications must not be used during pregnancy; these guidelines recommend contraception requirements for patients of childbearing potential; those receiving semaglutide for weight reduction should use adequate contraception and discontinue semaglutide if pregnancy occurs.^[6] There are no adequate data or clinical studies of semaglutide use for the treatment of type 2 diabetes mellitus (T2DM) in pregnant women to inform a drug-associated risk for adverse developmental outcomes; use in pregnancy only if the potential benefit justifies the potential risk to the fetus. Rat studies have noted embryofetal mortality, structural abnormalities, and alterations to growth at maternal exposures below the maximum recommended human dose (MRHD) based on exposure AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at below the MRHD (rabbit) and 5-fold or greater the MRHD (monkey). Poorly controlled diabetes during pregnancy also increases fetal risk. In addition, salcaprozate sodium (SNAC), an absorption enhancer in oral semaglutide tablets, crosses the placenta, and reaches fetal tissues in rats. In a pre- and postnatal development study of SNAC exposure, an increase in gestation length, an increase in the number of stillbirths, and a decrease in pup viability were observed. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in pregnant women with diabetes mellitus and gestational diabetes mellitus (GDM) requiring medical therapy; insulin does not cross the placenta.^[4]

Cyanocobalamin
Cyanocobalamin is a medication of the FDA pregnancy category C. Up to now, no adequate and well-controlled reproduction studies have been conducted in humans and animals to determine its effects on pregnant women.^[36] However, there is also no reports of maternal or fetal harms with the ingestion of normal daily recommended amounts during pregnancy. In fact, the requirements for vitamin B12 increase during pregnancy. Therefore, parenteral cyanocobalamin should be administered to a pregnant woman if the benefits outweigh the risks.^[31]^[32]

Semaglutide
Use injectable semaglutide with caution during lactation; oral semaglutide therapy is not recommended during breastfeeding. There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats and was detected at levels 3- to 12- fold lower than in maternal rat plasma. Salcaprozate sodium (SNAC) (an absorption enhancer in oral semaglutide tablets) and/or its metabolites concentrated in the milk of lactating rats. There are no data on the presence of SNAC in human milk. Since the activity of UGT2B7, an enzyme involved in SNAC clearance, is lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC from breastfeeding and because semaglutide injection can be considered for use during lactation, advise patients that breastfeeding is not recommended during treatment with oral semaglutide tablets. If semaglutide is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Other oral hypoglycemics may be considered as possible alternatives during breastfeeding. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected.^[22]Also, while the manufacturers of metformin recommend against breastfeeding while taking the drug, data have shown that metformin is excreted into breast milk in small amounts and adverse effects on infant plasma glucose have not been reported in human studies.^[23]^[24]^[25] Tolbutamide is usually considered compatible with breastfeeding.^[26] Glyburide may also be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide.^[27] If any oral hypoglycemics are used during breastfeeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.^[28]

Cyanocobalamin
Cyanocobalamin is excreted in the breast milk of nursing women in levels similar to the level of vitamin B12 in maternal plasma.^[37] The distributed cyanocobalamin in breast milk has been found to be compatible with breastfeeding by the American Academy of Pediatrics.^[38] In addition, there has not been any reports of adverse effects associated with the intake of normal daily requirements of vitamin B12 during lactation. The Food and Nutrition Board, the National Academy of Sciences-National Research Council recommend that lactating women should consume 4 mcg of vitamin B12 daily.^[32]

Upon receipt of medication, immediately store between 35°F to 46°F (2°C – 8°C). Keep all medicines out of the reach of children. Throw away any unused medicine within 29 days of puncture or the BUD, which ever comes first. Do not flush unused medications or pour down a sink or drain.

Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381:841-851.
Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:26
Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care
American Diabetes Association. Standards of Medical Care in Diabetes – 2022. Diabetes Care. 2022; 45(Suppl 1):S1-S270. Available at: https://diabetesjournals.org/care/issue/45/Supplement_1– LinkOpens in New Tab
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2019 Executive Summary. End
Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines.
Markle HV, Greenway DC. Cobalamin. Critical reviews in clinical laboratory sciences. 1996; 33: 247-356.
Herrmann W, Obeid R. Cobalamin deficiency. Subcell Biochem. 2012; 56: 301-322.
Paul C, Brady DM. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms. Integrative Medicine: A Clinician’s Journal. 2017; 16: 42–49.
Vidal‐Alaball J, Butler C, Cannings‐John R, Goringe A, Hood K, McCaddon A, McDowell I, Papaioannou A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database of Systematic Reviews. 2005: CD004655.
O’Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010; 2: 299-316.
Sweetman SC, editor. Martindale: the complete drug reference, 34th ed. London: Pharmaceutical press; 2014.
CaloMist™ Nasal Spray (cyanocobalamin, USP) label. 2007. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022102s000lbl.pdf– LinkOpens in New Tab [Accessed October 23, 2020].
Berry RJ. Lack of historical evidence to support folic acid exacerbation of the neuropathy caused by vitamin B12 deficiency. The American journal of clinical nutrition. 2019; 110: 554-61.
Russell -Jones D, Vaag A, Schmidtz O, et al. Liraglutide vs. insulin glargine and placebo in combination with metformin andsulphonylurea therapy in type 2 diabetes mellitus: a randomised controlled trial (LEAD-5 met + SU). Diabetologia 2009;52:20
Alamin A, Gupta V. Vitamin B12 (Cobalamin). In: StatPearls [Internet]. 2020. StatPearls Publishing.
Froese DS, Fowler B, Baumgartner MR. Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation. Journal of inherited metabolic disease. 2019; 42: 673-685.
Berney M, Berney-Meyer L, Wong KW, Chen B, Chen M, Kim J, Wang J, Harris D, Parkhill J, Chan J, Wang F. Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences. 2015; 112: 10008-10013.
Vasavada A, Sanghavi D. Cyanocobalamin. In: StatPearls [Internet] 2020. StatPearls Publishing.
Sanz-Cuesta T, González-Escobar P, Riesgo-Fuertes R, Garrido-Elustondo S, del Cura-González I, Martín-Fernández J, Escortell-Mayor E, Rodríguez-Salvanés F, García-Solano M, González-González R, Martín-de la Sierra MÁ. Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health. 2012; 12:1-1.
Food and Drug Administration (US FDA) Drug Medwatch-FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes.
Everett J. Use of oral antidiabetic agents during breastfeeding. J Hum Lact 1997;13:319-21.
Hale TW, Kristensen JH, Hackett LP, et al. Transfer of metformin into human milk. Diabetologia 2002;45:1509-14.
Gardiner SJ, Kirkpatrick CMJ, Begg EJ, et al. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.
Briggs GG, Ambrose PJ, Nageotte MP, et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol 2005;105:1437-41.
American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
Feig DS, Donat DJ, Briggs GG, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care 2005;28:1851-5.
Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breastfeeding mother. Am Fam Physician 2001; 64:119-126.
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Caballero MR, Lukawska J, Lee TH, Dugué P. Allergy to vitamin B12: two cases of successful desensitization with cyanocobalamin. Allergy. 2007; 62: 1341-1342.
CYANOCOBALAMIN INJECTION, USP 1000 mcg/mL Sterile (Vitamin B12) [Label]. 2014. Available from: https://pdf.hres.ca/dpd_pm/00026115.PDF– LinkOpens in New Tab [Accessed October 26, 2020].
CYANOCOBALAMIN- cyanocobalamin injection, USP. West-Ward Pharmaceuticals Corp [Label]. 2018. Available from: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a66eb3c4-3e1d-4d49-b963-4fa2334cc9b6– LinkOpens in New Tab [Accessed October 26, 2020].
Nascobal® (Cyanocobalamin, USP) Nasal Spray 500 mcg/spray 0.125 mL [Label]. 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021642s020lbl.pdf– LinkOpens in New Tab [Accessed October 26, 2020].
Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008; 112: 2214-2221.
Solomon LR. Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood reviews. 2007; 21: 113-130.
Chandyo RK, Ulak M, Kvestad I, Shrestha M, Ranjitkar S, Basnet S, Hysing M, Shrestha L, Strand TA. The effects of vitamin B12 supplementation in pregnancy and postpartum on growth and neurodevelopment in early childhood: Study Protocol for a Randomized Placebo Controlled Trial. BMJ open. 2017; 7: e016434.
Samson RR, McClelland DB. Vitamin B12 in human colostrum and milk: quantitation of the vitamin and its binder and the uptake of bound vitamin B12 by intestinal bacteria. Acta Pædiatrica. 1980; 69: 93-99.
American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001; 10

Semaglutide / Cyanocobalamin Injection 1/0.5 mg/mL 1 mL – 2 Week Supply

Semaglutide / Cyanocobalamin Injection (1 mL)

1/0.5 MG/ML, 5/0.5 MG/ML

The lack of vitamin B12 may result from any of the following conditions:

Addisonian (pernicious) anemia — this condition causes autoantibody formation against parietal cells, which results in a lack of IF essential for absorption of vitamin B12 from the intestine

Malabsorption — impaired absorption of vitamin B12

Diphyllobothrium latum and related species (the fish tapeworm) infestation — these parasites compete with vitamin B12 for intestinal absorption; this leads to a malabsorption of the vitamin

Certain medications use — long term metformin use and chronic acid-reducing drugs decrease the absorption of vitamin B12 from food particles

Malignancy of the pancreas or bowel

Folic acid deficiency

Semaglutide should not be used for the treatment of type 1 diabetes mellitus.

Cyanocobalamin
Cyanocobalamin is contraindicated in those with hypersensitivity to cobalt moiety or cobalamin molecule due to the risk of anaphylaxis.^[30]

Hypersensitivity reactions, including anaphylaxis, anaphylactoid reactions, angioedema, rash, and urticaria, have been reported postmarketing with use of semaglutide.

Hair loss (alopecia) was reported in 3% of patients receiving semaglutide injection for weight management during clinical trials vs. 1% of patients receiving placebo.

Cyanocobalamin
Vitamin B12 is known to be non-toxic even in high doses. The reported adverse reactions following parenteral administration of vitamin B12 include:

Generalized: Anaphylaxis and death

Cardiovascular: Pulmonary edema and congestive cardiac/heart failure during early treatment; peripheral vascular thrombosis

Hematological: Polycythemia vera (a rare type of blood cancer)

Gastrointestinal: Mild, transient diarrhea

Dermatological: Itching; transitory exanthema (widespread skin rash)

Miscellaneous: Feeling of swelling of entire body

Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381:841-851.
Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:26
Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care
American Diabetes Association. Standards of Medical Care in Diabetes – 2022. Diabetes Care. 2022; 45(Suppl 1):S1-S270. Available at: https://diabetesjournals.org/care/issue/45/Supplement_1– LinkOpens in New Tab
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2019 Executive Summary. End
Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines.
Markle HV, Greenway DC. Cobalamin. Critical reviews in clinical laboratory sciences. 1996; 33: 247-356.
Herrmann W, Obeid R. Cobalamin deficiency. Subcell Biochem. 2012; 56: 301-322.
Paul C, Brady DM. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms. Integrative Medicine: A Clinician’s Journal. 2017; 16: 42–49.
Vidal‐Alaball J, Butler C, Cannings‐John R, Goringe A, Hood K, McCaddon A, McDowell I, Papaioannou A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database of Systematic Reviews. 2005: CD004655.
O’Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010; 2: 299-316.
Sweetman SC, editor. Martindale: the complete drug reference, 34th ed. London: Pharmaceutical press; 2014.
CaloMist™ Nasal Spray (cyanocobalamin, USP) label. 2007. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022102s000lbl.pdf– LinkOpens in New Tab [Accessed October 23, 2020].
Berry RJ. Lack of historical evidence to support folic acid exacerbation of the neuropathy caused by vitamin B12 deficiency. The American journal of clinical nutrition. 2019; 110: 554-61.
Russell -Jones D, Vaag A, Schmidtz O, et al. Liraglutide vs. insulin glargine and placebo in combination with metformin andsulphonylurea therapy in type 2 diabetes mellitus: a randomised controlled trial (LEAD-5 met + SU). Diabetologia 2009;52:20
Alamin A, Gupta V. Vitamin B12 (Cobalamin). In: StatPearls [Internet]. 2020. StatPearls Publishing.
Froese DS, Fowler B, Baumgartner MR. Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation. Journal of inherited metabolic disease. 2019; 42: 673-685.
Berney M, Berney-Meyer L, Wong KW, Chen B, Chen M, Kim J, Wang J, Harris D, Parkhill J, Chan J, Wang F. Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences. 2015; 112: 10008-10013.
Vasavada A, Sanghavi D. Cyanocobalamin. In: StatPearls [Internet] 2020. StatPearls Publishing.
Sanz-Cuesta T, González-Escobar P, Riesgo-Fuertes R, Garrido-Elustondo S, del Cura-González I, Martín-Fernández J, Escortell-Mayor E, Rodríguez-Salvanés F, García-Solano M, González-González R, Martín-de la Sierra MÁ. Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health. 2012; 12:1-1.
Food and Drug Administration (US FDA) Drug Medwatch-FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes.
Everett J. Use of oral antidiabetic agents during breastfeeding. J Hum Lact 1997;13:319-21.
Hale TW, Kristensen JH, Hackett LP, et al. Transfer of metformin into human milk. Diabetologia 2002;45:1509-14.
Gardiner SJ, Kirkpatrick CMJ, Begg EJ, et al. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.
Briggs GG, Ambrose PJ, Nageotte MP, et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol 2005;105:1437-41.
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Feig DS, Donat DJ, Briggs GG, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care 2005;28:1851-5.
Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breastfeeding mother. Am Fam Physician 2001; 64:119-126.
Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
Caballero MR, Lukawska J, Lee TH, Dugué P. Allergy to vitamin B12: two cases of successful desensitization with cyanocobalamin. Allergy. 2007; 62: 1341-1342.
CYANOCOBALAMIN INJECTION, USP 1000 mcg/mL Sterile (Vitamin B12) [Label]. 2014. Available from: https://pdf.hres.ca/dpd_pm/00026115.PDF– LinkOpens in New Tab [Accessed October 26, 2020].
CYANOCOBALAMIN- cyanocobalamin injection, USP. West-Ward Pharmaceuticals Corp [Label]. 2018. Available from: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a66eb3c4-3e1d-4d49-b963-4fa2334cc9b6– LinkOpens in New Tab [Accessed October 26, 2020].
Nascobal® (Cyanocobalamin, USP) Nasal Spray 500 mcg/spray 0.125 mL [Label]. 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021642s020lbl.pdf– LinkOpens in New Tab [Accessed October 26, 2020].
Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008; 112: 2214-2221.
Solomon LR. Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood reviews. 2007; 21: 113-130.
Chandyo RK, Ulak M, Kvestad I, Shrestha M, Ranjitkar S, Basnet S, Hysing M, Shrestha L, Strand TA. The effects of vitamin B12 supplementation in pregnancy and postpartum on growth and neurodevelopment in early childhood: Study Protocol for a Randomized Placebo Controlled Trial. BMJ open. 2017; 7: e016434.
Samson RR, McClelland DB. Vitamin B12 in human colostrum and milk: quantitation of the vitamin and its binder and the uptake of bound vitamin B12 by intestinal bacteria. Acta Pædiatrica. 1980; 69: 93-99.
American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001; 10

Metformin HCl ER Tablet 500 mg – 120 Tablets – 4 Months supply

Metformin Tablet (Extended Release) (Each) †

500 MG, 750 MG, 1000 MG

Metformin is an oral biguanide antidiabetic agent similar to phenformin, a drug that was withdrawn from US marketing in 1977 due to the development of lactic acidosis. The risk for this adverse reaction is considerably lower with metformin, however.^[1] The actions of metformin differ from, yet complement, those of the sulfonylureas and other antidiabetic therapies. Compared to glyburide in type 2 diabetes, metformin was found to achieve similar glycemic control. although it lead to a higher incidence of digestive complaints.^[2]Metformin has been found useful in the treatment of polycystic ovary syndrome (PCOS); it lowers serum androgens and restores normal menstrual cycles and ovulation, and may improve pregnancy rates.^[3] Additionally, limited data indicate that it may delay puberty onset in females with precocious puberty and delay menarche onset in females with early-normal onset of puberty.^[4]^[5] The use of metformin versus intensive lifestyle modification in patients with impaired glucose tolerance has been investigated, and while both reduce the incidence of diabetes, lifestyle intervention has the greater effect.^[6] Although lifestyle intervention is highly effective, most patients fail lifestyle modifications when used alone within the first year of diagnosis. Therefore, a joint consensus algorithm for the treatment of type 2 diabetes mellitus, developed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes, suggests that the combination of metformin with lifestyle interventions should be initiated at the time of diagnosis. Metformin was chosen as the initial drug therapy based on its efficacy, safety, and cost.^[7]^[8]^[9]Additionally, in a follow-up study to the UKPDS, researchers found that after 10-years of resuming typical care, patients originally randomized to metformin therapy had a 33% relative reduction (RR 0.67, 95% CI 0.51—0.89; p=0.005) in the risk of myocardial infarction and a 27% relative reduction (RR 0.73, 95% CI 0.59—0.89; p=0.002) in the risk of death from any cause as compared to patients originally randomized to conventional therapy; it should be noted that these reductions in cardiovascular risks persisted even though HbA1c concentrations were similar in the 2 groups after 1 year of follow-up.^[10] Metformin was introduced in Europe in the 1950’s but was not approved by the FDA until December 1994. It is approved for type 2 diabetes either as monotherapy or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin. The regular-release tablets were approved for use in children >= 10 years in January 2001. An oral solution (Riomet) was approved in September 2003. Three extended-release formulations have been approved, Glucophage XR in October 2000, Fortamet in April 2004, and Glumetza in June 2005, each with a unique drug delivery system (see Pharmacokinetics section). The extended-release formulations provide similar glycemic control compared to regular-release metformin, but have the advantage of once-daily administration. Another advantage is a claim of decreased adverse events, specifically gastrointestinal-related adverse events (i.e., flatulence, diarrhea); however, larger trials comparing regular-release to extended-release metformin are needed to confirm these claims as current trial results are conflicting.^[11]^[12]^[13]

Metformin is an antihyperglycemic agent that improves glucose tolerance, lowering both basal and postprandial plasma glucose with mechanisms different from other classes of oral antidiabetic agents. Metformin decreases hepatic gluconeogenesis production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin improve glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetics without some residual functioning pancreatic islet cells.^[14] Unlike the sulfonylureas, metformin rarely causes hypoglycemia since it does not significantly change insulin concentrations. An important distinction is that sulfonylureas increase insulin secretion thus making them useful in non-obese patients with type 2 diabetes while metformin improves insulin resistance, a common pathophysiologic finding in obese patients with type 2 diabetes.^[14]Metformin causes a 10—20% decrease in fatty-acid oxidation and a slight increase in glucose oxidation. Unlike phenformin, metformin does not inhibit the mitochondrial oxidation of lactate unless plasma concentrations of metformin become excessive (i.e., in patients with renal failure) and/or hypoxia is present.^[1]

Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25—30%. Unlike oral sulfonylureas, metformin rarely causes hypoglycemia. Thus, metformin demonstrates more of an antihyperglycemic action than a hypoglycemic action. Metformin does not cause weight gain and in fact, may cause a modest weight loss due to drug-induced anorexia. Metformin also decreases plasma VLDL triglycerides resulting in modest decreases in plasma triglycerides and total cholesterol. Patients receiving metformin show a significant improvement in hemoglobin A1c, and a tendency toward improvement in the lipid profile, especially when baseline values are abnormally elevated.

Insulin resistance is a primary cause of polycystic ovarian syndrome (PCOS). In PCOS patients, metformin reduces insulin resistance and lowers insulin levels, which lowers serum androgen concentrations, restores normal menstrual cycles and ovulation, and may help to resolve PCOS-associated infertility. Metformin, when administered to lean, overweight, and moderately obese women with PCOS, has been found to significantly reduce serum leuteinizing hormone (LH) and increase follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). Serum testosterone concentrations were also found to decrease by approximately 50%.^[3]

Your health care provider needs to know if you have any of these conditions: anemia; frequently drink alcohol-containing beverages; become easily dehydrated; heart attack; heart failure that is treated with medications; kidney disease; liver disease; polycystic ovary syndrome; serious infection or injury; vomiting; an unusual or allergic reaction to metformin, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding.

Do not use metformin in patients who have a known metformin hypersensitivity.

Metformin should not be used for Type 1 diabetes mellitus. Metformin is not an effective treatment of and use is contraindicated in diabetic ketoacidosis (DKA). DKA, with or without coma; DKA should be treated with insulin.

Metformin is contraindicated in patients with metabolic acidosis. It should not be used in patients with lactic acidosis. Lactic acidosis should be suspected in any diabetic patient withmetabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia or significant renal dysfunction. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person-years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis.^[17] The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.

Gastrointestinal side effects are common during metformin initiation. However, once a patient is stabilized on any dose of metformin, GI symptoms are unlikely to be drug related. Later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis or other serious disease. Patients stable on metformin therapy who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms. These include, but are not limited to, diarrhea and nausea/vomiting. Furthermore, withholding metformin therapy until the cause of the GI symptoms is known may be necessary. Finally, diarrhea and nausea/vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood glucose. Patients should be advised to contact their prescriber if an increase in gastrointestinal symptoms occurs while taking metformin; patients should also be advised to monitor their blood glucose concentrations more frequently.

Before initiation of metformin and at least annually thereafter, renal function should be assessed. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. According to the manufacturer, metformin is contraindicated for use in patients with renal failure or renal impairment (defined as serum creatinine >= 1.4 mg/dl for females and >= 1.5 mg/dl for males by the manufacturer, although pharmacokinetic studies indicate significant metformin accumulation with CrCl < 60 ml/min) (see Pharmacokinetics). However, the American Diabetes Association and others suggest that metformin can be used in patients with lower creatinine clearances with close monitoring (see Dosage Adjustment Guidelines).^[18]^[19] Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis (see Drug Interactions). According to the manufacturer, metformin should be used with caution in patients with congestive heart failure requiring pharmacologic treatment. However, a systematic review evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes concluded that metformin is not associated with any measurable harm in patients with heart failure; in this analysis, metformin was associated with reduced mortality.^[20] It should be noted that in acute congestive heart failure characterized by acute hypoxia, lactic acidosis has occurred in patients taking metformin. To reduce the risk of lactic acidosis, metformin should be promptly withheld in the presence of any condition associated with hypoxemia. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia. If such events occur, discontinue metformin. Use metformin with caution in geriatric patients; less than 3% of patients in clinical trials were >= 75 years of age. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Monitor renal function regularly. Unless renal function is normal, do not use metformin in those patients >= 80 years of age. Generally, elderly or debilitated patients should not be titrated up to maximum dosages (see Dosage).

Since the liver is important for clearing accumulated lactic acid, metformin should generally be avoided in patients with hepatic disease as the risk of lactic acidosis may be increased. Hepatic disease causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism and patients should be warned against ethanol intoxication (acute or chronic) while on metformin. This drug is not recommended for those with alcoholism.

Parenteral radiographic contrast administration is contraindicated in patients taking metformin; it may cause acute renal failure and has been associated with lactic acidosis. Patients undergoing studies involving iodinated radiographic contrast media should have metformin temporarily withheld just prior to and for 48 hours after the completion of the procedure. Reinstitute therapy only after normal renal function is confirmed.

To reduce the risk of lactic acidosis, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin therapy should be temporarily suspended for any surgery, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any change in clinical status, including diarrhea or vomiting, may also increase the risk of lactic acidosis and may require laboratory evaluation in patients on metformin and may require the drug be withheld.

Delayed stomach emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully. Conditions that predispose patients to developing hypoglycemia or hyperglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions while receiving metformin.

The safety and effectiveness of metformin have not been established in neonates, infants and children < 10 years; in general, there are limited experiences with metformin use in pediatric patients with Type 2 diabetes mellitus. The oral solution and regular-release tablet formulations of metformin have been approved for use in children >= 10 years and experience with children 10-16 years of age has demonstrated similar glycemic control to adults. However, the safety and efficacy of the extended-release tablet formulations have not been established in children under the age of 18 years.

Metformin may result in suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Certain individuals may be predisposed to this type of anemia; a nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15—3.87) as did taking metformin for >= 3 years (OR 2.39, 95% CI 1.46—3.91).^[21] Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment.

Premenopausal anovulatory females with insulin resistance (i.e., those with polycystic ovary syndrome (PCOS)) may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used in those not desiring to become pregnant. In some cases, metformin is used as an adjunct in PCOS patients to regulate menstrual cycles or to enhance fertility. Metformin is classified in FDA pregnancy risk category B; however, metformin is not recommended for routine use during pregnancy.^[15]Based on the results of a small study, it appears that metformin does pass through the placenta and the fetus is exposed to therapeutic concentrations of metformin. In 13 patients taking metformin throughout pregnancy, metformin concentrations were higher in the infant umbilical vein and umbilical artery than the maternal blood sample; the authors postulated that metformin is excreted into the amniotic fluid by the fetus and then swallowed allowing for reabsorption. Adverse effects on the pH of umbilical artery blood were not found.^[22] A study of 109 women with PCOS who were treated with metformin 1.5—2.55 g/day at the time of conception and continued treatment throughout pregnancy found no difference in the development of preeclampsia and a lower rate of gestational diabetes when compared to a control group of pregnant women without PCOS. Among the 126 infants born to the women with PCOS, two birth defects occurred: one sacrococcygeal teratoma and one tethered spinal cord. Follow up to 18 months of age found no differences in height or weight in infants exposed to metformin compared to controls and no abnormalities in motor or social development.^[23] Other epidemiologic data suggest no increase in the rates of expected birth defects in women taking metformin who become pregnant. Metformin has been studied during the second and third trimesters of pregnancy. The neonatal mortality rate appeared lower in patients receiving metformin than in mildly diabetic controls, but slightly higher incidences of polycythemia and necrotizing enterocolitis were noted in the metformin group. The most frequently encountered infant problems were jaundice, polycythemia, and hypoglycemia.^[24] The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type I or II diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.^[25]^[26] More recent studies comparing metformin to insulin in the treatment of gestational diabetes found no significant differences in glycemic control or pregnancy outcomes.^[27] One study comparing metformin (n = 100) to insulin (n = 100) for the treatment of gestational diabetes found significantly lower weight gain during pregnancy and improved neonatal morbidity with respect to prematurity, neonatal jaundice, and admission to the neonatal unit in the metformin group.^[28]

Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies.^[29]^[30]^[31] Furthermore, the use of metformin 2550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known.^[32] In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11—1.08% of the mother’s dose. While the manufacturers of metformin recommend that a decision should be made to discontinue breast-feeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant; if patients elect to continue metformin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breastmilk is not expecte;^[33] therefore, this agent may represent a reasonable alternative for some patients. In addition, the American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding; other sulfonylureas have not been evaluated by the AAP.^[34] If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.^[35]

This list may not include all possible contraindications.

Possible interactions include: digoxin; diuretics; female hormones, like estrogens or progestins and birth control pills; isoniazid; medicines for blood pressure, heart disease, irregular heart beat; morphine; nicotinic acid; phenothiazines like chlorpromazine, mesoridazine, prochlorperazine, thioridazine; phenytoin; procainamide; quinidine; quinine; ranitidine; steroid medicines like prednisone or cortisone; stimulant medicines for attention disorders, weight loss, or to stay awake; thyroid medicines; trimethoprim; vancomycin.

Furosemide increased the metformin plasma and blood maximum concentrations by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.^[37] On the other hand, metformin decreased furosemide plasma and blood maximum concentrations by 31% and 12%, respectively, than when administered alone. Furosemide’s terminal half-life was also decreased by 32% without any significant change in furosemide renal clearance. In addition, furosemide may cause hyperglycemia and glycosuria in patients with diabetes mellitus,^[38] likely due to diuretic-induced hypokalemia. Blood glucose concentrations should be monitored in patients taking furosemide with metformin.

Torsemide or bumetanide may cause hyperglycemia and glycosuria in patients with diabetes mellitus,^[39]^[40] likely due to diuretic-induced hypokalemia. Blood glucose concentrations should be monitored in patients taking either with metformin.

Endogenous counter-regulatory hormones such as glucocorticoids, growth hormone, or glucagon, are released in response to hypoglycemia. When released, blood glucose concentrations rise.^[41] When these agents are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents.^[42]^[43]^[44] In addition, blood lactate concentrations and the lactate to pyruvate ratio increase when metformin is coadministered with corticosteroids (e.g., hydrocortisone). Elevated lactic acid concentrations are associated with increased morbidity rates.^[45] Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when corticosteroids are instituted. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.

Triamterene can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose concentrations.^[46] In addition, certain medications used concomitantly with metformin may increase the risk of lactic acidosis; cationic drugs that are eliminated by renal tubular secretion such as triamterene may decrease metformin elimination by competing for common renal tubular transport systems. Monitor patients receiving both metformin and triamterene for changes in blood glucose control. Dosage adjustments may be necessary.

Thiazide diuretics can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. It appears that the effects of thiazide diuretics on glycemic control are dose-related and low doses can be instituted without deleterious effects on glycemic control.^[45] In addition, thiazide diuretics reduce the risk of stroke and cardiovascular disease in patients with diabetes.^[47] Patients receiving metformin should be monitored for changes in blood glucose control if any of these diuretics are added or deleted. Dosage adjustments may be necessary.

Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.^[48] Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.

Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.^[42]^[49] Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, clofibrate and fenofibrate may displace glyburide from protein binding sites which may lead to enhanced hypoglycemic action.^[50]

Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion (e.g., adefovir, amiloride, cimetidine, ranitidine, entecavir, lamivudine, 3TC, memantine, midodrine, morphine, procainamide, quinidine, quinine, trospium, vancomycin, etc.) may decrease metformin elimination by competing for common renal tubular transport systems.^[37]^[51]^[52]^[53]^[54]^[55]^[56]^[57]^[58]^[59]^[60]^[61] Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. The interaction between metformin and cimetidine has been observed, with a 60% increase in metformin Cmax and a 40% increase in metformin AUC.^[62]

Increased serum digoxin concentrations have been reported in patients who received digoxin and metformin. Both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems.^[15]^[63] This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of digoxin may increase the risk of digoxin toxicity.Measure serum digoxin concentrations before initiating metformin. Monitor patients who take both metformin and digoxin for possible digoxin toxicity and lactic acidosis; reduce the dose of digoxin and metformin as necessary.^[15]^[63]

Dofetilide should be co-administered with metformin with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems.^[15]^[64] This results in a possible increase in plasma concentrations of either drug. Reduced clearance of metformin may increase the risk for lactic acidosis; increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of metformin and dofetilide is recommended.^[15]

Both cyclosporine and tacrolimus have been reported to cause hyperglycemia. Furthermore, tacrolimus has been implicated in causing insulin-dependent diabetes mellitus in patients after renal transplantation. Both of these drugs may have direct beta-cell toxicity; the effects from cyclosporine may be dose-related.^[49]^[65] Patients should be monitored for worsening of glycemic control if therapy with either of these immunosuppressant drugs is initiated in patients receiving antidiabetic agents.

Alcohol (ethanol) may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy.^[42]^[45] Alcohol ingestion can decrease endogenous glucose production potentiating the risk of hypoglycemia.^[66] Alternatively, alcohol can worsen glycemic control as it provides a source of additional calories. In addition, blood lactate concentrations and the lactate to pyruvate ratio increase when metformin is coadministered with ethanol. Elevated lactic acid concentrations are associated with increased morbidity rates. Ethanol should be avoided, if possible, in patients taking metformin. Many non-prescription drug products may be formulated with ethanol; have patients scrutinize product labels prior to consumption.

Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor.^[37]The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin, vitamin B12 supplementation. Certain individuals may be predisposed to this interaction. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in the urine.^[37] Metformin half-life was unaffected. Nifedipine appears to enhance the absorption of metformin.

ACE inhibitors may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.^[42]^[45]^[49] In addition, ACE inhibitors have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.^[67] Patients receiving these drugs concomitantly with metformin should be monitored for changes in glycemic control.

Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity.^[68] In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease.^[67] Patients receiving these drugs concomitantly with metformin should be monitored for changes in glycemic control.

Large doses of salicylates may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis.^[45] If these agents are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control.

Beta-blockers exert complex actions on the body’s ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. Beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Furthermore, a prospective trial in non-diabetic patients with hypertension indicated that treatment with beta-blockers increased the risk of the development of diabetes by 28% at six years.^[69] In addition, beta-blockers may mask the signs and symptoms of hypoglycemia, specifically the tachycardic response, and exaggerate the hypertensive response to hypoglycemia. Although no significant pharmacokinetic interactions between beta-blockers and antidiabetic agents have been observed, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia.^[45] While beta-blockers may have negative effects on glycemic control, they reduce the risk of cardiovascular disease and stroke in patients with diabetes.^[47] Furthermore, their use should not be avoided in patients with compelling indications for beta-blocker therapy (i.e., post-MI, heart failure, etc.) when no other contraindications are present. Decreased mortality has been shown in the post-MI and heart failure populations when beta-blockers are used, especially in patients with coexisting diabetes mellitus.^[45]

Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents, including metformin, are coadministered.^[70]^[71] Gatifloxacin is contraindicated for use in patients with diabetes mellitus as serious alterations in blood glucose have been reported with its use; therefore, gatifloxacin should not be used in combination with antidiabetic agents.^[72]

Drugs that may cause hyperglycemia may cause temporary loss of glycemic control in patients receiving antidiabetic agents. These drugs include phenytoin and fosphenytoin and possibly ethotoin.^[15]^[73] Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.

Because cisapride can enhance gastric emptying in diabetic patients,^[74] blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive GI prokinetic agents concomitantly.

Because metoclopramide can enhance gastric emptying in diabetic patients,^[75] blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive GI prokinetic agents concomitantly.

Because tegaserod ^[76] can enhance gastric emptying in diabetic patients, blood glucose can be affected, which, in turn, may affect the clinical response to antidiabetic agents. The dosing of metformin may require adjustment in patients who receive GI prokinetic agents concomitantly.

Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas.^[45]

The phenothiazines, especially chlorpromazine, may increase blood sugar.^[77] Patients should be closely monitored for worsening glycemic control when phenothiazines are instituted.

The atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have been associated with causing hyperglycemia, even diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.^[69] While a causal relationship has not been established, temporal associations of atypical antipsychotic therapy with the aggravation of diabetes mellitus have been reported.^[78]Patients should be closely monitored for worsening glycemic control when any of these antipsychotics is instituted.

Lithium may cause variable effects on glycemic control when used in patients receiving antidiabetic therapy.^[42]^[45] Blood glucose concentrations should be closely monitored if lithium is taken by the patient. Dosage adjustments of antidiabetic therapy may be necessary.

Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. Close monitoring of blood glucose is necessary for individuals who use insulin or oral hypoglycemics whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.^[37]

Isoniazid, INH may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when this drug is initiated.^[37]

Because diazoxide inhibits the release of insulin from pancreatic islet cells and thus increases blood glucose,^[79] a pharmacodynamic interaction exists between this drug and all other antidiabetic agents.

Oral contraceptives (estrogens and progestins)^[37] can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.

Exogenously administered androgens (testosterone derivatives or anabolic steroids) have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance. Further, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. In one study in men with diabetes , testosterone undecenoate 120 mg PO/day for 3 months decreased HbA1c concentrations from a baseline of 10.4% to 8.6% (P<0.05); fasting plasma glucose concentrations decreased from 8 mmol/l at baseline to 6 mmol/l (P<0.05). Significant reductions in HbA1c and fasting plasma glucose concentrations did not occur in patients taking placebo.^[80] Similar results have been demonstrated with intramuscular testosterone 200 mg administered every 2 weeks for 3 months in hypogonadal men with diabetes.^[81] In healthy men, testosterone enanthate 300 mg IM/week for 6 weeks or nandrolone 300 mg/week IM for 6 weeks did not adversely affect glycemic control; however, nandrolone improved non-insulin mediated glucose disposal.^[82] It should be noted that some studies have shown that testosterone supplementation in hypogonadal men has no effect on glycemic control.^[83]^[84] Conversely, the administration of large doses of anabolic steroids in power lifters decreased glucose tolerance, possibly through inducing insulin resistance.^[85] While data are conflicting, it would be prudent to monitor all patients with type 2 diabetes on antidiabetic agents receiving androgens for changes in glycemic control, regardless of endogenous testosterone concentrations. Hypoglycemia or hyperglycemia can occur; dosage adjustments of the antidiabetic agent may be necessary. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations.^[41] A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.^[86] Patients receiving metformin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. Fenfluramine and dexfenfluramine may potentiate the actions of some antidiabetic agents via increasing glucose uptake by muscle cells.^[87]^[88] Monitor patients taking either of these drugs in combination with metformin for hypoglycemia. Limited animal data suggest that selected constituents in Garlic, Allium sativum might have some antidiabetic activity, resulting in increased serum insulin concentrations and increased glycogen storage in the liver.^[89]Patients with diabetes frequently purchase alternative remedies that have been purported to improve glycemic control, but there is no scientific or controlled evidence in humans of this action.^[90] Limited clinical evidence suggests that garlic does not affect blood glucose in those without diabetes.^[91] Until more data are available, individuals receiving antidiabetic agents should use caution in consuming dietary supplements containing garlic, and follow their normally recommended strategies for blood glucose monitoring. Niacin, Niacinamide interferes with glucose metabolism and can result in hyperglycemia.^[92] When used at daily doses of 750—2000 mg, niacin significantly lowers LDL cholesterol and triglycerides while increasing HDL cholesterol. Changes in glycemic control can usually be corrected through modification of hypoglycemic therapy.^[93] Monitor patients on antidiabetic therapy for blood glucose control if niacin (nicotinic acid) is added or deleted to the medication regimen. Dosage adjustments may be necessary. Dextrothyroxine (based on the actions of thyroxine)^[94] can decrease the hypoglycemic effects of antidiabetic agents by producing an increase in blood glucose levels. Monitor patients on antidiabetic agents for blood glucose control if dextrothyroxine is added or deleted. Disopyramide may enhance the hypoglycemic effects of antidiabetic agents by lowering blood glucose concentrations.^[95] Patients receiving disopyramide concomitantly with antidiabetic agents should be monitored for changes in glycemic control. Guanethidine may enhance the hypoglycemic effects of antidiabetic agents; furthermore, because of its sympatholytic activity, guanethidine may mask the signs and symptoms of hypoglycemia.^[42]^[96] Patients receiving guanethidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia.^[42] Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. Reserpine may mask the signs and symptoms of hypoglycemia.^[42] Patients receiving reserpine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. Patients who have both acromegaly and diabetes mellitus and are being treated with antidiabetic agents may require dose reductions of these medications after the initiation of pegvisomant. Growth hormone decreases insulin sensitivity by opposing the effects of insulin on carbohydrate metabolism; therefore, pegvisomant, which antagonizes growth hormone, is expected to have the opposite effect. Although none of the acromegalic patients with diabetes mellitus who were treated with pegvisomant during the clinical studies developed clinically relevant hypoglycemia, such patients should monitor their blood glucose regularly, with doses of anti-diabetic medications reduced as necessary.^[97]Carbonic anhydrase inhibitors can cause glycosuria and hyperglycemia in diabetic patients, thereby decreasing the effects of antidiabetic therapy. Carbonic anhydrase inhibitors may also cause hypoglycemia. In addition, carbonic anhydrase inhibitors frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.^[98] Patients should be closely monitored for changes in glycemic control when using carbonic anhydrase inhibitors in combination with antidiabetic therapy.^[99]Dosage adjustments may be required. Zonisamide frequently decreases serum bicarbonate and induces non-anion gap, hyperchloremic metabolic acidosis. Use zonisamide with caution in patients treated with metformin, as the risk of lactic acidosis may increase. Careful patient monitoring during use of metformin is recommended.^[98] Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents.^[42]^[49] Monitor serum glucose concentrations. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function.^[69]Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.^[78] Chromium, as part of the glucose tolerance factor (GTF) molecule, appears to facilitate the binding of insulin to insulin receptors in tissues and to aide in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents (e.g., insulin, metformin. sulfonylureas, thiazolidinediones, etc.) may need dose adjustments. Close monitoring of blood glucose is recommended.^[100]^[101] Because baclofen can increase blood glucose,^[102] doses of antidiabetic agents may need adjustment in patients receiving these drugs concomitantly. Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine.^[103] Administration of octreotide to patients receiving oral antidiabetic agents or insulin can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added.^[104] Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in obese diabetic patients, which may be additive to the effects of antidiabetic agents.^[105] Lower blood glucose as a result of orlistat-induced changes in body composition may necessitate a dosage reduction of antidiabetic agents with time. Propantheline slows GI motility, which may increase the absorption of metformin from the small intestine.^[106] A 19% increase in metformin AUC has been reported in studies of this interaction in healthy volunteers. However, no serious side effects resulted. During clinical trials of bortezomib, hypoglycemia and hyperglycemia were reported in diabetic patients receiving antidiabetic agents. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and dosage adjustment of their medication.^[107] Per the manufacturer, metformin and combination products containing metformin (e.g., metformin; rosiglitazone combinations, glyburide; metformin combinations or glipizide; metformin combinations) should be temporarily discontinued prior to the administration of iodinated radiopaque contrast agents. Metformin should be held for at least 48 hours after contrast administration and not restarted until renal function returns to normal post-procedure. Lactic acidosis has been reported in patients taking metformin that experience nephrotoxicity after iodinated contrast media.^[37] Drug interactions with Horse chestnut, Aesculus hippocastanum are not well documented. Based on animal studies of oral glucose tolerance tests in rats, selected escins in Horse chestnut may exhibit glucose-lowering activity.^[108] Thus, Horses chestnut might interact with antidiabetic agents by enhancing hypoglycemic activity. The mechanism of the effect is not certain; clinical documentation of the interaction in humans is lacking at this time. In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin Cmax and AUC increased by an average of 34% and 24%, respectively; metformin renal clearance decreased by an average of 14%. No information is available about the interaction of cephalexin and metformin following multiple dose administration.^[109]^[110] Green tea catechins have been shown to decrease serum glucose concentrations in vitro.^[111]^[112] Patients with diabetes mellitus taking antidiabetic agents should be monitored closely for hypoglycemia if consuming green tea products. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.^[113] Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed. Use caution in combining mecasermin, recombinant, rh-IGF-1 and mecasermin rinfabate (rh-IGF-1/rh-IGFBP-3) with antidiabetic agents. The hypoglycemic effect induced by IGF-1 activity may be exacerbated. Although the rh-IGF-1/rh-IGFBP-3 complex has less propensity to rapidly lower blood glucose compared to unbound mecasermin, hypoglycemia is possible with either agent.^[114] The amino acid sequence of mecasermin (rh-IGF-1) is approximately 50 percent homologous to insulin and cross binding with either receptor is possible.^[115] Treatment with mecasermin (rh-IGF-1) has been shown to improve insulin sensitivity and to improve glycemic control in patients with either Type 1 or Type 2 diabetes mellitus when used alone or in conjunction with insulins.^[116] Patients should be advised to eat within 20 minutes of mecasermin administration. Glucose monitoring is important when initializing or adjusting mecasermin therapies, when adjusting concomitant antidiabetic therapy, and in the event of hypoglycemic symptoms. Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin.^[117]Monitor patients for decreased efficacy of levomefolate if these agents are used together. Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated.^[118] During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%.^[119] The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. Limit the dose of metformin to 1700 mg/day if coadministered with ranolazine 1000 mg twice daily. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Monitor blood glucose concentrations and risks associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased when coadministered with ranolazine 500 mg twiice daily.^[120]This list may not include all possible drug interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Possible side effects include: Diarrhea; headache; heartburn; metallic taste in mouth; nausea; stomach gas, upset. This list may not describe all possible side effects. Call your doctor for medical advice about side effects.

Gastrointestinal adverse effects are the most common experienced by patients taking metformin.^[15] In clinical trials, diarrhea was experienced by 53.2% of patients receiving immediate-release metformin monotherapy, and was a reason for drug discontinuation in 6%. Extended-release formulations cause diarrhea in roughly 9.6% of patients. Nausea and vomiting are reported in 6.5—25.5% of all patients taking metformin; with the lower incidences seen in patients receiving extended-release products. Other common GI effects include flatulence (1—12.1%), indigestion or dyspepsia (1—7.1%), and abdominal pain or discomfort (1—6.4%). GI effects occurring in 1—5% of patients include include anorexia, dysgeusia (metallic taste or other taste disturbance), and a change in stool appearance. Frequent side effects tend to decline with continued use and can be minimized by initiating therapy with low doses of metformin. In pediatric patients with diabetes mellitus type 2 treated with metformin, the adverse event profiles and incidences are similar to those seen in adults.

The risk of hypoglycemia is much less common with metformin than with the sulfonylureas,^[14] however, it has been reported with metformin monotherapy in clinical trials at an incidence of 1—5%.^[15] Other studies have reported varying incidences of hypoglycemia. In one nested case-control analysis of over 50,000 subjects with type 2 diabetes mellitus, the rate of hypoglycemia due to metformin monotherapy yielded a crude incidence rate of 3.3 cases among 100,000 person-years compared with 4.8 cases among sulfonylurea users per 100,000 person years; the incidence of hypoglycemia was significantly higher in sulfonylurea-treated patients.^[17] In a separate systematic review, the rates for hypoglycemia with metformin monotherapy varied in the studies reviewed between 0—21%, with the risk of major hypoglycemic episodes reported to be rare.^[121] Hypoglycemia is more common when metformin is coadministered with other oral hypoglycemic agents (especially sulfonylureas), when ethanol has been ingested, or when there is deficient caloric intake or strenuous exercise not compensated by caloric supplementation.^[15]^[121] Since metformin reverses insulin resistance, and subsequently causes a decrease in insulin concentrations, metformin-induced hypoglycemia is usually mild and does not necessitate the discontinuation of therapy. In overdose, hypoglycemia is noted in roughly 10% of patients, but causal association with metformin is not established.^[15]

Asymptomatic vitamin B12 deficiency was reported with metformin monotherapy in 7% of patients during clinical trials.^[15] Serum folic acid concentrations did not decrease significantly. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin treatment or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful. Rare cases of megaloblastic anemia have been reported with metformin (none in the US); incidence rates are expected to be < 1% for symptomatic deficiency.^[15] Mild weight loss may occur during therapy with metformin, perhaps as a result of its ability to cause anorexia. Such weight loss can be expected in almost any patient with type 2 diabetes receiving metformin monotherapy; however, weight loss may attenuate when metformin is combined with other treatments. A mean weight loss of 1—8.4 lbs was reported in clinical trials of adults receiving monotherapy with metformin immediate release products; a mean weight loss of 2—3 lbs was reported in pediatric studies.^[15] When extended-release tablets were used, the weight loss was not clinically significant in adults and mean reductions ranged from 0.7—2.2 lbs.^[15] Lactic acidosis is a rare, but serious, form of metabolic acidosis that can occur if metformin accumulates during treatment; when it occurs, it is fatal in approximately 50% of cases. The onset of lactic acidosis often is subtle, and accompanied only by early nonspecific symptoms such as malaise and myalgia (1—5% of patients), and quickly followed by respiratory distress (dyspnea 1—5%), increasing somnolence, and nonspecific abdominal distress. Lactic acidosis is a medical emergency that must be treated in a hospital setting; metformin should be discontinued immediately and general supportive measures promptly instituted. Prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.^[15] Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked metabolic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years); of nearly 20,000 patients in clinical trials, there were no reports of lactic acidosis.^[15] A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis; all of the subjects had relevant co-morbidities known to be risk factors for lactic acidosis.^[17] The incidence of lactic acidosis appears to be no more common in metformin recipients without comorbid conditions than in recipients of other antidiabetic agents.^[121] Risk factors include significant renal insufficiency, the presence of multiple concomitant medical/surgical problems (e.g., liver disease, alcoholism, cardiorespiratory insufficiency or other conditions associated with tissue hypoperfusion or hypoxemia), and exposure to multiple concomitant medications known to increase risks. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. Lactic acidosis is less likely to occur with metformin than with other biguanide agents (e.g., phenformin), because metformin is not metabolized, does not bind to liver or plasma proteins, and is excreted by active tubular processes. Regular monitoring of renal function and by use of the minimum effective dose of metformin may reduce the risk of this adverse reaction. Patients should be informed to discontinue metformin should symptoms suggestive of lactic acidosis appear and promptly report the symptoms to their physician.

The following miscellaneous adverse reactions were reported in 1—5% of patients treated with metformin and occurred more commonly than in patients treated with placebo: lightheaded (dizziness), nail disorder, rash (unspecified), hyperhidrosis (sweating increased), chest pain (unspecified) or chest discomfort, chills, flu syndrome or upper respiratory infection, flushing, and palpitations.^[15]

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies.^[29]^[30]^[31] Furthermore, the use of metformin 2550 mg/day by mothers breastfeeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known.^[32] In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11—1.08% of the mother’s dose. While the manufacturers of metformin recommend that a decision should be made to discontinue breastfeeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breastfeeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant; if patients elect to continue metformin while breastfeeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breastmilk is not expected;^[33] therefore, this agent may represent a reasonable alternative for some patients. In addition, the American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breastfeeding; other sulfonylureas have not been evaluated by the AAP.^[34] If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.^[36]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

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Lipo Burn 3 (Caffeine / Phentermine HCl / Naltrexone HCl / Methylcobalamin) (Slow Release) Capsule 100/20/8/1 mg Each — 60 count

Lipo Burn 3 Capsule (Caffeine / Phentermine HCl / Naltrexone HCl / Methylcobalamin) (Slow Release) (Each)

100/20/8/1 MG

Caffeine
Caffeine is a naturally occurring xanthine derivative used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine derivatives include the bronchodilator theophylline and theobromine, a compound found in cocoa and chocolate. Caffeine is found in many beverages and soft drinks. Caffeine is often combined with analgesics or with ergot alkaloids for the treatment of migraine and other types of headache. Caffeine is also sold without a prescription in products marketed to treat drowsiness, or in products for mild water-weight gain. Caffeine was first approved by the FDA for use in a drug product in 1938. Clinically, it is used both orally and parenterally as a respiratory stimulant in neonates with apnea of prematurity. Caffeine reduces the frequency of apneic episodes by 30—50% within 24 hours of administration.^[1] Caffeine is preferred over theophylline in neonates due to the ease of once per day administration, reliable oral absorption, and a wide therapeutic window. A commercial preparation of parenteral caffeine, Cafcit®, was FDA approved for the treatment of apnea of prematurity in October 1999, after years of availability only under orphan drug status (e.g., Neocaf). The FDA has continued the orphan drug status of the approved prescription formulation.

DHEA
Dehydroepiandrosterone (DHEA) is a C19 steroid also known as 5-androsten-3 beta-ol-17-one. DHEA and DHEAS (an active, sulfated form of DHEA), are endogenous hormones secreted by the adrenal cortex in primates and a few non-primate species in response to ACTH. DHEA is a steroid precursor of both androgens and estrogens, and thus is often called ‘the mother hormone’. Endogenous DHEA is thought to be important in several endocrine processes, but current medical use of DHEA is limited to controlled clinical trials. In 1997, Pharmadigm, Inc. received an orphan drug designation to enroll patients with thermal burns who require skin-grafting into trials using injectable DHEAS, known as PB-005. Researchers continue to investigate the role of both endogenous and exogenous DHEA in CNS, psychiatric, endocrine, gynecologic and obstetric, immune, and cardiovascular functions.^[2] GeneLabs Technologies, Inc., submitted an NDA in September 2000 for its proprietary DHEA product, called prasterone (Prestara™, formerly known Aslera™ or GL-701). Prasterone appears to attentuate some symptoms of mild-to-moderate systemic lupus erythematosus (SLE) and may increase bone density based on evidence from two phase III studies in women; studies in men with SLE are ongoing. The FDA placed Prestara™ under a 6-month priority review status in October 2000; on April 19, 2001 the FDA stated that although the drug showed advantages over placebo in one study, the advantages were not statistically significant. Additional data were submitted to the FDA following a ‘not approvable’ letter on June 26, 2001. On September 2, 2002, the FDA issued an ‘approvable’ letter for the Prestara™ product, but the agency has asked for additional clinical trial data regarding the drug’s effects on bone mineral density before granting final approval for SLE. The manufacturer began a confirmatory phase III trial in early 2003; the primary endpoint will be measurement of bone mineral density of the lumbar spine; the trial is targeted for completion at the end of 2003. In October 2004, the manufacturer released information that Prestara™ therapy did not meet the primary end point in the confirmatory trial. In August 2003, Paladin Labs Inc., received orphan drug designation from the FDA for prasterone, dehydroepiandrosterone, DHEA, under the brand name Fidelin™, for adrenal insufficiency.

Exogenously administered DHEA is sold as a nutritional supplement in health and drug stores and many older individuals are using it to ‘maintain the vitality of their youth’. There is currently no objective, well-controlled, large-scale, scientific evidence to back claims that taking DHEA combats the signs or symptoms of aging, diabetes, neurologic disease, sexual dysfunction, or heart disease.^[3] Some athletes abuse DHEA believing that it can enhance the body’s synthesis of testosterone; the potential action of DHEA as an anabolic steroid has lead to the prohibition of supplementation in competitive sport, even though evidence of anabolic effects in athletes is lacking.^[4] DHEA is also abused by athletes in an attempt to normalize the testosterone:epitestosterone ratio. However, the sensitivity and specificity of currently available testing for athletic ‘doping’ can readily identify the presence of banned substances, including testosterone. Because of DHEA’s complex physiologic actions, more than 500 scientific articles investigating it have been published since 1993. Many of the short-term trials of DHEA to date have lacked the rigor and statistical applications needed to support therapeutic claims. Most claims will need to be confirmed by large-scale, properly conducted, and controlled studies. In 1984, the FDA banned the non-prescription (OTC) sale of exogenous DHEA due to concern over hepatotoxicity (hepatitis and hepatic tumors) as noted in animal studies. The FDA formally relegated DHEA to a Category II OTC ingredient at that time (i.e., not generally recognized as safe and effective). However in 1994, the passage of the US Dietary Supplement Health and Education Act (DSHEA) allowed DHEA to be marketed as a nutritional or dietary supplement.

Inositol
Inositol is a family of cyclic sugar alcohols consisting of nine stereoisomers of hexahydroxycyclohexane. The stereoisomers of the inositol family are myo-, scyllo-, muco-, neo-, allo-, epi-, cis-, and the enantiomers L- and D-chiro-inositol. Of these, myo-inositol and D-chiro-inositol are among the most abundant biologically active forms. The enzyme epimerase converts myo-inositol to the D-chiro-inositol isomer, maintaining organ-specific ratios of the two isomers. Physiologically, the concentration of myo-inositol is several times higher than D-chiro-inositol in most tissues.^[5]

The myo-inositol derivative phosphatidylinositol is an important component of the lipid bilayer of cell membranes. Phosphatidylinositol and its phosphorylated forms act as second messengers that are involved in a host of cellular functions including membrane trafficking, autophagy, cell migration, and survival. Disruption of phosphoinositide lipid signaling is implicated in cancer, diabetes, and cardiovascular disorders.^[6]

Inositol has shown clinical benefits in treating disorders associated with metabolic syndrome. Inositol supplementation has been effectively used to accelerate weight loss, reduce fat mass,^[7] improve serum lipid profiles and upregulate the expression of genes involved in lipid metabolism and insulin sensitivity^[8] in women with polycystic ovarian syndrome. Myo-inositol alone or in combination with D-chiro-inositol significantly reduced weight, BMI, and waist-hip circumference ratios in overweight/obese women with PCOS. Weight loss, reduction in fat mass and increase in lean mass were accelerated when inositol supplementation was accompanied by a low-calorie diet.^[9] In addition, inositol supplementation was associated with lower rate of gestational diabetes and preterm delivery in pregnant women.^[7] Currently, research is being performed to assess whether inositol may be used in treating various cancers.

Methionine
Methionine is a sulfur-containing branched-chain amino acid. A precursor for cellular methylation reactions, methionine plays an important role in lipid metabolism, polyamine synthesis, immune function, heavy metal chelation, and maintenance of redox balance.^[10]Conversely, dietary methionine restriction in rodents increased energy expenditure, improved insulin resistance, and enhanced lipolysis and fatty acid oxidation in adipose tissue.^[11]

The lipotropic effects of methionine may be attributed to its metabolite S-adenosyl methionine (SAM). SAM is synthesized from methionine via an energy-consuming reaction. SAM administered orally or by injection has been investigated as a treatment for liver diseases, osteoarthritis, and depression.^[12] The benefits bestowed by SAM may be due to its role as a methyl donor in biochemical processes governing lipid homeostasis, DNA stability, gene expression, and neurotransmitter release.^[13]^[14]^[15]

Methylcobalamin
Methylcobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although methylcobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product (see Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur.

The most chemically complex of all the vitamins, methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Methylcobalamin cannot be made by plants or by animals; the only type of organisms that have the enzymes required for the synthesis of methylcobalamin are bacteria and archaea. Higher plants do not concentrate methylcobalamin from the soil, making them a poor source of the substance as compared with animal tissues.

Naltrexone HCl
Naltrexone is an oral opiate receptor antagonist. It is derived from thebaine and is very similar in structure to oxymorphone. Like parenteral naloxone, naltrexone is a pure antagonist (i.e., agonist actions are not apparent), but naltrexone has better oral bioavailability and a much longer duration of action than naloxone. Clinically, naltrexone is used to help maintain an opiate-free state in patients who are known opiate abusers. Naltrexone is of greatest benefit in patients who take the drug as part of a comprehensive occupational rehabilitative program or other compliance-enhancing program. Unlike methadone or LAAM, naltrexone does not reinforce medication compliance and will not prevent withdrawal. Naltrexone has been used as part of rapid and ultrarapid detoxification techniques. These techniques are designed to precipitate withdrawal by administering opiate antagonists. These approaches are thought to minimize the risk of relapse and allow quick initiation of naltrexone maintenance and psychosocial supports. Ultrarapid detoxification is performed under general anesthesia or heavy sedation. While numerous studies have been performed examining the role of these detoxification techniques, a standardized procedure including appropriate medications and dose, safety, and effectiveness have not been determined in relation to standard detoxification techniques.^[16]Naltrexone supports abstinence, prevents relapse, and decreases alcohol consumption in patients treated for alcoholism. Naltrexone is not beneficial in all alcoholic patients and may only provide a small improvement in outcome when added to conventional therapy. The FDA approved naltrexone in 1984 for the adjuvant treatment of patients dependent on opiate agonists. FDA approval of naltrexone for the treatment of alcoholism was granted January 1995. The FDA approved Vivitrol, a once-monthly intramuscular naltrexone formulation used to help control cravings for alcohol in April 2006, and then in October 2010, the FDA approved Vivitrol for the prevention of relapse to opioid dependence after opioid detoxification.

Phentermine HCl
Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s, there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a ‘Dear Health Care Professional’ letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of exogenous obesity.^[17]

Yohimbine HCl
Yohimbine is an oral alpha-2 blocker that is chemically related to reserpine. It is an alkaloid found in the bark of Rubiaceae and related trees, but can also be found in Rauwolfia serpentina. Yohimbine has been proposed as a treatment for erectile dysfunction (ED), however only limited evidence exist. According to ED treatment guidelines, only one small study in the published literature used acceptable efficacy outcome measures; therefore, conclusions about the clinical efficacy of yohimbine have not been established and its use in the treatment of ED is not recommended. Further, associated adverse events such as elevations of blood pressure and heart rate, increased motor activity, irritability, and tremor may limit its use.^[18]^[19] Yohimbine has been available since before 1938.

Caffeine
Caffeine is a mild, direct stimulant at all levels of the CNS and also stimulates the heart and cardiovascular system. The related xanthine, theophylline, shares these properties and is widely used in the treatment of pulmonary disease. Both caffeine and theophylline are CNS stimulants, with theophylline exerting more dramatic effects than caffeine at higher concentrations. Caffeine also stimulates the medullary respiratory center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary muscle and gastric acid secretion, increases renal blood flow, and is a mild diuretic.

While the clinical responses to caffeine are well known, the cellular mechanism of action is uncertain. Several theories have been proposed. At high concentrations, caffeine interferes with the uptake and storage of calcium by sarcoplasmic reticulum of striated muscle. While this action would explain the effects of caffeine on cardiac and skeletal muscle, it does not appear to occur at clinically achievable concentrations. Inhibition of phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also does not appear to occur at clinically achievable concentrations.

Currently, it is believed that xanthines act as adenosine-receptor antagonists. Adenosine acts as an autocoid, and virtually every cell contains adenosine receptors within the plasma membrane. Adenosine exerts complex actions. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine.Recently, a distinct syndrome has been associated with caffeine withdrawal. It is possible that the manifestations of caffeine withdrawal may be secondary to catecholamine or neurotransmitter depletion.

The following mechanisms of action are hypothesized for caffeine’s action in apnea of prematurity: 1) stimulation of the respiratory center, 2) increased minute ventilation, 3) decreased threshold to hypercapnia, 4) increased response to hypercapnia, 5) increased skeletal muscle tone, 6) decreased diaphragmatic fatigue, 7) increased metabolic rate, and 8) increased oxygen consumption. All of these actions are thought to be related to adenosine receptor antagonism.

DHEA
Endogenous DHEA is a complex hormone, and researchers still have much to discover in regards to its physiologic effects in males and females. Less is known regarding the mechanisms of action of exogenously administered DHEA.

CNS actions: Both DHEA and DHEAS may be synthesized de-novo by the central nervous system, and concentrations of DHEA and DHEAS are higher in the brain than in other organs. The two neurohormones appear to have excitatory activity at both GABA and NMDA receptors.^[2]

Dermatologic actions after burn injury: Animal studies have suggested that DHEA and DHEAS expedite the re-epithelialization of donor skin-graft sites.^[20]

Endocrine actions: Endogenous DHEA is synthesized by the conversion of cholesterol via CYP11A1 to pregnenolone, followed by CYP17 conversion to DHEA and then to DHEAS via dehydroepiandrosterone sulfatransferase. The synthesis of DHEA occurs exclusively in the adrenal cortex in women, while in men 10—25% of DHEA is synthesized by the testes and roughly 80% of the DHEA comes from the adrenal glands. DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues. DHEA is of only minor importance as an androgenic substance itself. The production rate of DHEA by the body changes dramatically throughout life, typically peaking at adrenarche, the adrenal contribution to the onset of puberty. In males, DHEA serum levels are high in neonates right after birth, rapidly fall within 5 months, then begin to rise at the age of 9 years. Endogenous DHEA concentration then peaks again in males at roughly the 20th—30th years of life. In females, DHEA serum levels are high in neonates right after birth, rapidly fall within 5 months, then begin to rise at the age of 7 years. Endogenous DHEA concentration then peaks again in females at roughly the 20th and 40th year of life. DHEA levels decline steadily after the fifth decade in both males and females. DHEAS concentrations in males and females follow similar patterns. The administration of DHEA supplements results in different hormonal concentration changes in males and females; the actions are dependent on the dose, formulation and route of administration, and age of the person receiving the DHEA.^[2]

Hemostasis: Inhibition of platelet aggregation by exogenous DHEA has been demonstrated in vivo in humans; DHEA either prolonged or completely inhibited the rate of arachidonate-stimulated platelet aggregation after 14 days of administration. The degree of inhibition of platelet aggregation was noted to be time and dose dependent.^[21]

Immunologic actions: Because SLE occurs more frequently in women than men and because SLE is known to worsen during pregnancy, a hormonal etiology is suspected for this disease. DHEA up-regulates interleukin-2 (IL-2) production by T-lymphocytes in murine lupus models and reverses the clinical autoimmune disease. Lower endogenous levels of DHEA and DHEAS have been noted in both male and female patients with lupus at the time of diagnosis. Chronic corticosteroid treatment, which may cause adrenal atrophy, contributes to reduced DHEA levels in these patients. Supplementation of DHEA in SLE may augment immune system activity and potentially offset the undesired effects of chronic corticosteroid use in these patients.^[22] Exact mechanisms of DHEA on immune function are not yet clear. DHEA has been shown to increase the numbers of natural killer cells in aging women. Serum DHEA levels are observed to be reduced in patients with AIDS or age-related immunodeficiency, suggesting that DHEA may serve as a marker of the integrity of the immune system. No studies to date have shown that DHEA supplementation augments currently available therapies for AIDS.^[2]

Inositol
Structurally, all inositol stereoisomers are 6-carbon sugar alcohols with the same molecular formula as glucose (C6H12O6). Myo-inositol and D-chiro-inositol have insulin-mimetic effects. Inositol administration in diabetic rodents, rhesus monkeys, and humans lowers post-prandial blood glucose levels and improves insulin sensitivity.^[23]^[24]^[25] These benefits may be attributed to the effects of inositol on the insulin signaling pathway. Stimulating the insulin receptor activates the phosphatidylinositol-3-kinase (PI3K) pathway. Phosphorylated forms of phosphatidylinositol act as second messengers that lead to downstream activation of Akt. Akt inactivates the enzyme glycogen synthase kinase-3, enhancing glycogen synthase activity. This increases translocation of the glucose transporter (GLUT4) to the surface of skeletal muscle cells, increasing glucose uptake and lowering blood glucose levels.^[26]

Excess circulating glucose is often deposited as fat in the liver and around visceral organs. Dietary supplementation with inositol reduced weight gain and lipid accumulation in the liver of rats.^[27]^[28]^[29] Inositol-mediated activation of PI3K/Akt signaling is believed to play a role in hepatic lipid metabolism and gluconeogenesis. Inositol also affects transcription of SREBP-1 and PPAR-α – genes involved in fatty acid synthesis, oxidation, and lipid transport.

Methionine
An essential sulfur-containing amino acid, methionine undergoes transmethylation reactions to generate metabolic by-products including S-adenosyl methionine (SAM) and homocysteine. SAM is a universal methyl group donor that serves as a co-factor in numerous cellular and physiological processes including lipid homeostasis. By donating its methyl group, SAM is converted first to S-adenosyl homocysteine (SAH) and then to homocysteine. As a methyl donor, SAM contributes to the formation of phosphatidylethanolamine and subsequently to phosphatidylcholine. In the liver, phosphatidylcholine is packaged into very low-density lipoproteins (VLDL) and transported to other tissues. Inadequate levels of SAM in the liver disrupts VLDL assembly and leads to hepatic accumulation of triglycerides or fatty liver.^[30]

By promoting DNA methylation SAM plays a crucial role in epigenetic regulation. Methylation near gene promoters is a well-known mechanism of transcriptional repression. Therefore, SAM may act as a sensor for cellular nutrient status and epigenetically alter the expression of genes influencing appetite, glucose metabolism, and lipogenesis.^[31]^[32] SAM also functions as a methyl donor in the synthesis of creatine – a high-energy molecule known to improve exercise.^[33]

Methylcobalamin
Vitamin B12 is used in the body in two forms, methylcobalamin and 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine which is, in turn, required for DNA methylation. The other form, 5-deoxyadenosylcobalamin, is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA. This conversion is an important step in the extraction of energy from proteins and fats. Furthermore, succinyl CoA is necessary for the production of hemoglobin, the substance that carries oxygen in red blood cells.

Vitamin B12, or methylcobalamin, is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for methylcobalamin. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which also requires folate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.

Naltrexone HCl
Like naloxone, naltrexone is a competitive antagonist at opiate receptors mu, kappa, and delta. Opiate receptors have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Naltrexone can either displace opiate agonists from binding at these receptors or prevent opiate binding. Naltrexone does not antagonize the effects of non-opiates such as cocaine, ethanol, amphetamines, barbiturates, or benzodiazepines. Blockade of opiate receptors by naltrexone is a competitive phenomenon and results in elimination of the euphoric effect of opiates. At usual opiate concentrations, naltrexone’s greater affinity for the receptor prevents the binding of the opiate agonist to the receptor. However, when opiate concentrations are extremely high, the opiate can displace naltrexone, and respiratory depression and/or death is possible. Although naltrexone itself may possess some agonistic properties, these are minor compared to its potent antagonistic actions. Naltrexone is 17-times more potent than nalmorphine and twice as potent as naloxone. In patients who are physically dependent on opiates, naltrexone will precipitate an opiate withdrawal syndrome. Naltrexone use is not associated with tolerance or dependence, therefore, withdrawal from naltrexone does not occur. When co-administered with opiate agonists, naltrexone blocks the physical dependence to morphine, heroin, and other opiate agonists. Depending on the dose, the clinical effects of naltrexone can persist for up to 72 hours.

Endogenous opiods such as beta-endorphins and enkephalins may play an important role in alcoholism. An opioid reward system mediated by mu- and delta-receptors and an opposing aversions system mediated by kappa-receptors must be in balance to maintain a neutral state in regards to the development of addiction. Several therories regarding alcohol addiction and the function of endongeous opioids exist. All of these therories are based on an imbalance in favor of the endongenous reward pathways due to alcohol. Naltrexone inhibits the effects of endogenous opioids and decreases the positive or reward pathways associated with alcoholism. Naltrexone is not aversive therapy and will not produce a disulfiram-like reaction if opiates or ethanol are ingested while receiving naltrexone.

Phentermine HCl
Limited data are available in reference texts regarding the mechanism of action of this drug. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic.^[34] Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself.^[35] Clinical effects include CNS stimulation and elevation of blood pressure. Appetite suppression is believed to occur through direct stimulation of the satiety center in the hypothalamic and limbic region.

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased.

Yohimbine HCl
The exact mechanism of action of yohimbine in the treatment of erectile dysfunction (ED) has yet to be determined; there are few data which support its role in ED. It is believed that yohimbine exerts its effects by blocking central alpha-2 receptors thereby producing an increase in sympathetic drive secondary to an increase in norepinephrine release and in firing rate of cells in the brain noradrenergic nuclei. This activity increases penile blood inflow, decreases penile blood outflow, or both, which causes erectile stimulation without increased sexual desire. Yohimbine-mediated norepinephrine release at the level of the corporeal tissues may also be involved as well as other neurotransmitters (e.g., dopamine and serotonin). Other actions of yohimbine include a stimulant effect on mood and an increase in blood pressure at higher doses. At high doses, yohimbine may nonselectively inhibit monoamine oxidase (MAO). Mild antidiuretic actions may also be present possibly due to release of antidiuretic hormone.

Caffeine
Caffeine with sodium benzoate injection is not recommended for use in premature neonates because the benzoate may displace bilirubin and induce kernicterus. Elevated serum concentrations of benzoate, similar to benzyl alcohol, have also been associated with neurological disturbances, hypotension, gasping respiration, and metabolic acidosis (i.e., ‘gasping syndrome’) in neonates.^[36] Clinicians should use Cafcit, which does not contain sodium benzoate, or use an extemporaneously compounded caffeine citrate injection in newborns and premature neonates. The safety and efficacy of the prescription use of caffeine in neonates and infants for longer than 12 days, prophylaxis of sudden infant death syndrome (SIDS), or for use prior to extubation in mechanically ventilated infants has not been established.^[37]

The OTC use of caffeine products is not recommended in children under the age of 12 years.

Caffeine is a central nervous system stimulant. Caffeine should be used cautiously in patients with anxiety disorders and/or panic disorder because it can aggravate these conditions. Patients suffering from insomnia should not consume caffeine, nor should caffeine be consumed prior to retiring because it can cause insomnia. In overdoses, caffeine has been associated with seizures and it should be prescribed cautiously to those patients with a seizure disorder.

Caffeine should be used cautiously in those patients, including neonates, with cardiac disease. Caffeine can stimulate the force of contraction and can increase heart rate. It may increase left ventricular output and stroke volume. Patients who have angina or a history of cardiac arrhythmias should not receive or should minimize their intake of caffeine. Caffeine should not be taken in the first few days—weeks after a myocardial infarction. Patients with hypertension should minimize their intake of caffeine.

Caffeine should be used cautiously in those with hepatic disease or hepatic impairment. Caffeine clearance may be delayed, leading to toxicity. Renal impairment or renal failure may also delay caffeine clearance. It should be noted that caffeine elimination is more dependent on renal clearance in premature neonates and term neonates than in older infants or adults, due to the underdeveloped hepatic metabolism and renal elimination of drugs in general. Thus monitoring of serum caffeine concentrations is recommended in neonates or premature neonates, especially those with renal or hepatic impairment.

Although the effects are mild, caffeine can either raise or decrease blood sugar; use with caution in patients with diabetes mellitus. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed in neonates receiving caffeine citrate. Therefore, blood glucose may need to be periodically monitored in infants receiving caffeine citrate.^[37]

Patients with thyroid disease, especially hyperthyroidism, should not receive or should minimize their intake of caffeine. The stimulatory effects of caffeine can be augmented in hyperthyroidism.

In neonates, there are reports in the literature suggesting a possible association between the use of methylxanthines like caffeine and the development of necrotizing enterocolitis. In a clinical trial (n = 85 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo. Preterm neonates treated with caffeine should be monitored for the development of gastric side-effects (i.e., abdominal distension, vomiting, bloody stools, and lethargy).^[37]^[38]Caffeine can stimulate gastric secretions and may aggravate gastroesophageal reflux disease (GERD). Clinical trial data are conflicting regarding the limitation of caffeine as an effective strategy to control GERD symptoms; however, recommended lifestyle modifications for patients with GERD often include moderation of caffeine intake.^[39]

Caffeine citrate is used for neonatal apnea so concerns for teratogenicity are not relevant when administered to infants, however, when 50 mg/kg of sustained-release pellets were administered to pregnant mice during the period of organogenesis, a low incidence of cleft palate and exencephaly have been noted in the fetuses.^[37] Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1 to 2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (more than 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking.^[40] There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.^[41]

Although the American Academy of Pediatrics has considered the use of mild to moderate use of caffeinated beverages to be compatible with lactation, mothers who are breast-feeding should limit their intake of caffeinated beverages if possible.^[42] Caffeine-containing drug-products should be used cautiously during lactation due to their high caffeine contents. Mothers who are breast-feeding infants who have been prescribed caffeine for apnea should generally avoid additional caffeine use.^[37] The CYPP450 hepatic metabolism of caffeine is inhibited in infants who are breastfed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants.^[43] Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk: plasma ratios of 0.5 to 0.7 reported.^[44]^[45] Although only small amounts are secreted in breast milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (more than 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding.^[46] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

Tobacco smoking (cigarettes) has been shown to increase the clearance of caffeine. Passive smoke exposure may also cause an increase in caffeine clearance. This may help to explain why tobacco smokers often have concomitantly high caffeine intakes. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of caffeine, despite the initiation of nicotine replacement. Caffeine dosage may need to be reduced at the cessation of smoking.

Caffeine can usually be ingested in normal amounts found in food or beverages (e.g., coffee) in the elderly; however, geriatric patients should be aware of the effects of caffeine on sleep and other physiologic functions, such as urination. Excessive caffeine intake, such as intake of non-prescription caffeine dietary supplements/medicines, should generally be avoided, as excessive use can cause tremor, insomnia, palpitations, and gastrointestinal complaints. Because caffeine is an ingredient in some non-prescription products, patients should be advised to read labels carefully or check with their prescriber or pharmacist if they are unsure if the medication contains caffeine.^[47]

Caffeine intake should be limited along with MAOI therapy.

DHEA
Your health care provider needs to know if you have any of these conditions: breast cancer (men or women); cancer of the lining of the uterus (endometrial cancer); diabetes or high blood sugar; immune system problems; infertility; liver disease; post-menopause; prostate cancer or an enlarged prostate gland; rheumatoid arthritis; uterine cancer; vaginal bleeding or menstrual problems; vaginal cancer; an unusual or allergic reaction to progesterone, DHEA, soy, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding. Visit your doctor or health care professional for regular checks on your progress. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. DHEA use is banned in competitive sports. Both college (NCAA) and olympic (USOC) committees do not allow DHEA use among athletes.

NOTE: DHEA has not yet been evaluated by the Food and Drug Administration. Nutritional supplement products containing DHEA are not intended to diagnose, treat, cure, or prevent any disease. Consumers should also be informed that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.

Dehydroepiandrosterone (free and sulfate) test systems measure dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) in urine, serum, plasma, and amniotic fluid. These measurements are used in the diagnosis and treatment of DHEA-secreting adrenal cancers. It is unclear at this time if supplementation with DHEA would result in false-positives of these tests.

The effect of DHEA on hormone-dependent tumors in males and females is unknown. Many hormonal agents with androgenic or estrogenic activity are contraindicated for use in persons with various hormonally-dependent neoplasms. Some data suggests an association between elevated endogenous DHEA and DHEAS serum concentrations and the development of breast cancer andovarian cancer in women. As with other hormones, DHEA supplementation in a woman with undiagnosed abnormal vaginal bleeding, endometrial cancer, endometrial hyperplasia, uterine cancer, or vaginal cancer is not recommended. DHEA may stimulate the growth of cancerous tissue and should not be used in male patients with either breast or prostate cancer. Male patients with symptoms of prostatic hypertrophy or erectile dysfunction that have not been medically evaluated should not take DHEA supplements. Because the incidence of some hormonally-dependent cancers naturally increases with age, “andropausal” men and post-menopausal women should approach DHEA supplementation with caution. It is recommended that a qualified healthcare prescriber’s recommendations be sought prior to DHEA supplementation.^[48]Benefit versus risk should be determined individually. Women taking DHEA should receive an annual clinical breast examination and pelvic examination and regular mammograms as recommended by their healthcare professional. Men taking DHEA should receive annual physical examinations, including prostate examination or PSA levels, as recommended by their healthcare provider.

Dehydroepiandrosterone, DHEA is contraindicated for use in children <= 18 years of age. Because endogenous DHEA, DHEAS, and androstenedione serum concentrations are related to the onset of puberty, there is concern that the use of DHEA supplements in children or adolescents would interfere with natural growth and sexual maturation. Females of childbearing age with infertility due to hyperandrogenism or chronic anovulation should not take DHEA supplements. The relationship of DHEA and DHEAS to ovulation and fertility is complex and still poorly understood. However, women with hirsutism and infertility or polycystic ovary syndrome (PCOS) are commonly found to have elevated endogenous DHEA or DHEAS serum concentrations on assay.^[49] Women with higher serum levels of endogenous DHEAS and who are receiving fertility treatments have been noted to have higher rates of ovarian hyperstimulation syndrome (OHSS) associated with their treatments. DHEA may also induce changes in the normal menstrual cycle in women of childbearing age. Dehydroepiandrosterone, DHEA should be considered a pregnancy category X drug, similar to other androgenic hormones. Studies of the role of endogenous fetal and maternal DHEA in pregnancy indicate that the ratio of DHEA or DHEAS to other hormones in the serum or placenta may influence the processes of fetal development, parturition, and labor. Endogenous DHEA and DHEAS appear to be important in the functional development of the adrenal cortex and other endocrine activities in the fetus; it is assumed that exogenous DHEA supplementation to a pregnant woman could potentially have deleterious effects on fetal development or viability. The androgenic effects of DHEA could potentially result in masculinization of a female fetus. No controlled trials of DHEA in primate or human gestation exist. Do not administer DHEA to a pregnant woman. DHEA is a hormone and should not be supplemented in a lactating woman who is breast-feeding her infant. Most hormones are excreted in breast milk. Like other androgenic hormones, it is possible that DHEA could inhibit lactation. It is unknown what effect DHEA would have on the breast-feeding infant. Dehydroepiandrosterone, DHEA should be considered contraindicated for use in patients with hepatic disease, hepatitis,hepatocellular cancer, or jaundice. In 1984, the FDA banned the non-prescription (OTC) sale of DHEA due to concern over its ability to cause hepatotoxicity. DHEA supplements are now able to be sold as “nutritional supplements” secondary to the US Dietary Supplement Health and Education Act (DSHEA) of 1994, and are no longer regulated as drugs outside of clinical trials. Transient drug-induced hepatitis has been reported in association with the use of DHEA nutritional supplements. Because both estrogens and androgens may exacerbate acute intermittent or variegate hepatic porphyria, DHEA, which has androgenic actions, should be used with caution in patients with these diseases. Treatment of patients with diabetes mellitus with DHEA is currently not warranted. The role of endogenous DHEA in relationship to insulin resistance is not clear. DHEA and DHEAS may not be mediators of insulin action. Long-term trials evaluating the effectiveness and safety of exogenous DHEA supplementation in patients with diabetes are currently unavailable. Patients with diabetes mellitus who are pursuing the use of DHEA supplements should see a qualified health care professional.^[50]DHEA treatment of patients with human immunodeficiency virus (HIV) infection should be approached with caution. DHEA may possess immunomodulating effects, perhaps by enhancing the secretion of IL-2 from activated T cells as demonstrated in murine models. While this suggests that DHEA may play a role in the function of the immune system, the role of DHEA supplementation in the treatment of human HIV infection, especially acquired immunodeficiency syndrome (AIDS), has not yet been determined. Safety and efficacy have not been established.^[51] Most non-essential hormones are discontinued several weeks prior to major surgery where feasible. DHEA may inhibit platelet aggregation, an effect that may be important to consider during surgical procedures. The decision of when to resume DHEA after surgery would be based on the perceived additional risk from DHEA use and the need for DHEA therapy. Soy oil is the raw product from which many DHEA supplements are manufactured. Cholesterol from soy oil is converted into DHEA. DHEA products should be used cautiously in patients with a history of allergies to soy-containing foods or who exhibit immediate-type soya lecithin hypersensitivity. One of the functions of endogenous DHEA is to inhibit the enzyme glucose-6-phosphate dehydrogenase. Use DHEA with caution in patients with G6PD deficiency. Prasterone (DHEA) should be used with caution in patients with bipolar disorder. One case report exists of the appearance of mania in a predisposed patient consuming large doses of a DHEA supplement on a routine basis. Until more information is known, clinicians should be aware that emotional lability or changes in mood may occur in selected patients. Methylcobalamin Who should not take this medication? Patients with early hereditary optic nerve atrophy, cyanocobalmin hypersensitivity, and those who are pregnant. Your health care provider needs to know if you have any of these conditions: kidney disease; Leber’s disease; megaloblastic anemia; an unusual or allergic reaction to methylcobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding. Methylcobalamin is contraindicated in patients with methylcobalamin hypersensitivity or hypersensitivity to any of the medication components. Methylcobalamin is also contraindicated in patients with cobalt hypersensitivity because methylcobalamin contains cobalt. In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered because anaphylactic shock and death have followed parenteral administration of methylcobalamin. Methylcobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber’s disease). Optic nerve atrophy can worsen in patients whose methylcobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population (see separate monograph in Less Common Drugs). Most formulations of methylcobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Methylcobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Methylcobalamin, vitamin B12 preparations containing benzyl alcohol should be avoided in premature neonates because benzyl alcohol has been associated with ‘gasping syndrome,’ a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction. Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with methylcobalamin or hydroxocobalamin may unmask this condition. Folic Acid, vitamin B9 is not a substitute for methylcobalamin, vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. However, exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. Before receiving folic acid or methylcobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. The intranasal formulations are not approved to treat acute B12 deficiency; all hematologic parameters should be normal before beginning the methylcobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may result in a blunted or impeded response to methylcobalamin therapy. Certain conditions may blunt or impede therapeutic response to methylcobalamin therapy. These include serious infection, uremia or renal failure, drugs with bone marrow suppression properties (e.g., chloramphenicol), or concurrent undiagnosed folic acid or iron deficiency anemia. The mechanism appears to be interference with erythropoiesis. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of methylcobalamin. Clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution. Elderly patients tend to have a greater frequency of decreased hepatic, renal, or cardiac function, and also have concomitant disease or receiving other drug therapy. Start with doses at the lower end of the dosing range. Naltrexone HCl Naltrexone is contraindicated in patients with hypersensitivity to naltrexone or any components of the commercially available product. Naltrexone is incorporated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres. The diluent is composed of carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection. Naltrexone should also not be used in patients with a known hypersensitivity to naloxone or nalmefene because these three drugs are all structurally similar. The use of naltrexone in patients with hepatic disease should be carefully considered due to the hepatotoxic effects of naltrexone and the potential for decreased clearance of naltrexone. Naltrexone does not appear to be hepatotoxic at recommended doses. However, the margin between a safe dose and a hepatotoxic dose appears to be five-fold or less. There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits. There are reports of hepatitis and significant hepatic dysfunction in association with exposure to naltrexone oral tablets and parenteral naltrexone. In patients treated with naltrexone tablets or injection who presented with elevated transaminases, other potential causes were often identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Opioid withdrawal does not typically manifest as clinically significant hepatic dysfunction, however, abruptly precipitated opioid withdrawal may lead to systemic sequelae including acute liver injury. Warn patients of the potential risk of hepatic injury and advise them to seek medical attention if they experience symptoms of acute hepatitis. Discontinue use of naltrexone if signs/symptoms of acute hepatitis occur.^[52]^[53]^[54] Depression, suicide, attempted suicide and suicidal ideation have been reported in patients receiving naltrexone for the treatment of opioid dependence. No causal relationship has been demonstrated. In the literature, endogenous opioids have been theorized to contribute to a variety of conditions. Monitor alcohol and opioid dependent patients, including those taking naltrexone, for the development of depression or suicidal thinking. Inform families and caregivers of patients being treated with naltrexone to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.^[54] Naltrexone is contraindicated in patients who are receiving opioid analgesics, partial opiate agonists (e.g., buprenorphine), those with current physiologic opioid dependence, and those in acute opioid withdrawal. Administration of naltrexone to these patients may precipitate an abrupt withdrawal severe enough to require hospitalization, and in some cases management in the intensive care unit. To prevent precipitation of withdrawal, patients should be opioid-free (including tramadol) for a minimum of 7—10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. In every case, be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. Since the absence of an opiate drug in the urine is often not sufficient proof that a patient is opiate-free, a naloxone challenge should be done if there is any question of occult opioid dependence. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. A positive reaction to the naloxone challenge predicts a similar response to naltrexone. Use of naltrexone is contraindicated in an individual who fails the naloxone challenge test or who has a positive urine test for opioids.The naloxone challenge can be repeated in 24 hours. Assess patients treated for alcohol dependence for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids.^[52]^[53]^[54] If a painful procedure such as surgery is planned, then naltrexone should be discontinued 72 hours prior to the procedure. Patients should be abstinent from opiate analgesia for at least 7 days before restarting naltrexone. Naltrexone treated patients who require emergent opiate analgesia may require the administration of large opiate doses to provide adequate pain control, which may increase the risk of deep or prolonged respiratory depression. A rapidly acting opiate agonist is preferred for emergent analgesia to limit the duration of respiratory depression. Non-opiate receptor mediated actions (i.e., histamine-mediated) may occur with the use of opiates and should be expected (e.g., facial swelling, itching, generalized erythema or bronchoconstriction). Other alternatives for emergent analgesia in patients taking naltrexone include the use of regional analgesia, conscious sedation, non-opiate analgesics, or general anesthetics. Attempts to overcome the antagonistic effects of naltrexone with large doses of an opiate agonist by patients maintained on naltrexone may result in potential for overdose or poisoning that may be fatal; cases of opioid overdose with fatal outcomes have been reported in patients after discontinuing treatment. Despite a prolonged pharmacologic effect, the blockade produced by naltrexone is surmountable. As the naltrexone blockade wanes and eventually dissipates, patients may respond to lower doses of opioids than previously used, potentially resulting in life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Patients are at particular risk at the end of the dosing interval, after missing a scheduled dose or after discontinuing naltrexone treatment. Patients should be informed of the serious consequences of attempting to overcome the opiate blockade and that they may be more sensitive to lower doses of opiate agonists once naltrexone therapy is stopped. Advise patients to inform family members and those closest to them of this increased sensitivity and risk of overdose.^[52]^[53]^[54] Naltrexone and its major active metabolite are excreted primarily by the kidney. Use caution in administering naltrexone to patients with renal impairment. Pharmacokinetic parameters of naltrexone given intramuscularly are essentially unchanged in patients with a creatinine clearance of 50—80 ml/minute. The disposition of naltrexone in patients with moderate to severe renal impairment has not been evaluated. Dosage adjustments may be necessary in patients with renal dysfunction. Naltrexone is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. In some individuals, opiate antagonists have been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones, although the clinical significance is not known. In rat studies, there was an increase in early fetal loss and pseudopregnancy, and a decrease in pregnancy rate. There was no evidence of teratogenicity; however, rats do not form a significant amount of the major human metabolite, 6-B-naltrexol; therefore, the potential reproductive toxicity of 6-B-naltrexol in rats is not known. There were small increases in the numbers of testicular mesotheliomas in male rats and vascular tumors in female rats during a 2-year carcinogenicity study; however, no evidence of carcinogenicity was observed in mice.^[52] When considering the use of naltrexone during pregnancy for relapse prevention in alcohol or opiate dependence, the risks to the fetus of continued substance abuse by the mother should be weighed against the potential adverse effects from fetal exposure to naltrexone. Drug therapy should be considered only if supportive substance abuse prevention measures are ineffective. The effects of naltrexone during labor and delivery are unknown. According to the manufacturer, naltrexone and its metabolite are excreted into human milk, and a decision should be made to discontinue breast-feeding or discontinue naltrexone, taking into consideration the importance of the drug to the mother. Animal studies have shown the potential for tumorigenicity.^[52] No reports describing the use of naltrexone during breast-feeding are available. According to the American Academy of Pediatrics (AAP), the maternal ingestion of large amounts of ethanol or opiates can cause adverse effects in the nursing infant.^[55] If supportive substance abuse prevention measures are ineffective, the risks to the nursing infant of continued ethanol or opiate abuse by the mother should be weighed against the potential for adverse drugs effects when determining whether to use naltrexone as a substance abuse deterrent during breast-feeding. The safe use of naltrexone in neonates, infants, children, and adolescents < 18 years has not been established. Naltrexone may cause dizziness (see Adverse Reactions). Tell patients about the importance of not driving or operating machinery until they know how this medicine will affect them. Administer the extended-release injectable suspension of naltrexone cautiously to patients with thrombocytopenia, coagulopathy, or other bleeding disorders. Patients with thrombocytopenia, vitamin K deficiency, a coagulopathy (e.g., hemophilia), or receiving anticoagulant therapy should be monitored closely when given intramuscular naltrexone because bleeding can occur at the IM injection site. All steps to avoid hematoma formation are recommended. Naltrexone extended-release injectable suspension (Vivitrol) is only for intramuscular administration; intravenous administration and subcutaneous administration should be avoided. The risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue (see Adverse Reactions). Proper administration techniques and patient selection are imperative (see Administration). Consider alternate treatment for patients whose body habitus (obesity) precludes a gluteal intramuscular injection with the provided needle. Women may be physiologically at higher risk for injection site reactions because of typically higher gluteal fat thickness, and in fact, post-marketing reports of injection site reactions occur primarily in females. Also, a variable depth of subcutaneous tissue exists between patients; the depth is dependent on the gender and weight of the patient. Phentermine HCl Phentermine is contraindicated for use in any patient with a prior history of sympathomimetic amine hypersensitivity.^[56]^[57] According to the manufactures of phentermine capsules and tablets, its products are contraindicated in patients with cardiac disease, advanced arteriosclerosis, moderate to severe hypertension, agitated states, or glaucoma.^[58] Likewise, orally disintegrating tablets, are contraindicated in patients with a history of cardiac disease including coronary artery disease, stroke, cardiac arrhythmias, heart failure, and uncontrolled hypertension.^[57] Valvular heart disease has been reported in women receiving the combination of fenfluramine and phentermine; the safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended. Further, primary pulmonary hypertension (PPH) has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between the use of phentermine alone and PPH or valvular heart disease cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema. Because phentermine is a sympathomimetic agent, it is contraindicated in patients with hyperthyroidism. It should also be used with caution in patients with thyroid disease. Phentermine is contraindicated for use during or within 14 days following the use of MAOI therapy or other drugs with MAO-inhibiting activity. Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine.^[56] Phentermine is contraindicated in patients with agitated states.aggravate these effects or cause an adverse drug reaction.^[56] Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from other psychotic disorders, like schizophrenia. Phentermine could aggravate certain mental conditions, such as those patients who exhibit highly nervous or agitated behavior, including psychosis, mania, or severe anxiety. The use of phentermine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor performance. In general, ethanol ingestion may aggravate these effects or cause an adverse drug reaction.^[56] Advise patients to avoid alcohol while taking phentermine. Use phentermine cautiously in patients with diabetes mellitus. Insulin or other antidiabetic medication requirements may be altered in these patients when using phentermine during weight loss and due to altered dietary regimens. Patients should monitor their blood glucose regularly and follow the recommendations of their health care provider.^[57] Appetite suppressant therapy is not recommend for use in those patients with a history of anorexia nervosa or other eating disorders. Use of phentermine is contraindicated in patients with a known history of drug or substance abuse. Phentermine is chemically and pharmacologically related to the amphetamines which have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion.^[57] Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy.^[57]^[58] Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.^[58] Abrupt discontinuation of phentermine after prolonged high doses may result in severe mental depression or extreme fatigue; sleep EEG changes have also been noted. Gradual withdrawal of therapy is recommended. If immediate discontinuation is medically necessary, careful monitoring and symptom management is warranted.^[56] Phentermine is contraindicated during breast-feeding.^[57] It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breast-feeding while taking phentermine is not recommended.^[59]^[58] Safety and effectiveness of phentermine in children have not been established. Phentermine is not recommended for children or adolescents 16 years of age and under. There is no established use of phentermine in infants or neonates.^[56]^[57] The debilitated or geriatric patient may be more susceptible to the CNS and sympathomimetic side effects of phentermine; use with caution in elderly patients. Patients with renal impairment may also be more susceptible to side effects. Exposure increases can be expected in patients with renal impairment or renal failure. Use caution when administering phentermine to patients with renal impairment.^[56] The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs. Because of this, and its effects on blood pressure, in general, phentermine should be discontinued several days prior to surgery. Avoid abrupt discontinuation. Yohimbine HCl NOTE: Limited information about precautions and contraindications to yohimbine therapy exists. Yohimbine is contraindicated in patients with a hypersensitivity to yohimbine. Yohimbine should not be used in patients with a history of rauwolfia alkaloid hypersensitivity. Rauwolfia alkaloids include deserpidine, rauwolfia serpentina, or reserpine. Patients sensitive to these agents may also be sensitive to yohimbine. Yohimbine may worsen renal impairment, therefore administration of this drug in patients with renal disease or renal failure is contraindicated. Serious renal effects, including renal failure, have been reported to the FDA after the use of products containing yohimbe. Yohimbine should not be used concurrently with MAOI therapy (see Drug Interactions). Yohimbine should not be used in patients with angina pectoris, cardiac disease, or hypertension because these conditions may be aggravated or worsened by yohimbine. It is also recommended that this drug not be used in cardio-renal patients with history of peptic ulcer disease, children, and geriatric patients. Further, because yohimbine may enhance anxiety or other CNS symptoms, it should be used cautiously in patients with depression or other psychiatric illness. According to the German E Commission monographs, the use of yohimbine in those with hepatic disease is contraindicated. In theory, patients with hepatic impairment may exhibit impaired metabolism of yohimbine. Although recommendations on the use of yohimbine in those with hepatic disease are not available from the manufacturer, it should be noted that patients with hepatic disease have generally been excluded from participation in clinical trials that assess safety and efficacy of the drug. Therefore, it is advisable to avoid the use of yohimbine in those with hepatic disease, including biliary cirrhosis or hepatic failure. In general, yohimbine is not for use in females and must certainly not be used during pregnancy.^[60] A FDA pregnancy risk category has not been assigned to this drug. However, given yohimbine’s similarity to other rauwolfia alkaloids, it is suggested that yohimbine most closely corresponds to an FDA pregnancy risk category D (see Reserpine monograph). There is no known indication at this time for the use of yohimbine in pregnancy which would justify the potential risks to the fetus. Generally, this drug is not for use in females ^[60], and therefore should not be used during breast-feeding. Many of the rauwolfia alkaloids are excreted in human breast milk. A decision should be made to discontinue the medication or discontinue breast-feeding.

Caffeine
Caffeine has been noted to produce a variety of gastrointestinal (GI) effects. At therapeutic or nontoxic doses, caffeine can stimulate gastric secretions and may cause GI upset (dyspepsia), nausea, loose stools, and may aggravate gastroesophageal reflux disease (GERD).^[39]^[36]^[38]^[64] Occasionally diarrhea is reported. The mild dehydration that caffeine produces may aggravate constipation. A temporary reduction in weight gain has also been reported. In a study comparing caffeine to placebo, the mean difference in weight gain was the greatest after 2 weeks of therapy.^[65] Feeding intolerance (8.7%), gastritis (2.2%), and GI bleeding (2.2%) also occurred in the caffeine treatment groups.^[36] During a controlled clinical trial of caffeine citrate in premature infants (n = 85 neonates), necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated infants. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo.^[37]^[38]^[65] In a study evaluating the effect of caffeine on the splanchnic perfusion after a caffeine loading dose, the blood flow velocity was depressed for 2 to 3 hours after the infusion and slowly returned to baseline after approximately 6 hours.^[66] Clinicians should be alert for signs and symptoms of gastric distress, abdominal bloating, nausea, vomiting, bloody stools, and lethargy in treated infants.^[37]^[36] Excessive caffeine intake or intoxication in children, adolescents, and adults may cause vomiting along with other signs of caffeine intoxication.^[64] In humans, a caffeine concentration of greater than 50 mg/L may produce toxic symptoms.

Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of caffeine’s pharmacologic actions. At therapeutic or nontoxic doses, caffeine can commonly cause nervousness, mild tremor, and heightened attentiveness.^[64] Less frequent adverse reactions with usual consumption also include excitement, irritability, insomnia, headache, and muscle twitches.^[67]^[68] Increased caffeine use among children and adolescents has been associated with insomnia, chronic headache, motor tics, irritability, learning difficulties, and other adverse health effects.^[64]^[69]^[70] After excessive doses, caffeine can cause considerable anxiety. Seizures and delirium are also possible.^[64] In humans, a caffeine level of > 50 mg/L may produce toxic symptoms. Other neurologic events have been reported in preterm neonates. In clinical trials of caffeine citrate in preterm neonates, cerebral hemorrhage (intracranial bleeding) was reported in 2.2% of treated patients versus 0% of neonates receiving placebo.^[37]

Caffeine is a mild diuretic and patients may have increased urinary frequency. Polyuria can occur. Increased creatinine clearance and increased urinary calcium (hypercalciuria) and sodium excretion are reported in the literature.^[37]

Adverse events to caffeine that have been described in the published literature include alterations in serum glucose such as hypoglycemia and hyperglycemia.^[37]

In controlled clinical trials of caffeine citrate injection in premature neonates, the following adverse events occurred more commonly in caffeine-treatment groups than with placebo: accidental injury (2.2%), bleeding (2.2%), disseminated intravascular coagulation (2.2%), dyspnea (2.2%), pulmonary edema (2.2%), metabolic acidosis (2.2%), xerosis (2.2%), rash (unspecified) (8.7%), renal failure (unspecified) (2.2%), retinopathy of prematurity (2.2%), and skin breakdown (2.2%). In neonates, intolerance or overdose of caffeine may manifest as tachypnea. No deaths have been reported in relation to overdose of caffeine in neonates.^[37]

Too much caffeine may occasionally cause rapid heartbeat.^[71] Cardiovascular effects of caffeine have been reported in the literature (i.e., palpitations, sinus tachycardia, increased left ventricular output, and increased stroke volume).^[37]

High caffeine intake has been reported to negatively affect sperm quality, including spermatogenesis inhibition). The propensity for caffeine to negatively affect fertility is controversial. Although controversial, infertility, as manifested by increased difficulty in getting pregnant, has been reported in females. Couples who are pursuing pregnancy should probably limit excessive intake of caffeine.

A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or rebound headache upon caffeine withdrawal.^[64]

DHEA
NOTE: Some prasterone, dehydroepiandrosterone, DHEA preparations are a combination of several hormones and/or herbs, and each individual component may need to be evaluated in the presence of adverse reactions. Only adverse reactions pertaining to DHEA are discussed in this monograph. Human side-effect data to date have been collected in non-systematic fashion via the FDA special nutritional adverse effect monitoring system (SNAEMS) or relatively small clinical trials.

DHEA has been observed to cause reversible reductions in HDL cholesterol and total cholesterol in some clinical trials; other trials have not noted changes in the serum lipid profile. DHEA may also exhibit anti-platelet effects. The influence of these changes on the development of side effects, atherosclerosis, or other cardiac-related endpoints is unknown.

In one 3-month study of 28 women with SLE, the following ADRs were noted in the females receiving DHEA: acneiform rash (57%), hirsutism (14%), weight gain (14%), menstrual irregularity (7%), and emotional lability (7%). The statistical significance of these side effects relative to placebo was not determined.^[72] Some events commonly associated with SLE and reported as adverse events in clinical trials were less frequent in patients treated with prasterone (GL701) compared with placebo, including muscle pain, nasal and oral ulceration, and hair loss.

Prasterone, DHEA is a hormone with androgenic actions, however, the incidence of androgenic side effects is not known. When androgens are given to women, they may cause virilization, manifested by clitoromegaly, reduced breast size, and deepening of the voice or voice hoarseness. If treatment is discontinued when these symptoms first appear, they usually subside. Prolonged treatment with androgenic substances can lead to irreversible masculinity, so the benefit of DHEA treatment should be offset against the risk of androgen-like side effects.

The effect of prasterone or DHEA supplementation on normal endocrine processes in women is not clear. Women should report any menstrual changes, including amenorrhea, unusual vaginal bleeding, dysmenorrhea, or abdominal bloating to their health care providers. Breast changes, including breast discharge, breast enlargement, breast tenderness, or galactorrhea should also be reported.

Prasterone (DHEA) has androgenic actions, and it is not clear what effect prasterone may have in male patients. Similar to female patients, male patients may experience worsening of acne vulgaris. Male patients may theoretically experience feminization during prolonged therapy with DHEA resulting from inhibition of gonadotropin secretion and conversion of testosterone to estrogens. Feminizing effects in males might include gynecomastia. Feminizing effects secondary to androgens are generally reversible. It is not clear if DHEA would affect testicular function or prostatic function. Symptoms of urinary retention or urinary urgency, prostate pain, or signs of an enlarged prostate in a male patient should prompt clinical evaluation.

Mild peripheral edema can occur with DHEA use as the result of increased fluid retention (in association with sodium retention) and may be associated with mild weight gain.

Prasterone (DHEA) may cause emotional lability. At least one case of possible DHEA-induced mania has been reported in the literature, in a patient predisposed to bipolar illness who was consuming doses >= 300 mg/day PO on a routine basis. There was a temporal association between the time of drug use and the appearance of manic symptoms. Clinicians should be alert to possible alterations in psychiatric status in patients taking this medication for supplemental or medicinal purposes.

Hepatic dysfunction can occur from use of androgenic steroids, especially the oral 17-alpha-alkylandrogens (e.g., methyltestosterone). DHEA does not contain the 17-alkyl group in its structure, however, transient cases of drug-induced hepatitis in humans have been reported in association with DHEA use; these have included a few reports to the FDA Special Nutritionals Adverse Event Monitoring System (SN/AEMS). Liver toxicity has not been reported in human studies, but elevated hepatic transaminases have been reported and confirmed upon rechallenge in some trials. In 1984, the FDA banned the non-prescription (OTC) sale of DHEA due to concern over hepatitis. Clastogenesis has been noted in hepatic tissues of animals exposed to DHEA. DHEA appears to act as a perisoxome proliferator, resulting in liver tumors and nodules in the periportal areas of the liver lobule in rats. DHEA should be discontinued in any patient developing signs or symptoms of potential liver problems, including elevated hepatic enzymes, continued nausea and vomiting, fatigue, jaundice, or severe abdominal pain; the patient should be evaluated.

In studies of male patients with HIV virus infection, side effects attributed to DHEA treatments and confirmed upon rechallenge included nasal congestion, fatigue, headache, and mild insomnia.^[2]

Prasterone (DHEA) therapy is reported to cause libido increase. No objective evidence of this side effect exists at this time.

The effect of DHEA on the progression of hormonally-dependent tumors in males or females, or the risk of secondary malignancy, such as breast cancer, is not known. One case-control study of women with ovarian cancer demonstrated higher serum androstenedione and DHEA/DHEAS levels in patients with ovarian tumors versus controls.^[73] Whether DHEA supplementation would be associated with similar the serum hormonal profiles is unknown. Male breast cancer, prostate cancer and prostatic hypertrophy can develop due to endocrine epithelial cell growth during therapy with androgens. One case report has been published of a patient with advanced prostate cancer who was symptomatically treated with DHEA. The patient experienced a “flare” of his cancer during the treatment period.^[74] A causal relationship has not been established. Widespread use of DHEA supplements in men or women should be discouraged until more is known about potential secondary malignancy risks.

Prasterone, dehydroepiandrosterone (DHEA) is an androgenic hormone and may potentially cause teratogenesis or changes the ability to conceive or carry a viable pregnancy. Dehydroepiandrosterone, DHEA should be considered contraindicated in pregnancy, similar to other androgenic hormones. It is assumed that exogenous DHEA supplementation to a pregnant woman could potentially have deleterious effects on fetal development or viability. No controlled trials of DHEA in primate or human gestation exist. If pregnancy is suspected, pregnancy should be ruled out before continuing DHEA use.

Methionine
Adverse reactions reported following methionine administration include gastrointestinal disorder: Nausea and vomiting and drowsiness ^[75]

Methylcobalamin
In most cases, methylcobalamin is nontoxic, even in large doses. Adverse reactions reported following methylcobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.

During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral methylcobalamin. This is believed to result from the increased blood volume induced by methylcobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral methylcobalamin.

Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin.

Diarrhea and headache.

Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg.

Naltrexone HCl
Naltrexone can cause hepatocellular injury when given in excessive doses. Naltrexone does not appear to be a hepatotoxin at the recommended doses. The hepatotoxic potential of naltrexone has been described in a placebo-controlled study using a 300 mg/day dose of naltrexone. In this study, 20% of patients experienced elevated hepatic enzymes (3—19 times baseline values). All patients were asymptomatic, and transaminase levels returned to baseline or decreased in a matter of weeks. Other studies of naltrexone doses > 50 mg/day in patients with opiate dependence or alcoholism also resulted in increased hepatic enzymes. Clinical trial data indicate that 7—13% of study patients receiving 380 mg of intramuscular naltrexone experienced elevated hepatic enzymes compared to 2—6% of those on placebo.^[76] Hepatitis, elevated hepatic enzymes, and hyperbilirubinemia have been reported in post-marketing reports with naltrexone. Warn patients of the risk of hepatic injury, and advise them to get immediate medical attention if they experience symptoms of acute hepatitis. A high index of suspicion for drug-related hepatic injury is critical if the occurrence of naltrexone-induced liver damage is to be detected at the earliest possible time. Evaluations to detect liver injury are recommended at a frequency appropriate to the clinical situation and to the naltrexone dose. Discontinue naltrexone if symptoms or signs of acute hepatitis develop.^[52]

Central nervous system (CNS) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence included headache (>= 7%), dizziness (4—9%), nervousness (>= 4%), insomnia (>= 3%), anxiety (>= 2%), fatigue (>= 4%), drowsiness (<= 2%), increased energy (< 10%), irritability (< 10%), paranoia (< 1%), restlessness (< 1%), confusion (< 1%), disorientation (< 1%), hallucinations (< 1%), nightmares (< 1%), yawning (< 1%), and hot flashes (< 1%).^[52] During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol opioid dependence, the following effects were reported more frequently with the active drug than placebo: dizziness or syncope (13% vs 4%), insomnia (6—14% vs 1—12%), headache (3—25% vs 2—18%), drowsiness (4% vs 1%), and anxiety (12% vs 8%).^[76] Cerebral arterial aneurysm, seizures, mental impairment, dysgeusia, euphoric mood (euphoria), migraine, ischemic stroke, irritability, disturbance in attention, abnormal dreams, agitation, delirium, hot flashes, and paresthesias were also reported during clinical trials of intramuscular naltrexone; however, the incidence of these effects is not known. CNS effects reported during post-marketing use of naltrexone include abnormal thinking, agitation, anxiety, headache, fatigue, confusion, euphoria, hallucinations, insomnia, nervousness, drowsiness, hot flashes, dizziness, and hyperkinesis. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.^[52] Depression, suicidal ideation, and attempted suicide have been reported in individuals receiving oral naltrexone, placebo, and in concurrent control groups undergoing treatment for alcoholism and opiate dependence.^[52] In controlled clinical trials of the extended-release injectable suspension of naltrexone, suicidal ideation, suicide attempts, or completed suicides occurred in 1% of patients and in no patients treated with placebo. In some cases, the suicidal thoughts or behavior occurred after study discontinuation but were in the context of an episode of depression that began while the patient was taking naltrexone. Two completed suicides occurred in patients who were taking naltrexone. Depression-related events associated with premature discontinuation of naltrexone also occurred in about 1% of patients and in no patients treated with placebo. In the 24-week, placebo-controlled, pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with naltrexone 380 mg IM as compared with 5% of patients treated with placebo. Monitor patients for the development of depression or suicidal thinking. Families and caregivers of patients being treated with naltrexone should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality and to report such symptoms to the patient’s health care provider. Physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in patients.^[76] In clinical trials of the extended-release injectable suspension of naltrexone, patients who took naltrexone had increases in eosinophil counts (eosinophilia) relative to patients on placebo, but eosinophil counts returned to normal over a period of several months in the patients who continued to take naltrexone. One diagnosed case and 1 suspected case of eosinophilic pneumonia occurred. The pneumonia resolved with antibiotics and corticosteroids. Consider eosinophilic pneumonia if progressive shortness of breath and hypoxia develop and if patients do not respond to antibiotics.^[76] Patients treated with naltrexone 380 mg IM experienced a mean maximal decrease in platelet count of 17,800/mm3 as compared with 2600/mm3 in placebo patients. In randomized controlled trials, naltrexone administration was not associated with an increase in bleeding related adverse events. Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitized to naltrexone in a previous course of treatment with naltrexone. The condition cleared without sequelae after discontinuation of naltrexone and corticosteroid treatment. In addition, deep vein thrombosis and pulmonary embolism were reported as treatment-emergent adverse reactions during clinical trials of naltrexone suspension for injection; the incidences are unknown.^[76] Gastrointestinal (GI) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence include nausea (>= 10%), vomiting (>= 3%), abdominal pain (> 10%), anorexia (< 10%), diarrhea (< 10%), constipation (< 10%), appetite stimulation (< 1%), weight loss (< 1%), weight gain (< 1%), xerostomia (< 1%), flatulence (< 1%), hemorrhoids (< 1%), and peptic ulcer (< 1%).^[52] During controlled trials of oral naltrexone 50 mg/day in alcohol dependence, approximately 5% of patients discontinued naltrexone due to nausea. During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol or opioid dependence, the following GI effects were reported more frequently with 380 mg of the active drug than placebo: nausea (33% vs 11%), vomiting (14% vs 6%), diarrhea (13% vs 10%), abdominal pain (11% vs 8%), xerostomia (5% vs 4%), dental pain (toothache 4% vs 2%), and anorexia (14% vs 3%).^[76]Weight loss, weight gain, abdominal discomfort, colitis, constipation, flatulence, appetite stimulation, gastroenteritis, gastroesophageal reflux disease (GERD), GI bleeding, hemorrhoids, acute pancreatitis, paralytic ileus, and perirectal abscess were also reported. In post-market experience of oral naltrexone, GI effects including anorexia, nausea, vomiting, abdominal pain, and diarrhea have been reported. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.^[52] Injection site reactions have been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. Of 440 patients who received 380 mg of the extended-release injectable suspension of naltrexone (Vivitrol) in clinical trials for alcohol dependence, 69% had an injection site reaction (pain, tenderness, induration, swelling, or itching) versus 50% of those receiving a placebo injection. Specific injection site reactions that occurred more frequently in the active treatment group than the placebo group included injection site tenderness (45% vs 39%), injection site induration (35% vs. 8%), injection site pain (5% to 17% vs. 1% to 7%), nodules/swelling (15% vs. 4%), itching at the injection site (10% vs. 0%), and injection site ecchymosis (7% vs. 5%). One patient developed an area of induration at the injection site that continued to enlarge after 4 weeks. Eventually, necrotic tissue that required surgical excision developed. The FDA has received 196 reports of injection site reactions including cellulitis, induration, hematoma, abscess, sterile abscess, and tissue necrosis. Sixteen patients required surgical intervention ranging from incision and drainage in the cases of abscesses to extensive surgical debridement in the cases that resulted in tissue necrosis. The extended-release injectable suspension of naltrexone should only be administered intramuscularly (IM); the risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue. Instruct patients to monitor the injection site and to get medical care if they develop pain, swelling, tenderness, induration, bruising, itching, or redness at the injection site that does not improve or worsens within 2 weeks. Promptly refer patients with worsening injection site reactions to a surgeon.^[76]Urticaria, angioedema, and anaphylactoid reactions (anaphylaxis) have occurred in association with naltrexone administration in both clinical trials and during post-marketing use. Patients should be advised of the potential for serious hypersensitivity reactions while using naltrexone and instructed to seek immediate medical attention in the event of such a reaction.^[76] During clinical trials using 380 mg of intramuscular (IM) naltrexone, infections reported more frequently within the active drug group than the placebo group included nasopharyngitis (7% vs 2%) and influenza (5% vs 4%).^[76] Other respiratory or related effects that were reported during IM naltrexone clinical trials included upper respiratory tract infection, advanced HIV disease in HIV-infected patients, bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, pharyngolaryngeal pain, pneumonia, sinus congestion, and sinusitis. Respiratory effects or symptoms of infection occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included nasal congestion, rhinorrhea, sneezing, sore throat, excess mucus, sinus trouble, hoarseness, cough, fever, and dyspnea.^[52] Additionally, eosinophilic pneumonia, which may present as dyspnea, coughing, and/or hypoxia, has been reported in association with injectable naltrexone use (see eosinophilic pneumonia). In clinical trials of intramuscular naltrexone (380 mg) in patients with opioid dependence, 5% of study patients experienced hypertension compared to 3% of those on placebo.^[76] Other cardiovascular effects observed during clinical trials of intramuscular naltrexone included angina, atrial fibrillation, congestive heart failure, coronary artery atherosclerosis, myocardial infarction, and palpitations. Cardiovascular effects occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included epistaxis, phlebitis, edema, increased blood pressure, unspecified ECG changes, palpitations, and sinus tachycardia. Cardiac effects reported during post-marketing use of naltrexone include chest pain (unspecified), palpitations, and changes in blood pressure. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.^[52] During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, the following musculoskeletal effects or pain symptoms were reported more frequently with the active drug than placebo: arthralgia (12% vs 5%), back pain (6% vs 5%), and muscle cramps (8% vs 1%).^[76] Myalgia, joint stiffness, limb pain, and muscle spasms have also been reported. Musculoskeletal effects or pain symptoms occurring during clinical trials of oral naltrexone for opiate dependence included arthralgia and myalgia (> 10%), shoulder pain (< 1%), knee or leg pain (< 1%), tremor (< 1%), twitching (< 1%), inguinal pain (< 1%), and side pain.^[52] Tremor and myalgia have been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome. Increased creatinine phosphokinase (CPK) concentrations have been associated with naltrexone use. In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. Increases in 1—2 times the upper limit of normal (ULN) were most common for both the oral naltrexone and IM naltrexone 380 mg groups. Although CPK elevations of 1—2 times ULN were most commonly encountered, elevations as high as 4 times ULN for the oral naltrexone group and 35 times ULN for the IM naltrexone group were noted. However, there were no differences between the placebo and either the oral or IM naltrexone groups with respect to the proportions of patients with a CPK value at least 3 times ULN. No factors other than naltrexone exposure were associated with the CPK elevations.^[52] Dermatologic or related effects occurring during clinical trials of oral naltrexone for opiate dependence included rash (unspecified) (< 10%), oily skin (< 1%), pruritus (< 1 %), acne vulgaris (< 1%), tinea pedis (< 1%), cold sores (< 1%), and alopecia (< 1%).^[52] During clinical trials using 380 mg of intramuscular naltrexone suspension, rash occurred more frequently with active drug than placebo (6% vs 4%).^[76] Other related effects reported with the intramuscular formulation included night sweats, pruritus, heat exhaustion, and hyperhidrosis. Rash and increased sweating have also been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.^[52]Genitourinary (GU) effects occurring during clinical trials of oral naltrexone included ejaculation dysfunction (delayed ejaculation < 10%), dysuria (< 1%), increased urinary frequency (< 1%), and libido increase or libido decrease (< 1%).^[52] Decreased libido and urinary tract infection have been reported with the use of the intramuscular formulation.^[76]Special senses effects (otic, ophthalmic) occurring in less than 1% of patients during clinical trials of oral naltrexone included blurred vision, ocular irritation (burning), light sensitivity (photophobia), eye swelling/ache (ocular inflammation), otalgia, and tinnitus. Unspecified visual impairment has been reported during post-marketing use of oral naltrexone.^[52]Conjunctivitis and blurred vision have also been reported with the use of the intramuscular formulation. Retinal artery occlusion has been reported rarely after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during clinical trials or post-market use of the intramuscular formulation of naltrexone.^[76] Lymphadenopathy and increased white blood cell count have been reported with the use of naltrexone extended-release suspension for injection during clinical trials.^[76] Acute cholecystitis and cholelithiasis have been reported as treatment-emergent adverse effects in patients who received naltrexone extended-release suspension for injection for alcohol and/or opioid dependence; the incidence of these effects is unknown.^[76] General effects occurring during clinical trials of oral naltrexone for opiate dependence included increased thirst (polydipsia) (< 10%), chills (< 10%), swollen glands (< 1%), and cold feet (< 1%).^[52] During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, asthenia was reported more frequently in the active treatment group than the placebo group (23% vs 12%). Other general events observed during clinical trial evaluation of intramuscular naltrexone included chest tightness, chills, face edema, pyrexia, rigors, and lethargy. Malaise and asthenia have been reported during post-market use of oral naltrexone.^[76] During clinical trial evaluation of intramuscular naltrexone suspension, metabolic or nutritional effects including dehydration and hypercholesterolemia were observed; however, the frequencies are unknown. In some individuals, the use of opiate antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of these changes is not fully understood.^[76] Abrupt withdrawal precipitated by administration of an opioid antagonist to an opioid-dependent patient may result in a withdrawal syndrome severe enough to require hospitalization, and in some cases management in the intensive care unit. Opioid withdrawal has been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. To prevent precipitation of withdrawal, patients should be opioid-free for a minimum of 7 to 10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. Precipitated opioid withdrawal has also been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids. Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. Studies of naltrexone in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid discontinuation-like symptom complex including, but not limited to, tearfulness, abdominal cramps, bone, muscle, or joint pain, nasal symptoms, and feeling restless. These symptoms may represent the unmasking of occult opioid use or it may represent symptoms attributable to naltrexone. Patients treated for alcohol dependence with naltrexone should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment. Because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period, prescribers should always be prepared to manage withdrawal symptomatically with non-opioid medications. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Withdrawal symptoms and death have been reported during the use of naltrexone in ultra rapid detoxification programs; the causes of death are not known. If rapid transition from agonist to antagonist therapy is considered necessary and appropriate by the healthcare provider, patients should be closely monitored in an appropriate medical setting where precipitated withdrawal can be managed.^[76]^[52]Phentermine HCl Central nervous system adverse reactions that have been reported in patients receiving phentermine include dizziness, dysphoria, euphoria, headache, insomnia, overstimulation, restlessness, and tremor. Psychosis at recommended doses may occur rarely in some patients.^[34]^[77]^[78]^[79] Primary pulmonary hypertension (PPH) and cardiac valvulopathy (regurgitant cardiac valvular disease) have been reported with phentermine. The initial symptom of PPH is usually dyspnea; other initial symptoms include: angina pectoris, syncope, or peripheral edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or peripheral edema. Other cardiovascular adverse effects that have been reported include hypertension, ischemic events, palpitations, and sinus tachycardia.^[34]^[77]^[78]^[79] Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.^[34]^[77]^[78]^[79] Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.^[34]^[77]^[78]^[79] Urticaria has been reported in patients receiving phentermine.^[34]^[77]^[78]^[79] Phentermine has not been systematically studied for its potential to produce dependence in obese patients treated with usual recommended dose ranges. Phentermine is related chemically and pharmacologically to the amphetamines, and these stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including this drug product as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with intense psychological dependence and severe social dysfunction.^[78]^[34]^[77]^[79] There are reports of patients who have increased the dosage of these drugs to many times than recommended. Physical dependence (physiological dependence) is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Limited data are available for phentermine. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal is required, appropriate medical monitoring is recommended.^[78]^[34]^[77]^[79] Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal.^[80]More data are needed to confirm the dependence potential of phentermine-containing obesity products. Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased. The maximum recommended dose should not be exceeded.^[34]^[77]^[78]^[79] Yohimbine HCl Yohimbine readily crosses the blood-brain barrier and can therefore produce central nervous system adverse reactions. The most common CNS adverse reactions include anxiety, antidiuresis, dizziness, flushing, headache, hypertension, increased motor activity, irritability, nervousness or restlessness, sinus tachycardia, and tremor. Although yohimbine is not administered intravenously, diaphoresis, nausea and vomiting have been reported following IV administration of yohimbine. Per the FDA (1993 out of print document), natural Yohimbe is a tree bark containing a variety of pharmacologically active chemicals; the major identified alkaloid in yohimbe is yohimbine. Yohimbe is marketed in a number of dietary supplements for body building and ‘enhanced male performance.’ Serious adverse effects, including renal failure (unspecified), seizures and death, have been reported to FDA with products containing yohimbe. Side effects that are well recognized may include central nervous system stimulation that causes anxiety attacks or agitation. At high doses, yohimbine is reported to inhibit monoamine oxidase (MAO). MAO inhibitors (MAOIs) can cause serious adverse effects (like severe hypertension) when taken concomitantly with tyramine-containing foods (e.g., liver, cheeses, red wine) or with over-the-counter (OTC) products containing phenylpropanolamine (PPA). Patients taking yohimbe should be warned to avoid these foods and PPA because of the increased likelihood of adverse effects.

Caffeine
Caffeine citrate is used for neonatal apnea so concerns for teratogenicity are not relevant when administered to infants, however, when 50 mg/kg of sustained-release pellets were administered to pregnant mice during the period of organogenesis, a low incidence of cleft palate and exencephaly have been noted in the fetuses.^[37] Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1 to 2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (more than 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking.^[40] There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.^[41]Caffeine citrate is used for neonatal apnea so concerns for teratogenicity are not relevant when administered to infants, however, when 50 mg/kg of sustained-release pellets were administered to pregnant mice during the period of organogenesis, a low incidence of cleft palate and exencephaly have been noted in the fetuses.^[37] Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1 to 2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (more than 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking.^[40] There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.^[41]

DHEA
DHEA should be considered a pregnancy category X drug, similar to other androgenic hormones. Studies of the role of endogenous fetal and maternal DHEA in pregnancy indicate that the ratio of DHEA or DHEAS to other hormones in the serum or placenta may influence the processes of fetal development, parturition, and labor. Endogenous DHEA and DHEAS appear to be important in the functional development of the adrenal cortex and other endocrine activities in the fetus; it is assumed that exogenous DHEA supplementation to a pregnant woman could potentially have deleterious effects on fetal development or viability. The androgenic effects of DHEA could potentially result in masculinization of a female fetus. No controlled trials of DHEA in primate or human gestation exist. Do not administer DHEA to a pregnant woman.

Inositol
Given its use in the treatment of polycystic ovarian syndrome and gestational diabetes, myo-inositol may be considered relatively safe during pregnancy. In a meta-analysis of randomized controlled trials, 2 g of myo-inositol administered orally twice daily was reported to be safe during pregnancy.^[61] However, high concentrations of D-chiro-inositol negatively affect the quality of oocytes.^[62] Therefore, D-chiro-inositol may not be used by women seeking to get pregnant. Effects of other inositol isomers are not well characterized.

Methionine
Excess methionine in the maternal diet may be detrimental to fetal development. This is because additional glycine and serine may be required to catabolize the excess methionine, inadvertently resulting in the deficiency of these amino acids. Excess methionine may also be metabolized to homocysteine. Elevated plasma homocysteine levels are associated with preeclampsia, spontaneous abortion, placental rupture, and miscarriage.^[63]

Methylcobalamin
Parenteral methylcobalamin is classified as pregnancy category C. Adequate studies in humans have not been conducted; however, no maternal or fetal complications have been associated with doses that are recommended during pregnancy, and appropriate treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Conversely, pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of vegetarian mothers whose diets contain no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy. The usual daily recommended amounts of methylcobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy (see Dosage).

Naltrexone HCl
Naltrexone is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. In some individuals, opiate antagonists have been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones, although the clinical significance is not known. In rat studies, there was an increase in early fetal loss and pseudopregnancy, and a decrease in pregnancy rate. There was no evidence of teratogenicity; however, rats do not form a significant amount of the major human metabolite, 6-B-naltrexol; therefore, the potential reproductive toxicity of 6-B-naltrexol in rats is not known. There were small increases in the numbers of testicular mesotheliomas in male rats and vascular tumors in female rats during a 2-year carcinogenicity study; however, no evidence of carcinogenicity was observed in mice.^[52]When considering the use of naltrexone during pregnancy for relapse prevention in alcohol or opiate dependence, the risks to the fetus of continued substance abuse by the mother should be weighed against the potential adverse effects from fetal exposure to naltrexone. Drug therapy should be considered only if supportive substance abuse prevention measures are ineffective. The effects of naltrexone during labor and delivery are unknown.

Phentermine HCl
Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy.^[57]^[57] Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.^[57]

Yohimbine HCl
In general, yohimbine is not for use in females and must certainly not be used during pregnancy.^[60] A FDA pregnancy risk category has not been assigned to this drug. However, given yohimbine’s similarity to other rauwolfia alkaloids, it is suggested that yohimbine most closely corresponds to an FDA pregnancy risk category D (see Reserpine monograph). There is no known indication at this time for the use of yohimbine in pregnancy which would justify the potential risks to the fetus.

Caffeine
Although the American Academy of Pediatrics has considered the use of mild to moderate use of caffeinated beverages to be compatible with lactation, mothers who are breast-feeding should limit their intake of caffeinated beverages if possible.^[42] Caffeine-containing drug-products should be used cautiously during lactation due to their high caffeine contents. Mothers who are breast-feeding infants who have been prescribed caffeine for apnea should generally avoid additional caffeine use.^[37] The CYPP450 hepatic metabolism of caffeine is inhibited in infants who are breastfed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants.^[43] Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk: plasma ratios of 0.5 to 0.7 reported.^[44]^[45] Although only small amounts are secreted in breast milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (more than 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding.^[46] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

DHEA
DHEA is a hormone and should not be supplemented in a lactating woman who is breast-feeding her infant. Most hormones are excreted in breast milk. Like other androgenic hormones, it is possible that DHEA could inhibit lactation. It is unknown what effect DHEA would have on the breast-feeding infant.

Methylcobalamin
Methylcobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of methylcobalamin by breast-feeding infants. Adequate maternal intake is important for both the mother and infant during nursing, and maternal requirements for vitamin B12 increase during lactation. According to the manufacturer, the usual daily recommended amounts of methylcobalamin, vitamin B12 for lactating women should be taken maternally during breast-feeding (see Dosage). The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Naltrexone HCl
According to the manufacturer, naltrexone and its metabolite are excreted into human milk, and a decision should be made to discontinue breastfeeding or discontinue naltrexone, taking into consideration the importance of the drug to the mother. Animal studies have shown the potential for tumorigenicity.^[52] No reports describing the use of naltrexone during breastfeeding are available. According to the American Academy of Pediatrics (AAP), the maternal ingestion of large amounts of ethanol or opiates can cause adverse effects in the nursing infant.^[55] If supportive substance abuse prevention measures are ineffective, the risks to the nursing infant of continued ethanol or opiate abuse by the mother should be weighed against the potential for adverse drugs effects when determining whether to use naltrexone as a substance abuse-deterrent during breast-feeding.

Phentermine HCl
Phentermine is contraindicated during breastfeeding.^[57] It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breast-feeding while taking phentermine is not recommended.^[59]^[58]

Yohimbine HCl
Generally, this drug is not for use in females ^[60], and therefore should not be used during breastfeeding. Many of the rauwolfia alkaloids are excreted in human breast milk. A decision should be made to discontinue the medication or discontinue breastfeeding.

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Helzlsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-1930.
Jones JA, Nguyen A, Straub M, et al. Use of DHEA in a patient with advanced prostate cancer: a case report and a review. Urology 1997;50:784-788.
Singh, P. (2018, October 17). Methionine drug information – indications, dosage, side effects and precautions. Medindia. Retrieved June 29, 2022, from https://www.medindia.net/doctors/drug_information/methionine.htm– LinkOpens in New Tab
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Hendricks EJ, Srisurapanont M, Schmidt SL, et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond). 2014;38:292-298.

NAD+ Nasal Spray 300 mg/mL 15 mL

NAD+ Nasal Spray (15 mL)

300 MG/ML

All of the body’s cells contain the universal coenzyme, signaling molecule, and electron transporter Nicotinamide Adenine Dinucleotide (NAD+) which is necessary for cell viability and function.^[1]^[2] NAD+ and its reduced (NADH) and phosphorylated (NADP+ and NADPH) forms are both important.^[1]^[2] All processes of cellular respiration, including glycolysis in the cytoplasm, the Krebs cycle, and the electron transport chain in the mitochondria, depend on NAD+ and its redox partner NADH to produce energy (ATP).

In anabolic events, such as the manufacture of cholesterol and nucleic acids, the elongation of fatty acids, and the regeneration of glutathione, a vital antioxidant in the body, NADP+ and NADPH are frequently involved.^[3] In various cellular processes, NAD+-dependent/-consuming enzymes modify proteins post-translationally using NAD+ and its other forms as substrates.^[1]^[2] NAD+ also acts as a precursor for cyclic ADP ribose, a secondary messenger molecule crucial for calcium transmission.^[4]

NAD+ can be produced in the body by biosynthetic intermediates such nicotinamide mononucleotide and nicotinamide riboside as well as by the amino acid tryptophan or the vitamin precursors nicotinic acid and nicotinamide, generally known as vitamin B3 or niacin.^[2]^[3] NAD+ is continuously recycled within cells as it is interconverted to and from its various forms through salvage pathways.^[3] Mammalian cells may be able to take up extracellular NAD+, according to studies on cell culture.^[5]

Newborns have the greatest NAD+ levels, which gradually decrease as they get older chronologically.^[6] They are around half of what they are in younger persons after age 50. In model organisms, the reason why NAD+ levels fall with aging has been looked at.^[6] The question of why NAD+ levels decline with age has been investigated in model organisms.^[7]^[8] NAD+ and NADH are continuously recycled during redox reactions, but during other metabolic activities, they are absorbed by NAD+-dependent enzymes and may subsequently become depleted over time, increasing the risk of DNA damage, age-related illnesses, and mitochondrial malfunction.^[2]^[6] Studies of NAD+ depletion and the accompanying oxidative damage and stress result in support theories of aging and senescence that emphasize the age-related reduction in mitochondrial health and function.^[1]^[2]

Increasing levels of CD38, a membrane-bound NADase that destroys both NAD+ and its precursor nicotinamide mononucleotide, are thought to be the cause of the age-related decline in NAD+ levels, according to a 2016 study in mice, which exhibit age-related declines in NAD+ levels similar to those seen in humans.^[7] The study also demonstrated that older persons (mean age, 61 years) have higher levels of CD38 gene expression than younger adults (mean age, 34 years). ^[7] However, other mouse investigations have shown that oxidative stress and inflammation brought on by aging decrease NAD+ production. ^[8]Therefore, it is likely that a number of processes work together to cause the drop in NAD+ with aging in humans.

When it was found that foods containing NAD+ precursors, particularly vitamin B3, may treat the fatal illness pellagra, which is characterized by diarrhea, dermatitis, dementia, and death, the clinical significance of maintaining NAD+ levels was established in the early 1900s.^[9] Notably, this side effect has not been noticed with NAD+ injection, in contrast to vitamin B3 (niacin) intake, which results in a flushing of the skin.^[10] Low NAD+ levels have recently been connected with a number of age-related disorders and illnesses that are linked to increased oxidative/free radical damage, including diabetes, heart disease, vascular dysfunction, ischemic brain injury, Alzheimer’s disease, and vision loss.^[8]^[12]^[11]^[13]^[14]^[15]^[16]^[17]

A 1961 report by Paul O’Hollaren, MD, of Shadel Hospital in Seattle, Washington, led to a study that led to the widespread use of IV infusions of NAD+ for the treatment of addiction.^[18]^[19]^[20] For the prevention, relief, or treatment of acute and chronic symptoms of addiction to a variety of substances, including alcohol, heroin, opium extract, morphine, dihydromorphine, meperidine, codeine, cocaine, amphetamines, barbiturates, and tranquilizers, Dr. O’Hollaren described the successful use of IV-infused NAD+ in over 100 cases.^[18] However, no clinical studies have examined the security and effectiveness of NAD+ treatment for addiction as of yet.

NAD+-replacement treatment may help cure addiction while promoting mitochondrial health and homeostasis, genomic stability, neuroprotection, healthy aging, and lifespan.^[1]^[2]^[3]^[20]Although clinical trials evaluating the efficacy and safety of NAD+-replacement therapy or augmentation in the context of human disease and aging have recently been completed, many more are still in progress. However, clinical trials evaluating these effects in humans treated with NAD+ injection have not yet been published.

For possible health benefits, such as promoting healthy aging and treating age-related disorders, metabolic and mitochondrial diseases, and addiction, the precise processes of NAD+ restoration or augmentation are unknown.^[1]^[2]^[3]^[20]

NAD+ supplementation could prevent mitochondrial deterioration and preserve metabolic function/energy (ATP) generation by balancing age-related degradation of NAD+ and its precursor nicotinamide mononucleotide via NADases, particularly CD38.^[7] The replacement of NAD+, however, appears to support a number of other metabolic pathways via NAD+-dependent enzymes, according to research in animal models and humans (and/or samples and cell lines).^[1]^[2]^[3]^[20]

Several prominent NAD+-dependent enzymes exist. The PARP 1–17 family of poly-ADP ribose polymerases regulate DNA repair and nuclear stability.^[1]^[3] In Ca2+ signaling and intercellular immunological communication, NADases CD38 and CD157 produce nicotinic acid adenine dinucleotides, ADP-ribose, and cADP-ribose.^[1]^[3] A family of histone deacetylases known as sirtuins (Sirt 1-7) controls a number of proteins involved in cellular metabolism, stress responses, circadian rhythms, and endocrine functions. Sirts have also been linked to longevity in model organisms and protective effects in cardiac and neuronal models.^[1]^[3]A recently identified NAD+ hydrolase, Sterile Alpha and Toll/Interleukin-1 Receptor motif-containing 1 (SARM1), is implicated in the aging and regeneration of neurons.^[21]^[22]

Studies of progeroid (premature aging) syndromes, which mimic the clinical and molecular characteristics of aging, have provided some insight into the mechanism of action of NAD+ replenishment. Werner syndrome (WS), which is distinguished by severe metabolic dysfunction, dyslipidemia, early atherosclerosis, and insulin resistance diabetes, is thought to most closely mimic normal aging.^[23] The Werner (WRN) DNA helicase gene, which controls the transcription of the crucial NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1, is the source of WS.^[25]^[24]

According to a study published in 2019, disruption of mitochondrial homeostasis caused by NAD+ depletion is a significant contributor to the metabolic dysfunction in WS.^[25] NAD+ deficient cells from WS patient samples and WS animal models displayed poor mitophagy (selective degradation of defective mitochondria).^[25] In human cells with mutant WRN, NAD+ repletion restored normal mitophagy, improved fat metabolism, decreased mitochondrial oxidative stress, and enhanced mitochondrial quality.^[25] With increasing numbers of proliferating stem cells in the germ line, NAD+ repletion greatly prolonged lifespan and postponed the onset of accelerated aging in animal models.^[25] The results were reproduced when NAD+ was replaced by giving several NAD+ precursor molecules, demonstrating that the positive effects are caused by NAD+ replacement.^[25]

Murine cells overexpressing the NADase CD38 consumed less oxygen, had higher lactate levels, and had abnormal mitochondria, including traits like missing or enlarged cristae, which lends more proof of NAD+’s role in promoting mitochondrial and metabolic health.^[7]These cells’ isolated mitochondria displayed a significant depletion of NAD+ and NADH in comparison to controls. NAD+ levels, mitochondrial respiratory rates, and metabolic processes were all preserved with age in mice lacking CD38.^[7]

There were no additional known contraindications or precautions for NAD+ injection at the time of writing. Users of this product should not have a known allergy to NAD+ injection.

Injection of NAD+ seems to be well tolerated and safe.^[10] Constipation,^[18] headache, shortness of breath, increased plasma bilirubin, decreased levels of gamma glutamyl transferase, lactate dehydrogenase, and aspartate aminotransferase are only a few of the possible adverse responses and side effects of NAD+ injection.^[10]

Preliminary information on side effects and safety was supplied by case studies on the use of NAD+ for the treatment of drug addiction. ^[18]^[19] According to a 1961 study, patients with addiction who got NAD+ at a moderate IV drip rate (no more than 35 drops per minute) reported “no distress” but those who received it at a quicker drip rate complained of headache and shortness of breath.^[18] In this study, the dosage was 500–1000 mg per day for 4 days, then two injections every week for a month, and then one injection every two months as a maintenance dose. One of the two patients who had therapy reported experiencing constipation.^[18]

A 2019 study used liver function tests (serum, total bilirubin, alkaline phosphatase, alanine aminotransferase, gamma-glutamyl transferase, lactate dehydrogenase, and aspartate aminotransferase) and clinical observation of any adverse events to evaluate the safety of IV infusion of NAD+ in a cohort of healthy male participants (n=11; NAD+ n = 8 and Control Neither the NAD+ cohort nor the placebo (saline) cohort experienced any negative side effects throughout the 6 hour infusion.^[10] At 8 hours following the start of the NAD+ infusion, it was shown that the NAD+ group had significant declines in the liver function enzymes gamma glutamyl transferase, lactate dehydrogenase, and aspartate aminotransferase as well as a large increase in plasma bilirubin.^[10] The modifications, however, were not regarded as clinically important.^[10] Because of the limited sample sizes, notably for the control group, which are acknowledged by the authors, these results should be evaluated with care.^[10]

Pregnant women have not had the safety of NAD+ injections assessed. Pregnant women should stay away from NAD+ injection due to the lack of safety information.

Children or nursing mothers have not been studied for the safety of NAD+ injection. Children and nursing mothers should refrain from receiving NAD+ injections due to the lack of safety information.

Pregnant women have not had the safety of NAD+ injections assessed. Pregnant women should stay away from NAD+ injection due to the lack of safety information.

Children or nursing mothers have not been studied for the safety of NAD+ injection. Children and nursing mothers should refrain from receiving NAD+ injections due to the lack of safety information.

Store this medication in a refrigerator between 36°F to 46°F (2°C – 8°C). Do not freeze. Protect from light. Keep all medicine out of the reach of children. Throw away any medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Cantó C, Menzies KJ, Auwerx J. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015;22(1):31-53. doi:10.1016/j.cmet.2015.05.023
Johnson S, Imai SI. NAD+ biosynthesis, aging, and disease. F1000Research. 2018;7. doi:10.12688/f1000research.12120.1
Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12-19. doi:10.1016/j.tibs.2006.11.006
Guse AH. The Ca2+-Mobilizing Second Messenger Cyclic ADP-Ribose. In: Calcium: The Molecular Basis of Calcium Action in Biology and Medicine. Springer Netherlands; 2000:109-128. doi:10.1007/978-94-010-0688-0_7
Billington RA, Travelli C, Ercolano E, et al. Characterization of NAD uptake in mammalian cells. J Biol Chem. 2008;283(10):6367-6374. doi:10.1074/jbc.M706204200
Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue. Polymenis M, ed. PLoS One. 2012;7(7):e42357. doi:10.1371/journal.pone.0042357
Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016;23(6):1127-1139. doi:10.1016/j.cmet.2016.05.006
Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528-536. doi:10.1016/j.cmet.2011.08.014
Goldberger J. Public Health Reports, June 26, 1914. The etiology of pellagra. The significance of certain epidemiological observations with respect thereto. Public Health Rep. 1975;90(4):373-375. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1437745/.– LinkOpens in New Tab Accessed October 11, 2020.
Grant R, Berg J, Mestayer R, et al. A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Front Aging Neurosci. 2019;11. doi:10.3389/fnagi.2019.00257
Pillai JB, Isbatan A, Imai SI, Gupta MP. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity. J Biol Chem. 2005;280(52):43121-43130. doi:10.1074/jbc.M506162200
Wu J, Jin Z, Zheng H, Yan LJ. Sources and implications of NADH/NAD+ redox imbalance in diabetes and its complications. Diabetes, Metab Syndr Obes Targets Ther. 2016;9:145-153. doi:10.2147/DMSO.S106087
Csiszar A, Tarantini S, Yabluchanskiy A, et al. Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Am J Physiol – Hear Circ Physiol. 2019;316(6):H1253-H1266. doi:10.1152/ajpheart.00039.2019
Ying W, Xiong Z-G. Oxidative Stress and NAD+ in Ischemic Brain Injury: Current Advances and Future Perspectives. Curr Med Chem. 2010;17(20):2152-2158. doi:10.2174/092986710791299911
Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci. 2007;64(17):2202-2210. doi:10.1007/s00018-007-7218-4
Abeti R, Duchen MR. Activation of PARP by oxidative stress induced by β-amyloid: Implications for Alzheimer’s disease. Neurochem Res. 2012;37(11):2589-2596. doi:10.1007/s11064-012-0895-x
Lin JB, Apte RS. NAD + and sirtuins in retinal degenerative diseases: A look at future therapies. Prog Retin Eye Res. 2018;67:118-129. doi:10.1016/j.preteyeres.2018.06.002
O’Hollaren P. Diphosphopyridine nucleotide in the prevention, diagnosis and treatment of drug addiction. West J Surg Obstet Gynecol. May 1961.
Mestayer PN. Addiction: The Dark Night of the Soul/ Nad+: The Light of Hope – Paula Norris Mestayer – Google Books. Balboa Press; 2019. https://books.google.com/books?id=t7qEDwAAQBAJ&lr=&source=gbs_navlinks_s.– LinkOpens in New Tab Accessed October 11, 2020.
Braidy N, Villalva MD, van Eeden S. Sobriety and satiety: Is NAD+ the answer? Antioxidants. 2020;9(5). doi:10.3390/antiox9050425
Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science (80- ). 2015;348(6233):453-457. doi:10.1126/science.1258366
Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017;93(6):1334-1343.e5. doi:10.1016/j.neuron.2017.02.022
Oshima J, Sidorova JM, Jr. Monnat RJ. Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 2017;33:105-114.
Fang EF, Hou Y, Lautrup S, et al. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019;10(1):1-18. doi:10.1038/s41467-019-13172-
Yu CE, Oshima J, Fu YH, et al. Positional cloning of the Werner’s syndrome gene. Science (80- ). 1996;272(5259):258-262. doi:10.1126/science.272.5259.258

Sermorelin Acetate Injection (Lyo) 9 mg

Sermorelin Acetate Injection (Lyo) (Each) 9 MG

Sermorelin is the structurally truncated analog of Growth Hormone Releasing Hormone (GHRH). It consists of the first 29 amino acids of the naturally occurring neurohormone that is produced in the hypothalamus.^[1] Sermorelin is the most widely used member of the GHRH analogue drug class. It can significantly promote the synthesis and release of growth hormone (GH) from cells in the pituitary gland, improving the serum concentrations of GH and subsequently insulin-like growth factor 1 (IGF-1) in animals and humans.^[2]^[3] It is able to influence the concert of hormonal signals that affect GH secretion from the anterior pituitary including GHRH, somatostatin, and insulin like growth factor (IGF) and others. The positive and negative opposing regulation of growth hormone by GHRH and somatostatin, respectively, creates a rhythmic-circadian pattern of GH secretion.^[4] Thus, modification of both pulse amplitude and frequency of GH secretion results from Sermorelin administration.^[5] After sermorelin stimulates the release of GH from the pituitary gland, it increases synthesis of IGF-1 in the liver and peripheral tissues.^[5]

Sermorelin acts on the growth hormone releasing hormone receptor (GHRHr) in the pituitary to regulate cellular activities. GHRHr is the natural receptor for the endogenous hormone, GHRH, and for sermorelin. This receptor regulates growth hormone release directly by stimulation and indirectly by a feedback relationships with somatostatin.^[6]

Sermorelin is readily degraded after reaching the bloodstream, having a biological half-life of approximately 10-20 min.^[7] Due to the biological half-life and bioavailability of Sermorelin, administration for growth in childhood GHD must occur periodically several times a day as subcutaneous-injections.^[8] However, single daily dosing is sufficient to treat most cases of adult-onset GH insufficiency. Three (3) mcg/kg subcutaneous-injections of Sermorelin have been reported to simulate a naturally occurring GHRH mediated GH release responses.^[9]

In addition to increasing production and secretion GHRH also affects sleep patterns by increasing the amount of slow wave sleep (SWS) while augmenting sleep-related GH secretion and reducing cortisol secretion.^[10]

To exert all its beneficial effects, Sermorelin requires a functioning pituitary and a host of peripheral tissues.^[11]^[12] This is due to the reliance on endogenous receptors controlling hormone secreting glands and tissues. More precisely, functioning growth hormone releasing hormone receptors (GHRHr) are required on somatotrophs in a functioning anterior pituitary.^[11]

Sermorelin essentially mimics the hypothalamic peptide, GHRH. Sermorelin acts directly on the pituitary stimulating the somatotroph cells ability to produce and secrete GH.^[13]Sermorelin increases proliferation of somatotroph cells during development.^[13] With the increase of serum GH, downstream effects occur. A notable hormone that is commonly used as a surrogate for growth hormone therapy, insulin like growth factor 1 (IGF-1), is known to increase with the administration of Sermorelin. IGF-I negatively regulates GHRH-mediated GH secretion.^[14]

Sermorelin is able to influence the concert of hormonal signaling that effects the GH axis. GH secretion from the anterior pituitary is regulated by GHRH, somatostatin, and GH secretagogues. The positive and negative opposing regulation of growth hormone by GHRH and somatostatin creates a rhythmic-circadian GH secretion. GH asked by signaling target cells, most notably increasing the synthesis of IGF-1 in the liver and peripheral tissues.^[13]

Sermorelin acts on the growth GHRHr in the pituitary to regulate cellular actives. GHRHr is the natural receptor for the endogenous hormone GHRH, a signaling hormone produced by the hypothalamus. This receptor among many other functions, controls growth hormone release, mainly by inhibition of somatostatin activity.^[15]

Tell your doctor of all prescription and nonprescription medication you may use, especially: corticosteroids and thyroid medications. This drug may affect the results of certain lab tests (e.g., inorganic phosphorus, alkaline phosphatase). Make sure laboratory personnel and your doctors know you use this drug. Do not start or stop any medicine without approval from your healthcare provider. Hypothyroidism: Untreated hypothyroidism can jeopardize the response to Sermorelin. Thyroid hormone determinations should be performed before the initiation and during therapy. Thyroid hormone replacement therapy should be initiated when indicated. Intracranial lesions: Patients with GH deficiency secondary to an intracranial lesion were not studied in clinical trials; Sermorelin treatment is not recommended in such patients. Obesity, hyperglycemia or hyperlipidemia: Subnormal GH responses have been seen in obesity and hyperglycemia, and in patients with elevated plasma fatty acids.

Call your doctor for medical advice if pain/swelling/redness occurs at the injection site (occurring in approximately 16% of patients). Other possible, but less common side effects of rhGH (not Sermorelin) are upper respiratory conditions, nerve sensitivity, insomnia, depression, nausea, hypothyroidism chest pain, gynecomastia, headache, flushing, dysphagia, dizziness, hyperactivity, somnolence, urticaria and sore bones. Call your health care provider immediately if you are experiencing trouble swallowing, vomiting, and tightness in the chest. Antibody formation to Sermorelin has been reported after chronic subcutaneous administration of large doses but their clinical significance is unknown. Antibodies do not appear to affect growth hormone release nor appear to be related to a specific adverse drug reaction profile. No generalized allergic reactions have been reported. A temporary allergic reaction described by severe redness, swelling and urticaria at the injection sites has been reported in one patient who developed antibodies. Additionally, its use may reduce insulin sensitivity, thereby raising blood sugar to levels which could be harmful to diabetes sufferers. It may also decrease triiodothyronine (T3) levels due to its tendency to reduce the bodily levels of sodium, potassium, and phosphorous.

Exercise caution during breastfeeding; it is not known if this drug is excreted in breast milk.

Store dry powder at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Once reconstituted keep this medicine in a refrigerator between 36°F to 46°F (2°C to 8°C). Keep all medicine out of the reach of children. Throw away any unused medicine after the beyonbeyond-use. Do not flush unused medications or pour down a sink or drain.

Wehrenberg WB, Ling N. 1983. “In vivo biological potency of rat and human growth hormone-releasing factor and fragments of human growth hormone-releasing factor”. Biochem Biophys Res Commun. 115 (2): 525–530.
Chen, R.G., et al., 1993. A comparative study of growth hormone (GH) and GH-releasing hormone (1-29)-NH2 for stimulation of growth in children with GH deficiency. Acta Paediatr Suppl, 388: p. 32-5; discussion 36.
Perez-Romero, A., et al., 1999. Effect of long-term GHRH and somatostatin administration on GH release and body weight in prepubertal female rats. J Physiol Biochem, 55(4): p. 315-24.
Tannenbaum, G.S. and Ling N. 1984. The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology, 115(5): p. 1952-7.
Tauber, M.T., et al., 1993. Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1-29)-NH2 in children with GH deficiency. Acta Paediatr Suppl, 388: p. 28-30; discussion 31.
Howard AD, Feighner SD, Cully DF et al. 1996, A Receptor in Pituitary and Hypothalamus That Functions in GH release. Science. Vol. 273, Issue 5277, pp. 974-977
Esposito, P., et al., 2003. PEGylation of growth hormone-releasing hormone (GRF) analogues. Adv Drug Deliv Rev, 55(10): p. 1279-91.
Kirk JM, Trainer PJ, Majrowski WH, Murphy J, Savage MO, Besser GM. 1994. Treatment with GHRH(1-29)NH2 in children with idiopathic short stature induces a sustained increase in growth velocity. Clin Endocrinol (Oxf). 41(4):487-93.
Aitman, T.J., et al., 1989. Bioactivity of growth hormone releasing hormone (1-29) analogues after SC injection in man. Peptides, 10(1): p. 1-4.
Steiger, A., et al., 1994. Growth hormone-releasing hormone (GHRH)-induced effects on sleep EEG and nocturnal secretion of growth hormone, cortisol and ACTH in patients with major depression. J Psychiatr Res, 28(3): p. 225-38.
Mayo, K.E., et al., 1995. Growth hormone-releasing hormone: synthesis and signaling. Recent Prog Horm Res, 50: p. 35-73.
Ceda, G.P., et al. 1987. The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology, 120(4): p. 1658-62.
Mayo, K.E., et al., Growth hormone-releasing hormone: synthesis and signaling. Recent Prog Horm Res, 1995. 50: p. 35-73.
Ceda, G.P., et al., The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology, 1987. 120(4): p. 1658-62.
Tannenbaum, G.S. and N. Ling, The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology, 1984. 115(5): p. 1952-7.

Tirzepatide / Niacinamide Injection 8/2 mg/mL 2.5 mL Vial

Tirzepatide / Niacinamide Injection (2.5 mL) 8/2 MG/ML

Tirzepatide is an FDA-approved medicine used to treat type 2 diabetes mellitus and may be used off-label for the treatment of obesity due to its effective weight loss qualities. It functions as a dual GLP-1 and GIP agonist. Similar to other GLP-1 medicines, it is currently used as a second-line diabetic treatment and administered as a once-weekly subcutaneous injection.^[1]^[2]

Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. It has not been tested on individuals with pancreatitis and is not approved to treat type-1 diabetes mellitus. As a GIP and GLP-1 receptor agonist, it is implemented as a second-line defense against type 2 diabetes for glycemic control and significantly reduces body weight.^[1]^[3]

According to recent clinical studies, tirzepatide decreases hemoglobin A1C levels more effectively than a placebo. In comparison to -0.86% with placebo, the SURPASS-5 clinical trial revealed a -2.11% drop in hemoglobin A1C levels at 5mg per week dose. Hemoglobin A1C decreased by -2.34% when tirzepatide was taken at the maximum dose of 15 mg per week. This was proven during a 40-week period. With a tirzepatide dosage of 5 mg, a weight loss of 5.4 kg was observed, while a weight loss of 10.5 kg was observed with a dosage of 15 mg. A popular GLP-1 drug used for weight loss therapy is similar to this dose-dependent link with weight loss.^[1]^[4]

Tirzepatide has been demonstrated to function similarly to GLP-1 medicines but more effectively. Given its ability to help people lose weight and absence of liver toxicity, it could help people with non-alcoholic fatty liver disease (NAFLD) in a secondary way.^[1]^[5]

Tirzepatide is a synthetic peptide that acts as an agonist for both the glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors. It is a gastric inhibitory polypeptide mimic and has 39 amino acids. Functionally, it causes the pancreas to release more insulin, which lowers blood sugar levels. Adiponectin concentrations are similarly raised by tirzepatide. Its dual agonism ability decreases hunger and significantly lowers hyperglycemia compared to GLP-1 agonist drugs used alone.^[1]^[6]

Tirzepatide causes thyroid C-cell tumors in rats. It is unknown whether Tirzepatide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.

Tirzepatide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors.

Patients with Hepatic Impairment: No dosage adjustment of tirzepatide is suggested for patients with hepatic impairment.

Patients with Renal Impairment: Tirzepatide is associated with gastrointestinal ADRs, including nausea, vomiting, and diarrhea leading to dehydration, which can cause acute kidney injury. Use with caution in patients prone to dehydration.

In vitro studies have shown low potential for tirzepatide to inhibit or induce CYP enzymes, and to inhibit drug transporters. Tirzepatide delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications.

The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses.

Following a first dose of tirzepatide 5 mg, acetaminophen maximum concentration (Cmax) was reduced by 50%, and the median peak plasma concentration (tmax) occurred 1 hour later. After coadministration at week 4, there was no meaningful impact on acetaminophen Cmax and tmax. Overall acetaminophen exposure (AUC0-24hr) was not influenced.

Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean Cmax of ethinyl estradiol, norgestimate, and norelgestromin was reduced by 59%,66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in tmax of 2.5 to 4.5 hours was observed.

Based on available data, most users do not experience significant adverse drug reactions. The primary adverse effects reported are gastrointestinal, but other side effects have also been infrequently reported. Decreased appetite is frequently reported, though this is a potential contributory etiology of intentional weight loss. Below are the adverse drug reactions reported by System Organ Class (SOC).^[1]

Gastrointestinal: Many people report having lowered appetite. Up to 10% of patients may experience nausea and diarrhea, and there may also be sporadic reports of vomiting and acid reflux. Additionally, some individuals have reported having constipation.^[1]^[2] Other oral drugs have a harder time being absorbed when stomach emptying is delayed. This is especially important for people who already have delayed stomach emptying because it can make their symptoms worse. It is significant to highlight that oral hormonal contraceptives no longer work as well as they once did, so patients should be urged to use non-oral contraceptive methods instead. ^[1]^[2]

Cardiovascular: If discovered, sinus tachycardia may be suppressed by taking other medications concurrently.^[2]

Renal: Acute renal injury has been documented in rare cases, most likely as a result of dehydration from gastrointestinal losses. These can happen to both healthy people and those who already have chronic renal illness. It is probably best to keep an eye out for indicators of dehydration to avoid kidney damage.

Dermatologic: Rarely, reports of hypersensitivity reactions at the injection site have been made. The prevalence is not more than what patients who use GLP-1 agonists report. Such occurrences should be handled with a doctor, who may also recommend stopping the prescription.

Pancreatitis: Acute pancreatitis is known to be a risk factor for GLP-1 drugs. Tirzepatide has a comparable level of risk as GLP-1 agonist drugs. If a patient receiving tirzepatide therapy experiences significant abdominal pain, they should be urged to visit their local emergency room for treatment. Some patients may also experience asymptomatic elevations of the enzymes lipase and amylase.^[8]

Hepatobiliary: There have been reports of cholelithiasis and cholecystitis occurring in patients on tirzepatide therapy.^[5]

Ocular: Patients with preexisting diabetic retinopathy should be advised that those symptoms may temporarily worsen if their glycemic control quickly improves. Any vision changes while using tirzepatide(GLP-1 receptor agonist) should be immediately discussed with a physician.^[9]

Endocrine: There is a small risk of hypoglycemia and dose dependent. This risk is more significant for those on insulin therapy and/or those utilizing sulfonylureas. Patients should be advised on the potential symptoms of hypoglycemia.^[10]

The amount of information on tirzepatide use during pregnancy is insufficient to evaluate the drug’s potential relation to congenital problems and poor maternal or fetal outcomes. An increased risk to the mother and fetus is linked to poorly managed pregnancy diabetes. Additionally, increased rates of skeletal, visceral, and exterior abnormalities have been noted in research on animal reproduction. Therefore, tirzepatide exposure during pregnancy can pose dangers to the fetus.^[1]

As a result, tirzepatide should only be used during pregnancy if the benefit outweighs the danger to the fetus. Tirozepatide should only be provided to women of childbearing age after being fully evaluated for possible teratogenic effects. Before recommending tirzepatide, doctors should also talk about starting a contraceptive regimen. Additionally, while using tirzepatide medication, the effectiveness of oral hormonal contraception decreases.^[1]
For at least four weeks following the start of tirzepatide therapy, barrier contraception should be used or switching to a non-oral method of contraception may need shared decision-making.^[1]

There is no information on tirzepatide’s presence in human or animal milk or how it may affect a nursing infant. Therefore, physicians should take into account breastfeeding’s positive effects on growth and health, the mother’s clinical need for tirzepatide, and any potential side effects of tirzepatide on the breastfed child.

Tirzepatide is a large molecule with a high molecular weight. So the concentration of milk is accordingly less and probably destroyed in the infant’s digestive system and absorption is unlikely. Tirozepatide should therefore be used with caution during nursing, especially in newborn or preterm infants, until further clinical data are available.^[1]^[7]

Upon receipt of medication, immediately store between 35°F to 46°F (2°C – 8°C). Keep all medicines out of the reach of children. Throw away any unused medicine within 28 days of puncture or the BUD, whichever comes first. Do not flush unused medications or pour them down a sink or drain.

Farzam K, Patel P. Tirzepatide. [Updated 2023 May 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585056/– LinkOpens in New Tab
Tirzepatide for type 2 diabetes.Med Lett Drugs Ther.2022 Jul 11;64(1654):105-107. https://pubmed.ncbi.nlm.nih.gov/35802842– LinkOpens in New Tab
Collins L, Costello RA. StatPearls [Internet].StatPearls Publishing; Treasure Island (FL): Jan 13, 2023. Glucagon-like Peptide-1 Receptor Agonists. https://pubmed.ncbi.nlm.nih.gov/31855395– LinkOpens in New Tab
Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022 Feb 08;327(6):534-545. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826179/– LinkOpens in New Tab
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jun 20, 2022. Tirzepatide.
Sun B, Willard FS, Feng D, Alsina-Fernandez J, Chen Q, Vieth M, Ho JD, Showalter AD, Stutsman C, Ding L, Suter TM, Dunbar JD, Carpenter JW, Mohammed FA, Aihara E, Brown RA, Bueno AB, Emmerson PJ, Moyers JS, Kobilka TS, Coghlan MP, Kobilka BK, Sloop KW. Structural determinants of dual incretin receptor agonism by tirzepatide. Proc Natl Acad Sci U S A. 2022 Mar 29;119(13):e2116506119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9060465/– LinkOpens in New Tab
Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Jun 20, 2022. Tirzepatide. https://pubmed.ncbi.nlm.nih.gov/35759552– LinkOpens in New Tab
Trujillo J. Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes. J Clin Pharm Ther. 2020 Sep;45 Suppl 1(Suppl 1):43-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540535/– LinkOpens in New Tab
Bethel MA, Diaz R, Castellana N, Bhattacharya I, Gerstein HC, Lakshmanan MC. HbA1c Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression. Diabetes Care. 2021 Jan;44(1):290-296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783944/– LinkOpens in New Tab
Chavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review. Molecules. 2022 Jul 05;27(13) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268041/

NAD+ Injection

NAD+ Injection (Lyo) (Each)

1,000 MG, 500 MG

Nicotinamide Adenine Dinucleotide (NAD+) is a prevalent cellular electron transporter, coenzyme, and signaling molecule found in all cells of the body and is vital for cell function and viability.^[1]^[2] Its reduced (NADH) and phosphorylated forms (NADP+ and NADPH) are as important as NAD+.^[1]^[2] Each step of cellular respiration—glycolysis in the cytoplasm, the Krebs cycle, and the electron transport chain in the mitochondria—requires the presence of NAD+ and NADH, their redox partner.

The manufacture of cholesterol and nucleic acids, elongation of fatty acids, and regeneration of glutathione, a vital antioxidant in the body, are just a few anabolic processes that frequently require NADP+ and NADPH.^[3] NAD+-dependent/-consuming enzymes modify proteins post-translationally in various cellular processes using NAD+ and its other forms as substrates.^[1]^[2] NAD+ also acts as a precursor for cyclic ADP ribose, an essential component of calcium signaling and a secondary messenger molecule.^[4]

The amino acid tryptophan and the vitamin precursors nicotinic acid and nicotinamide, often known as vitamin B3 or niacin, are used by the body to naturally produce NAD+. It can also be produced from biosynthetic intermediates including nicotinamide mononucleotide and nicotinamide riboside.^[2]^[3] NAD+ is continuously recycled within cells as it transitions between its many forms through salvage mechanisms.^[3] Mammalian cells may be able to take up extracellular NAD+, according to studies on cell culture.^[5]

The highest NAD+ levels are found in neonates, and they gradually decrease with increasing chronological age.^[6] They are around half of what they are in younger persons after age 50.^[6] Model organisms have been used to study the subject of why NAD+ levels fall with aging.^[7]^[8] However, during other metabolic activities, NAD+ is consumed by NAD+-dependent enzymes and may subsequently become depleted over time, contributing to increased DNA damage, age-related illnesses and diseases, and mitochondrial malfunction. During redox reactions, NAD+ and NADH are not consumed but rather continually regenerated.^[2]^[6] Views of aging and senescence frequently highlight a deterioration in mitochondrial health and function with age, and investigations of NAD+ depletion and the associated oxidative stress and damage corroborate these theories.^[1]^[2]

The age-related drop in NAD+ levels is caused by rising levels of CD38, a membrane-bound NADase that degrades both NAD+ and its precursor nicotinamide mononucleotide, according to a 2016 study in mice, which exhibit age-related declines in NAD+ levels similar to those seen in humans.^[7] The study also demonstrated that human adipose tissue from older adults (mean age, 61 years) expresses the CD38 gene at higher levels than that of younger adults (mean age, 34 years).^[7] Other research in mice, however, has shown that oxidative stress and inflammation brought on by aging lower NAD+ production.^[8] Therefore, it is likely that a number of mechanisms work together to cause individuals to lose NAD+ as they age.

When it was recognized that pellagra, a condition marked by diarrhea, dermatitis, dementia, and mortality, could be treated with foods containing NAD+ precursors, particularly vitamin B3, the clinical significance of maintaining NAD+ levels was established in the early 1900s.^[9] Notably, the skin does not flush with NAD+ injection, in contrast to vitamin B3 (niacin) intake, which also causes this negative effect.^[10] Low NAD+ levels have recently been associated with a variety of age-related ailments and diseases linked to increased oxidative/free radical damage, including diabetes, heart disease, vascular dysfunction, ischemic brain injury, Alzheimer’s disease, and vision loss.^[11]^[8]^[12]^[13]^[14]^[15]^[16]^[17]

Since a 1961 report by Paul O’Hollaren, MD, of Shadel Hospital in Seattle, Washington, NAD+ IV infusion has been widely utilized for the treatment of addiction.^[18]^[19]^[20] In more than 100 instances, Dr. O’Hollaren detailed the effective use of IV-infused NAD+ for the prevention, relief, or treatment of acute and chronic symptoms of addiction to a range of substances, including alcohol, heroin, opium extract, morphine, dihydromorphine, meperidine, codeine, cocaine, amphetamines, barbiturates, and tranquilizers.^[18] The security and effectiveness of NAD+ treatment for addiction, however, have not yet been assessed in clinical trials.

NAD+-replacement therapy may encourage optimal mitochondrial function and homeostasis, genomic stability, neuroprotection, long life, and may help with addiction treatment.^[1]^[2]^[3]^[20] Clinical trials assessing these effects in humans receiving NAD+ injection have not yet been published; nevertheless, many clinical trials assessing the effectiveness and safety of NAD+-replacement therapy or augmentation in the context of human disease and aging have recently been completed, and many more are currently underway.

Unknown are the precise mechanisms of NAD+ repair or enhancement for potential health benefits, such as supporting healthy aging and treating age-related illnesses, metabolic and mitochondrial diseases, and addiction.^[1]^[2]^[3]^[20]

In order to prevent mitochondrial malfunction and sustain metabolic function/energy generation (ATP), NAD+ supplementation may counterbalance the age-related degradation of NAD+ and its precursor nicotinamide mononucleotide by NADases, particularly CD38.^[7]NAD+ replenishment, however, appears to support a number of other metabolic pathways via NAD+-dependent enzymes in research involving human and animal models (as well as samples and cell lines).^[1]^[2]^[3]^[20]

There are numerous well-known NAD+-dependent enzymes. Poly-ADP ribose polymerases (PARP 1–17) control nuclear stability and DNA repair.^[1]^[3] cADP-ribose, ADP-ribose, and nicotinic acid adenine dinucleotides are produced by NADases CD38 and CD157 in Ca2+ signaling and intercellular immunological communication.^[1]^[3] A family of histone deacetylases known as sirtuins (Sirt 1-7) controls a number of proteins involved in cellular metabolism, stress responses, circadian rhythms, and endocrine functions. Sirts have also been linked to longevity in model organisms and protective effects in cardiac and neuronal models.^[1]^[3] A recently identified NAD+ hydrolase, Sterile Alpha and Toll/Interleukin-1 Receptor motif-containing 1 (SARM1), is implicated in the aging and regeneration of neurons.^[21]^[22]

The mechanism of action of NAD+ replenishment has been somewhat clarified by research on progeroid (premature aging) disorders, which resemble the clinical and molecular aspects of aging. It is believed that the Werner syndrome (WS), which is characterized by severe metabolic dysfunction, dyslipidemia, early atherosclerosis, and insulin resistance diabetes, most closely resembles the aging process.^[23] The source of WS is the Werner (WRN) DNA helicase gene, which regulates the transcription of the essential NAD+ biosynthetic enzyme Nicotinamide Nucleotide Adenylyltransferase 1.^[24]^[25]

NAD+ depletion through disruption of mitochondrial homeostasis is a substantial contributor to the metabolic dysfunction in WS, according to a 2019 study.^[25] WS patient samples and WS animal models’ NAD+-deficient cells showed impaired mitophagy (selective degradation of defective mitochondria).^[25] NAD+ repletion restored NAD+ metabolic profiles, improved fat metabolism, lowered mitochondrial oxidative stress, and improved mitochondrial integrity in human cells with mutant WRN via restoring normal mitophagy.^[25] In animal models, NAD+ repletion significantly increased lifespan, delayed the beginning of accelerated aging, and increased the number of proliferating stem cells in the germ line.^[25] Several NAD+ precursor molecules were released to replace NAD+, demonstrating that NAD+ replacement is what generates the beneficial effects.^[25]

More evidence of NAD+’s significance in promoting mitochondrial and metabolic health may be seen in murine cells overexpressing the NADase CD38, which also had greater lactate levels, aberrant mitochondria, including missing or enlarged cristae, and lower oxygen consumption.^[7] Isolated mitochondria from these cells showed a substantial reduction in NAD+ and NADH compared to controls. In CD38-deficient animals, NAD+ levels, mitochondrial respiratory rates, and metabolic activities remained constant with age.^[7]

At the time of writing, there were no other reported contraindications/precautions for NAD+ injection. Individuals with known allergy to NAD+ injection should not use this product.

At the time of writing, there were no reported interactions for NAD+ injection. It is possible that unknown interactions exist.

Injection of NAD+ seems to be secure and well-tolerated.^[10] The injection of NAD+ may cause adverse reactions and side effects, such as headache, shortness of breath, constipation, increased plasma bilirubin, and decreased levels of gamma glutamyl transferase, lactate dehydrogenase, and aspartate aminotransferase.^[18]^[10]

Case studies of the use of NAD+ to treat drug addiction offered early information on side effects and safety.^[18]^[19] According to a 1961 study, patients with addiction who got NAD+ at a moderate IV drip rate (no more than 35 drops per minute) reported “no distress” but those who received it at a quicker drip rate complained of headache and shortness of breath.^[18] In this study, the dosage was 500–1000 mg per day for 4 days, then two injections every week for a month, and then one injection every two months as a maintenance dose. One of the two patients who had therapy reported experiencing constipation.^[18]

In a 2019 study, a cohort of healthy male participants (n=11; NAD+ n = 8 and Control n = 3) aged 30-55 years had their safety of IV infusion of NAD+ evaluated using liver function tests (serum, total bilirubin, alkaline phosphatase, alanine aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, and aspartate aminotransfer.^[10] Neither the NAD+ cohort nor the placebo (saline) cohort experienced any negative side effects throughout the 6 hour infusion.^[10] At 8 hours following the start of the NAD+ infusion, it was shown that the NAD+ group had significant declines in the liver function enzymes gamma glutamyl transferase, lactate dehydrogenase, and aspartate aminotransferase as well as a large increase in plasma bilirubin.^[10] The modifications, however, were not regarded as clinically important. Because of the limited sample sizes, notably for the control group, which are acknowledged by the authors, these results should be evaluated with care.^[10]

The safety of NAD+ injection has not been evaluated in pregnant women. Due to this lack of safety data, pregnant women should avoid NAD+ injection.

The safety of NAD+ injection has not been evaluated in women who are breastfeeding or children. Due to this lack of safety data, women who are breastfeeding and children should avoid NAD+ injection.

Store dry powder at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Once reconstituted keep this medicine in a refrigerator between 36°F to 46°F (2°C to 8°C). Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

Cantó C, Menzies KJ, Auwerx J. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015;22(1):31-53. doi:10.1016/j.cmet.2015.05.023
Johnson S, Imai SI. NAD+ biosynthesis, aging, and disease. F1000Research. 2018;7. doi:10.12688/f1000research.12120.1
Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12-19. doi:10.1016/j.tibs.2006.11.006
Guse AH. The Ca2+-Mobilizing Second Messenger Cyclic ADP-Ribose. In: Calcium: The Molecular Basis of Calcium Action in Biology and Medicine. Springer Netherlands; 2000:109-128. doi:10.1007/978-94-010-0688-0_7
Billington RA, Travelli C, Ercolano E, et al. Characterization of NAD uptake in mammalian cells. J Biol Chem. 2008;283(10):6367-6374. doi:10.1074/jbc.M706204200
Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue. Polymenis M, ed. PLoS One. 2012;7(7):e42357. doi:10.1371/journal.pone.0042357
Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016;23(6):1127-1139. doi:10.1016/j.cmet.2016.05.006
Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528-536. doi:10.1016/j.cmet.2011.08.014
Goldberger J. Public Health Reports, June 26, 1914. The etiology of pellagra. The significance of certain epidemiological observations with respect thereto. Public Health Rep. 1975;90(4):373-375. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1437745/.– LinkOpens in New Tab Accessed October 11, 2020.
Grant R, Berg J, Mestayer R, et al. A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Front Aging Neurosci. 2019;11. doi:10.3389/fnagi.2019.00257
Wu J, Jin Z, Zheng H, Yan LJ. Sources and implications of NADH/NAD+ redox imbalance in diabetes and its complications. Diabetes, Metab Syndr Obes Targets Ther. 2016;9:145-153. doi:10.2147/DMSO.S106087
Pillai JB, Isbatan A, Imai SI, Gupta MP. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity. J Biol Chem. 2005;280(52):43121-43130. doi:10.1074/jbc.M506162200
Csiszar A, Tarantini S, Yabluchanskiy A, et al. Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Am J Physiol – Hear Circ Physiol. 2019;316(6):H1253-H1266. doi:10.1152/ajpheart.00039.2019
Ying W, Xiong Z-G. Oxidative Stress and NAD+ in Ischemic Brain Injury: Current Advances and Future Perspectives. Curr Med Chem. 2010;17(20):2152-2158. doi:10.2174/092986710791299911
Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci. 2007;64(17):2202-2210. doi:10.1007/s00018-007-7218-4
Abeti R, Duchen MR. Activation of PARP by oxidative stress induced by β-amyloid: Implications for Alzheimer’s disease. Neurochem Res. 2012;37(11):2589-2596. doi:10.1007/s11064-012-0895-x
Lin JB, Apte RS. NAD + and sirtuins in retinal degenerative diseases: A look at future therapies. Prog Retin Eye Res. 2018;67:118-129. doi:10.1016/j.preteyeres.2018.06.002
O’Hollaren P. Diphosphopyridine nucleotide in the prevention, diagnosis and treatment of drug addiction. West J Surg Obstet Gynecol. May 1961.
Mestayer PN. Addiction: The Dark Night of the Soul/ Nad+: The Light of Hope – Paula Norris Mestayer – Google Books. Balboa Press; 2019. https://books.google.com/books?id=t7qEDwAAQBAJ&lr=&source=gbs_navlinks_s.– LinkOpens in New Tab Accessed October 11, 2020.
Braidy N, Villalva MD, van Eeden S. Sobriety and satiety: Is NAD+ the answer? Antioxidants. 2020;9(5). doi:10.3390/antiox9050425
Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science (80- ). 2015;348(6233):453-457. doi:10.1126/science.1258366
Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017;93(6):1334-1343.e5. doi:10.1016/j.neuron.2017.02.022
Oshima J, Sidorova JM, Jr. Monnat RJ. Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 2017;33:105-114.
Yu CE, Oshima J, Fu YH, et al. Positional cloning of the Werner’s syndrome gene. Science (80- ). 1996;272(5259):258-262. doi:10.1126/science.272.5259.258
Fang EF, Hou Y, Lautrup S, et al. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019;10(1):1-18. doi:10.1038/s41467-019-13172-

Glutathione Injection

Glutathione Injection (Preserved) (30 mL) 200 MG/ML

Glutathione (GSH) is composed of three amino acids combined to produce a peptide that is both a powerful antioxidant and performs several critical roles in the body. According to researchers this peptide is so essential to optimum health that the level of Glutathione in cells could possibly be used to predict how long an organism lives.^[1]^[2]

Glutathione catalyzes glutathione S-transferases (GST) and glutathione peroxidases (GPx). Thus, playing a role in detoxification by eliminating toxic electrophilic molecules and reactive peroxides. Glutathione plays a crucial role in a detoxification system that is fundamental in plants, mammals, and fungi.^[3]

Aside from its detoxification role it is important for a variety of essential cellular reactions. Its presence in the glyoxalase system, is fundamental to DNA and RNA nucleotide reduction. Glutathione is also a constituent in the regulation of protein and gene expression, exchange reactions including thiol to disulfide ratios involve glutathione.^[4]

Glutathione can exist intracellularly in either an oxidized (glutathione disulfide) or reduced (glutathione) molecular state. The ratio of reduced glutathione to glutathione disulfide has been shown to be critical in cell survival, this system is very tightly regulated.

Deficiency of glutathione puts the cell at risk for oxidative damage. An imbalance of glutathione is present in many pathologies including cancer, neurodegenerative disorders, cystic fibrosis (CF), HIV and aging.

While Glutathione is vitally essential to maintaining a healthy immune system, it isn’t classified as an essential nutrient; this is because the body does create its own supply from the amino acids:

L-cysteine
L-glutamic acid
Glycine
One of the reasons why Glutathione is so important for optimum health is that it’s present in every cell in the body. One way antioxidants like glutathione help maintain good physical health is by neutralizing free radicals, which can cause cellular damage through oxidation. Since glutathione is naturally present within all types of cells, it is in a prime position to do this. It’s considered one of the most important antioxidants in the human body.^[5]

Glutathione is an essential molecule required for detoxification. Glutathione acts by assisting the body’s machinery in the removal of harmful destructive oxygen containing molecules.

During the body’s normal functioning an excess of oxygen containing molecules are produced, these molecules are typically very reactive with other molecules they come in contact with. In modern biochemistry these are referred to as reactive O2 species.

Reactive O2 species molecules include peroxide (H2O2) and superoxide anions (O2 with unpaired electron) these molecules are very toxic to the cell. The toxicity can be explained by the tendency of these molecules to bind or destroy important biomolecules.

The body has a natural system to remove these reactive O2 species. These systems metabolize and scavenge for reactive oxygen species, in a controlled and precise fashion.

Store this medication in a refrigerator at 36°F to 46°F (2°C to 8°C). Keep all medicines out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Richie JP Jr, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, Zimmerman JA. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J. 1994 Dec;8(15):1302-7.
Cascella R, Evangelisti E, Zampagni M, Becatti M, D’Adamio G, Goti A, Liguri G, Fiorillo C, Cecchi C. S-linolenoyl glutathione intake extends life-span and stress resistance via Sir-2.1 upregulation in Caenorhabditis elegans. Free Radic Biol Med. 2014 Aug;73:127-35. doi: 10.1016/j.freeradbiomed.2014.05.004. Epub 2014 May 15.
Anderson, M.E., Glutathione Injections: an overview of biosynthesis and modulation. Chem Biol Interact, 1998. 111-112: p. 1-14.
P., M. and C. G.P., Glutathione reductase: regulation and role in oxidative stress, in Oxidative stress and the molecular biology of antioxidant defenses. 1997, Cold Spring Harbor Laboratory Press
Lu, Shelly C. “REGULATION OF Glutathione SYNTHESIS.” Molecular aspects of medicine 30.1-2 (2009): 42–59. PMC. Web. 2 Oct. 2017.

Hydroxocobalamin Injection (B12) 2 mg/mL 10 mL Vial – 10 week supply

Hydroxocobalamin (Vitamin B12) Injection (Each) 2 mg/ML

Cobalamin is vitamin B12 which can only be synthesized by microorganisms and can only be sourced from an animal product-based diet. A deficiency of cobalamin can cause megaloblastic anemia which could be related to deficient intake of vitamin B12 or deficient intrinsic factor, among other factors. The type of anemia, resulting from a lack of intrinsic factors is referred to as pernicious anemia.^[1]

Hydroxocobalamin (OHCbl) is a natural form of vitamin B12 which is available commercially. It is administrated parenterally either as an intravenous or intramuscular injection. This form of cobalamin is bioidentical to the B12 forms occurring in human physiology.^[2] Initially present as a manufacturing impurity and result of photolysis in commercial cyanocobalamin (under the trade name Cytamen), hydroxocobalamin was later found to be superior for many clinical conditions.^[3]

Doses of OHCbl are quite efficient for the prevention and treatment of pernicious anemia, as an antidote in cases of cyanide poisoning as well as for the treatment of Leber’s optic atrophy and tobacco amblyopia. Pernicious anemia is a fatal condition where a deficiency of vitamin B12 affects the generation of healthy red blood cells and the proper functioning of the nervous system.^[4] In some individuals, an auto-immune response inhibits the production of a protein called intrinsic factor which is present in normal stomach secretion. It is responsible for vitamin B12 absorption and its absence causes clinical manifestation of its deficiency. Surgery involving stomach areas where cells responsible for intrinsic factors are affected could also lead to loss of B12 absorption. Besides this, several diseases like celiac disease, Crohn’s disease as well as HIV can interfere with vitamin B12 absorption. Other causes include wrong types of bacteria in the small intestine, some antibiotics, and B12 feeding tapeworm.^[5]

OHCbl is found to be safe and cost-effective along with being efficient against pernicious anemia to be listed as an anti-anemic in the list of essential medicines for children published by W.H.O.^[6]

As an antidote for cyanide poisoning, hydroxocobalamin has shown many benefits over alternative antidotes. It has a very rapid response, its by-products are non-toxic and can be easily eliminated from the body, it can be used safely even with non-poisoned patients and it does not affect the oxygen-carrying capability of blood. It has a long history of being used as an anti-dote safely against cyanide poisoning.^[7] The only limitation is that it needs to be administered intravenously for a significant period of time and might need a hospital setting.

Tobacco amblyopia is caused by tobacco consumption and can be treated with hydroxocobalamin. A notable difference in improved visual acuity and color vision was reported when OHCbl was administrated IM in patients suffering from it and the performance was superior to cyanocobalamin.^[8]

Hydroxocobalamin is converted intracellularly into methylcobalamin and adenosylcobalamin. Methylcobalamin and adenosylcobalamin are active forms of vitamin B12 and play several important roles together in the body ranging from the metabolism of carbohydrates, proteins, and fats to the development of the nervous system and DNA synthesis. However, they are not interchangeable.^[9] While methylcobalamin is specifically important for hematopoiesis, adenosylcobalamin is important for myelin synthesis. Thus, hydroxocobalamin can be used against a wider clinical manifestation of B12 deficiency.

Purines and pyrimidines needed for DNA synthesis and red blood cell formation are dependent on methylcobalamin as a co-enzyme for the conversion of homocysteine to methionine. This is accompanied by the conversion of methyltetrahydrofolate to tetrahydrofolate.^[10] In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Most requirement of Vitamin B12 is by cells that need to undergo rapid growth such as epithelial cells, bone marrow, and myeloid cells.

During a study for its efficacy as a B12 supplement, hydroxocobalamin was found to show better retention over cyanocobalamin (CnCbl), was absorbed more slowly from the site of injection, maintained higher and longer blood levels, and was eliminated more slowly from urine.^[11] Thus, it may be construed as a superior alternative to cyanocobalamin in most cases of B12 deficiency. However, in specific cases such as when cobalamin(Cbl) deficiency is caused by a lack of transcobalamin II (TCII) or of receptors to TCII-Cbl, OHCbl may not be the preferred form of treatment and CnCbl with its frequent dosages should be superior.^[9]

In the case of cyanide poisoning, the high affinity of cyanide for cobalt-containing compounds helps it to bind with different forms of cobalamin (a vitamin with cobalt in its core). Hydroxocobalamin reacts stoichiometrically with the cyanide group and rapidly removes cyanide from tissues to form cyanocobalamin which is non-toxic and can be eliminated using both renal and hepatic pathways.^[12]

Cyanide binds preferentially to hydroxocobalamin over cytochrome oxidase (a3) within the mitochondria and makes hydroxocobalamin an effective antidote. However, hydroxocobalamin does not impact the oxygen-carrying capability of the user unlike methemoglobin formed on the use of CN Antidote Kit. This is especially helpful in the case of fire victims who may have hemoglobin in their blood poisoned by carbon monoxide and have their oxygen-carrying capability already impaired. An additional advantage is that the by-product formed ie. cyanocobalamin can slowly release cyanide in the liver, which allows hepatic rhodanese to convert it to thiocyanate which can also be renally excreted without overwhelming this natural elimination pathway of cyanide.^[13]

Hydroxocobalamin holds FDA approval for its use in cyanide toxicity with only mild side effects noted during treatment in some patients.^[14] It has been used for over three decades in Europe where it has demonstrated its safety profile in several studies.

Hydroxocobalamin should be used with caution in patients with any known anaphylactic reaction to the drug or any of the formulation components.^[15] It is also contraindicated for patients hypersensitive to cobalt and cyanocobalamin. Cases have been reported where patients who tolerated cyanocobalamin without any adverse effects were found to be allergic to hydroxocobalamin.^[16]

Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with hydroxocobalamin, or cyanocobalamin, may unmask this condition.^[17]

Postmarketing reports have associated intravenous hydroxocobalamin therapy when used as a cyanide antidote with the development of renal impairment and crystalluria with hemodialysis being necessary in some cases for recovery. It is recommended to monitor the renal function of the patients for 7 days following administration of hydroxocobalamin.^[18]

Because of the rapid restoration of erythropoiesis in the bone marrow when severe megaloblastic anemia is treated with hydroxocobalamin, hypokalemia, that is, low serum potassium can occur.^[19]^[20]] Use of hydroxocobalamin for treating megaloblastic anemia in combination with folate is also known to cause tremors and thrombocytosis.^[21] Therefore, potassium levels and platelet counts should be closely monitored when hydroxocobalamin is used for the treatment of megaloblastic anemia.

The red color induced by OHCbl can interfere with several lab reports including bilirubin, creatinine, magnesium, serum iron, serum aspartate aminotransferase, COHb, methemoglobin, and oxyhemoglobin tests. Caution is advised when being administered to dialysis patients since it can also create a false alarm within dialysis machines and shut down the machine due to what is referred to as a “blood leak.”^[22]

Hydroxocobalamin can absorb visible UV light and therapy with this medication may cause photosensitivity. Its use can induce erythema and although it is unknown whether hydroxocobalamin-induced erythema increases the risk for photosensitivity, it is recommended that patients avoid direct sunlight until the redness of skin caused by usage of hydroxocobalamin has resolved.^[23]

Simultaneous administration of blood products including whole blood, packed red cells, platelets, and fresh frozen plasma, in the same intra-venous line as hydroxocobalamin should be avoided.^[24]

Bacillus Calmette-Guerin Vaccine, BCG medications known to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to hydroxocobalamin, vitamin B12 therapy.^[28]

Limited evidence from case reports indicates that chloramphenicol which is a bacteriostatic antibiotic can interfere with the red blood cell response to supplemental vitamin B12 in some patients through interference with erythrocyte maturation.^[29]

Although generally useful for cancer patients it has been known to interfere with chemotherapy by depletion of extracellular cysteine in combination with ascorbate.^[30]

Metformin, used in the treatment of diabetes, can possibly affect the intestinal cells involved in intrinsic factor metabolism and calcium-dependent absorption of vitamin B12 leading to reduced assimilation of the vitamin. It may also occur due to other factors such as increased bacterial overgrowth.^[31]^[32]

Histamine H2 receptor antagonists used to treat peptic ulcer disease and proton pump inhibitors used to treat gastroesophageal reflux disease can affect absorption of B12 and it is recommended to monitor the vitamin status in patients using them for prolonged periods.^[33] Antineoplastics are antimetabolites for B12 that can reduce its hematologic response.^[34]

Hydroxocobalamin has been found to be physically incompatible when mixed in solution with diazepam, dobutamine, dopamine, fentanyl, nitroglycerin, pentobarbital, propofol, and thiopental. It is chemically incompatible with sodium thiosulfate, sodium nitrite, and ascorbic acid.^[30]

Reddening of skin, allergic reactions, headache, and erythema at the injection site are some common side effects of this drug. OHCbl has been known to induce chromaturia in healthy volunteers. However, red-colored urine is harmless and resolves itself within 2 to 3 days but it can interfere with laboratory tests.

Anaphylactic reaction has been observed and documented in some patients but discontinuation of therapy resolved the symptoms within a few weeks. It has been observed that predisposing factors in certain patients might lead to these symptoms.^[35]

A transient increase in blood pressure also has been seen due to hydroxocobalamin’s inhibition of nitric oxide synthase and direct clearing of nitric oxide from the blood. However, it is generally considered beneficial and should not be treated but close observation is recommended.^[31]

No allergic effects against OHCbl were seen in a study at dosages below 2.5 gm although higher dosages from 5 g to 7.5g showed effects in few volunteers ranging from itching, facial erythema, swelling, eye reddening, shivering, dyspnoea, facial oedema, and spontaneous exanthema.^[36] Pustular rash was the most common among the side effects. Generally, clinically serious cases effects are not seen with OHCbl, however, in rare cases, anaphylactic shock and loss of consciousness have been observed even with small dosages when used in the treatment of pernicious anemia in patients which were known to be tolerant to cyanocobalamin.^[16]

Hydroxocobalamin is FDA-approved for use in pregnant patients in case of cyanide poisoning including suspected cases since 2010. Although adequate studies have still not been performed to ascertain its safety profile and some animal models have shown increased mortality of fetuses in high doses, it’s the only anti-dote known to be safe enough to be used in pregnant patients in case of cyanide toxicity. It can not only eliminate the effects of cyanide but also help reduce the effects of carbon monoxide which may have co-occurred especially in the case of fire victims.^[25]

For any other use, hydroxocobalamin is a pregnancy category C drug and should be used only if the potential benefit outweighs the potential risk to the fetus.^[18]

As per the WHO Model List of Essential Drugs when used as an anti-anemic hydroxocobalamin is compatible with breastfeeding.^[26] During treatment for cyanide poisoning with hydroxocobalamin, however, breastfeeding is not recommended since it may be excreted from breast milk and could carry cyanide with it. There is no data to determine when breastfeeding may be safely restarted following administration.^[27]

L. D. Smith and U. Garg, “Disorders of vitamins and cofactors,” in Biomarkers in Inborn Errors of Metabolism, Elsevier, 2017, pp. 361–397.
C. Paul and D. M. Brady, “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.,” Integr. Med. (Encinitas)., vol. 16, no. 1, pp. 42–49, Feb. 2017.
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E. R. Ahangar and P. Annamaraju, Hydroxocobalamin. Treasure Island (FL): StatPearls Publishing, 2020.
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G. Hovding, “Anaphylactic reaction after injection of vitamin B12.,” BMJ, vol. 3, no. 5610, pp. 102–102, Jul. 1968.
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Lipo-C Injection (Methionine / Choline Chloride / Carnitine / Dexpanthenol)

Lipo-C Injection (Methionine / Choline Chloride / Carnitine / Dexpanthenol) (30 mL). 15/50/50/5 MG/ML

Lipo-C injection contains a mixture of compounds that may aid in the reduction of adipose tissue (fat). The mixture of compounds individually may be effective, however in combination they may exhibit more lipotropic activity than when administered alone in a synergistic fashion. Injection of this mixture of lipotropic compounds may be more effective than oral supplementation, this is due to the increased bioavailability of parenteral exposure.

These lipotropic agents are structurally and functionally closely related to the B-vitamins, or are involved in the homeostasis of energy production from fat. These compounds are often employed together in the hope of potentiating fat-loss, thus while the Methionine Choline mixture and B vitamin(s) are often injected separately, they are part of the same overall injection cycle. The non-vitamin compounds that are injected into the body stimulate the liver into optimizing the process of metabolism, elevate the movement of and utilization of fat, and provide the needed metabolic environment of the body for a fatty acid (fat) mobilization and utilization.

Lipotropic compounds are used on the potential for release of fat deposits in some parts of the body. They sometimes go by the names Lipo-Den, Lipo-Plex, Lipo Shot, or MIC Injection. The lipotropic agents included in this injection are:

Methionine
Methionine helps the liver maintain the optimal ability to process fatty acids.^[1] Methionine is a major constituent of S-adenosylmethionine which has been shown to be associated in genetic regulation and activation of certain genes.^[2] Methionine contributes to methyl donation to histones that activate certain genetic processes that may be involved in the increase in lean tissue. Although indirectly linked to lipolysis, it is believed that the increase in lean tissue increases resting metabolic rate, therefore increasing the overall required calories that must be obtained from storage or dietary intake. Methionine, via S-adenosylmethionine, has been shown in animal models to increase CNS activity, therefore increasing the caloric requirements required by the CNS^[3] The downstream effects of this may ultimately lead to increased caloric requirements for the entire organism. Although studies have not been replicated.^[4] in humans, there may be an association due to the similarity in pathways shared between organisms.

Choline
Choline is a simple molecule usually classified as a B vitamin. The B vitamin class is usually involved in the generation of energy and support of metabolism. Choline is an important precursor to the neurotransmitter acetylcholine. This neurotransmitter is involved in a host of activities, one of which includes muscular function and contraction. Acetylcholine is a fundamental neurotransmitter that enables the communication between neurons. Increased neural communication results in increased CNS activity which ultimately leads to increased energy expenditure. Energy expenditure requires nutrient input, either from stored energy (fat), or dietary nutrients. Choline exist in a delicate balance and homeostasis with methionine and folate. When these nutrients are not in balance adverse health effects may be present. Along with the increase in CNS activity comes increased cognitive ability, reported by many users. Choline may be effective as a nootropic, or a substance with ability to increase cognition. Increased neural cognition is thought to be due to choline’s role as a precursor to acetylcholine.

The supplementation of choline has been shown to reduce serum and urinary carnitine.^[4]The reduction of carnitine in these fluids may indicate carnitine has been partitioned in tissues that utilize it as a fatty acid mitochondrial transport. When carnitine is used in the mitochondria it transports fatty acids to the location which they are broken down and used as energy. It has also been reported that molecular fragments of fat have been found in urine after carnitine and choline supplementation, which may be due to incomplete fatty acid oxidation and the removal of the subsequent byproducts.^[4] This means, choline supplementation may increase the utilization of carnitine and increase the removal of fatty acids, even though all fatty acids are not burned as energy. The fragments of fatty acids not burned as energy are extruded in the urine as molecular fragments.

Methionine, which helps the liver maintain the optimal ability to process fatty acids;^[5]Choline, which stimulates the mobilization of fatty acids and prevents their deposition in a given part of the body;^[6] and, Inositol, which aids in the transport of fat into and out of the liver and intestinal cells, acts synergistically with choline, exhibiting more lipotropic activity than when administered alone.^[7]
As soon as the effect of all 6 of these substances wears out, the body gradually begins returning to its normal rate of fat and general metabolism.

Typically, these compounds are administered in concert. Injections can be administered up to twice a week. B12 is purported by its users and practitioners to help speed up overall metabolic processes and create a greater feeling of overall energy & well-being.^[8] Because these lipotropics are structurally and functionally closely related to the B-vitams, they are often employed together in the hope of potentiating the potential for fat-loss, thus while the mixture and B vitamin(s) are often injected separately, they are part of the same overall injection cycle. The non-vitamin compounds that are injected into the body stimulate the liver into optimizing the process of metabolism, elevate the movement of and utilization of fat, and boost the metabolic power of the body for a while.

Other compounds are included as an attempt to further potentiate these effects:

L-Carnitine
Dexpanthenol (Vitamin B5)

If you have an allergy to methionine, choline, or any part of this medicine. Tell your healthcare provider if you are allergic to any medicine. This includes rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other symptoms involved.

Potential side effects include stomach upset and urinary problems due to the strain the injections place on the kidneys. Depression is another possible side effect. Some patients are unable to control their urine, and/or have diarrhea. Finally, some patients reported an unpleasant odor. Lipotropic injections change the function of the digestive system temporarily. This can result in extreme exhaustion, since the body is not used to working at this level and condition. Unexplained pain in unrelated parts of the body is another potential side effect. Patients have complained of pain in the neck and parts of the hand. How these injections cause these pains is not clear. Some patients have also experienced joint pains and allergic reactions to the injections. Call your healthcare provider immediately if you are experiencing any signs of an allergic reaction: wheezing; chest tightness; fever; itching; bad cough; blue skin color; fits; or swelling of face, lips, tongue, or throat; also if you experience severe behavioral problems, chest pain or pressure or fast heartbeat, severe dizziness or passing out, nervousness and excitability, or severe headache.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Best, C.H. and J.H. Ridout, The lipotropic action of methionine. J Physiol, 1940. 97(4): p. 489-94.
Jones, P.A. and D. Takai, The role of DNA methylation in mammalian epigenetics. Science, 2001. 293(5532): p. 1068-70.
Young, S.N. and M. Shalchi, The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain. J Psychiatry Neurosci, 2005. 30(1): p. 44-8.
Hongu, N. and D.S. Sachan, Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. J Nutr, 2003. 133(1): p. 84-9.
Best CH, Ridout JH. “The Lipotropic Action of Methionine”. Journal of Physiology. 3 Oct 1939;97:489-494.
Artom C. “Mechanism of Action of Choline”. American Journal of clinical Nutrition
Gavin G, Patterson J, McHenry W. ” Comparison of the Lipotropic Effects of Choline, Inositol, and Lipocaic in Rats”. Journal of Biochemistry. 29 Jan 1943;148:275-279.
Solomon L. “Disorders of cobalamin (Vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment”. Elsevier Review. pp. 1-15. Web.

Carnitine (L) Injection

Carnitine (L) Injection (30 mL Vial). 500 MG/ML

Levocarnitine (L-3-hydroxy-4-N-trimethylaminobutyrate) is synthesized in the liver from the amino acids methionine and lysine. This naturally occurring substance is found in all mammalian tissues, especially striated muscle, and is required in energy metabolism, such as the oxidation of fatty acids, facilitating the aerobic metabolism of carbohydrates, and enhancing the excretion of certain organic acids. While only the L isomer is present in the biologic system, commercial synthesis of carnitine produces a D,L racemic mixture, from which the L-isomer is obtained. The D-isomer has pharmacologic effects but does not participate in lipid metabolism. Commercially, carnitine is available as both a prescription and non-prescription product. The prescription version is levocarnitine, while most dietary supplements contain D,L-carnitine which is commonly sold in health food stores.

Levocarnitine has been used in the treatment of primary and secondary carnitine deficiency in adults and neonates, Alzheimer’s disease, dilated cardiomyopathy in adults and children, valproic acid-induced hepatotoxicity in children, and hyperlipoproteinemia. It has been designated an orphan drug for a variety of conditions. Its use in alcohol induced fatty liver, Down’s syndrome, and chronic fatigue syndrome has shown varying results. Some athletes use carnitine supplements to increase exercise performance, however, the concept of carnitine loading does not appear to be very effective.^[1] Further, D,L-carnitine competitively inhibits levocarnitine. This inhibition may lead to a deficiency. Prescription forms of levocarnitine were approved by the FDA in 1985 (tablets), 1986 (oral solution), and 1992 (injection).

Levocarnitine facilitates long-chain fatty acid transport from the cytosol to the mitochondria, providing substrates for oxidation and subsequent cellular energy production. Levocarnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters. Levocarnitine clears the acyl CoA esters by formation of acylcarnitine which is rapidly excreted.

Carnitine acetyltransferases (CATs) catalyze the interconversion of fatty acid esters of coenzyme A and carnitine, which are located in the cytosol and mitochondrial membranes. Translocases, which exist in mitochondrial membranes, rapidly transport both free carnitine and its esters in and out of cells. Fatty acid esters of CoA, formed in the cytosol, inhibit enzymes of the Krebs cycle, and are involved in oxidative phosphorylation. Hence, the oxidation of fatty acids requires the formation of acylcarnitines and their translocation into mitochondria where the CoA esters are reformed and metabolized. If oxygen tension is limited, carnitine serves to maintain a ratio of free to esterified CoA within mitochondria that is optimal for oxidative phosphorylation and for the consumption of acetyl CoA.

Levocarnitine may cause gastrointestinal symptoms and should be used conservatively in patients with diarrhea.

Levocarnitine is classified as pregnancy category B. Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose and have reported no evidence of impaired fertility or harm to the fetus. No adequate, well controlled studies exist in pregnant women. This drug should be used during pregnancy only if clearly needed.^[2]^[3]

Levocarnitine therapy has been associated with an increased seizure activity. It should be administered with caution to patients with a history of a seizure disorder.

Although levocarnitine is used in the treatment of some types of cardiomyopathy, it should be administered with caution to patients with a history of cardiac disease or cardiac dysfunction. Various cardiovascular adverse effects have been reported with the administration of intravenous levocarnitine in dialysis patients, including hypertension, peripheral edema, and ventricular arrhythmias.

Peripheral neuropathy may be potentiated by levocarnitine administration.

The safety and efficacy of oral levocarnitine has not been evaluated in the setting of renal impairment. Do not use oral formulations of levocarnitine to treat patients with severe renal impairment or renal failure, including patients on dialysis. The major metabolites formed following chronic oral administration, trimethylamine [TMA] and trimethylamine-N-oxide [TMAO] will accumulate in patients with renal failure since they can not be efficiently removed by the kidneys (manufacturer information). The accumulation of these potentially toxic metabolites is not desirable since it increases the amount of nitrogenous waste to be removed in the dialysis procedure. In addition, increased levels of TMA in dialysis patients have been reported to be associated with possible neurophysiologic effects. The inefficient removal of these metabolites may result in the development of a “fishy” body odor. Only the intravenous form of levocarnitine is indicated for use in ESRD patients on hemodialysis; accumulation of metabolites does not occur to the same extent following intravenous administration of levocarnitine.

Use levocarnitine with caution in hepatic disease since no specific information is available.

Supplementation with levocarnitine in women who are breast-feeding has not been specifically studied; however, levocarnitine is a normal component of human milk which is required for fat metabolism. Consumption of levocarnitine within the normal range of dietary intake leads to excretion into the breast-milk, which is relatively constant. Women with carnitine deficiency and preterm infants may require prescription levocarnitine supplementation under the supervision of a healthcare professional. It is unlikely that maternal levocarnitine supplements during nursing would be harmful to the infant, but it is probably best to avoid over-the-counter supplementation until more data is available. Levocarnitine has been studied in dairy cows; data indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.^[2]^[3]

Gastrointestinal (GI) adverse effects are possible with oral and intravenous (IV) levocarnitine therapy. These GI symptoms include abdominal pain, dyspepsia, diarrhea, gastritis, nausea, and vomiting. These adverse effects with oral therapy may be reduced by slowing the rate of consumption and administering as divided doses throughout the day. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, GI adverse reactions were reported at the following incidence compared to placebo: abdominal pain (5—21% vs 17%), anorexia (3—6% vs 3%), constipation (3% vs 6%), diarrhea (9—35% vs 19%), dyspepsia (5—9% vs 10%), gastrointestinal disorder (2—6% vs 2%), melena (2—6% vs 3%), nausea (5—12% vs 10%), vomiting (9—21% vs 16%), weight gain (2—3% vs 2%), and weight loss (3—8% vs 3%).^[2]^[3]

Drug-induced body odor (described as “fishy” odor), headache, paresthesias and weakness have been associated with intravenous as well as oral administration of levocarnitine. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, nervous system adverse reactions were reported at the following incidence compared to placebo: headache (3—37% vs 16%), anxiety (1—2% vs 5%), asthenia (8—12% vs 8%), depression (5—6% vs 3%), dizziness (10—18% vs 11%), drug dependence (2—6% vs 2%), hypertonia (1—3% vs 5%), insomnia (3—6% vs 6%), paresthesias (3—12% vs 3%), and vertigo (2—6% vs 0%).^[2]^[3]

Levocarnitine therapy has been associated with seizures in patients with and without a history of seizures and an increase in seizure activity (frequency and/or severity). It should be administered with caution to patients with a history of seizures.^[2]^[3]

During clinical trials of IV levocarnatine in patients on chronic hemodialysis, cardiovascular adverse reactions were reported at the following incidence compared to placebo: arrhythmia (2—3% vs 5%), atrial fibrillation (2—6% vs 0%), cardiovascular disorder (3—6% vs 6%), abnormal electrocardiogram (3—6% vs 0%), bleeding (2—9% vs 6%), chest pain (unspecified) (6—15% vs 14%), hypertension (18—21% vs 14%), hypotension (3—19% vs 19%), palpitations (3—8% vs 0%), peripheral edema (3—6% vs 3%), sinus tachycardia (5—9% vs 5%), and vascular disorder (2—6% vs 2%).^[2]

During clinical trials of IV levocarnatine in patients on chronic hemodialysis, respiratory and infectious adverse reactions were reported at the following incidence compared to placebo: infection (10—24% vs 17%), fever (5—12% vs 5%), bronchitis (3—5% vs 0%), cough (9—18% vs 16%), dyspnea (3—11% vs 19%), pharyngitis (15—27% vs 33%), rhinitis (6—11% vs 10%), and sinusitis (2—3% vs 5%).^[2]

During clinical trials of IV levocarnitine in patients on chronic hemodialysis, general adverse reactions were reported at the following incidence compared to placebo: anemia (3—12% vs 3%), injection site reaction (27—38% vs 59%), rash (unspecified) (3—5% vs 3%), pruritus (3—8% vs 13%), dysgeusia (2—9% vs 0%), amblyopia (3—6% vs 2%), eye disorder (3—6% vs 3%), back pain (6—9% vs 10%), parathyroid disorder (2—6% vs 2%), hypervolemia (3—12% vs 17%), hyperkalemia (6% vs 6%), and hypercalcemia (6—15% vs 3%).^[2]

Supplementation with levocarnitine in women who are breastfeeding has not been specifically studied; however, levocarnitine is a normal component of human milk which is required for fat metabolism. Consumption of levocarnitine within the normal range of dietary intake leads to excretion into the breast milk, which is relatively constant. Women with carnitine deficiency and preterm infants may require prescription levocarnitine supplementation under the supervision of a healthcare professional. It is unlikely that maternal levocarnitine supplements during nursing would be harmful to the infant, but it is probably best to avoid over-the-counter supplementation until more data is available. Levocarnitine has been studied in dairy cows; data indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.^[2]^[3]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr 2000;72(suppl):618S-623S.
Carnitor (levocarnitine) injection package insert. Gaithersburg, MD: Sigma Tau Pharmaceuticals; 2015 Apr.
Carnitor (levocarnitine) tablets, oral solution, and sugar-free oral solution package insert. Gaithersburg, MD: Sigma Tau Pharmaceuticals; 2015 Apr.

Arginine HCl Injection

Arginine HCl Injection (30 mL). 200 MG/ML

Arginine hydrochloride is a synthetic derivative of the essential amino acid L-arginine. Arginine hydrochloride may be used as an aid to the detection of growth hormone deficiency in conditions such as panhypopituitarism, pituitary dwarfism, chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, pituitary trauma, and in problems with growth and stature. The drug has also been used in the evaluation of pituitary function in gigantism and acromegaly. Further, arginine injection is used to treat high ammonia concentrations in patients with urea cycle disorders. Arginine tablets, which are dietary supplements, have been used to improve exercise capacity in patients with stable angina pectoris.[1] Arginine injection was originally approved by the FDA in February 1973.

Growth Hormone Deficiency Diagnosis: Arginine stimulates pituitary release of growth hormone in patients with normal pituitary function. Patients with impaired pituitary function who receive arginine will have lower or no increase in plasma concentrations of growth hormone after administration of arginine.[2]

Urea Cycle Disorders (UCDs): The urea cycle is normally responsible for maintaining low blood concentrations of ammonia and glutamine from protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to form nitrogenous waste such as urea. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or a cofactor: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), or argininosuccinate lyase (ASL). Arginine becomes an essential amino acid when any of these enzymes is deficient. If essential amino acids are not available, protein catabolism occurs, which increases ammonia concentrations. Exogenous arginine is administered in patients with UCDs to restore serum levels and prevent the breakdown of endogenous protein. Additionally, arginine administration lowers the blood ammonia level and increases the amount of nitrogen excreted in the urine by stimulating an alternative pathway for waste nitrogen excretion.[3][4][5]

Metabolic Alkalosis: Arginine is a precursor to hydrochloric acid and has a high chloride content and is, therefore, an alternative treatment for severe metabolic alkalosis.[6]

Cardiovascular disease: Arginine is a precursor of nitric oxide, which is a potent vasodilator with antiplatelet activity. Nitric oxide has been shown to induce vasodilation in patients with atherosclerosis.[7][8]

Arginine injection is contraindicated in patients having know arginine hypersensitivity or a hypersensitivity to any components of the product.

Use arginine injection cautiously in patients with renal impairment, hepatic disease and/or an electrolyte imbalance. Arginine can be metabolized to nitrogen-containing products. Consider the nitrogen or acute amino acid burden on patients with impaired renal function when administering arginine injection. Additionally, arginine injection contains 47.5 mEq chloride/100 mL, which should be considered in patients with an existing electrolyte imbalance.[2] In 2 adult patients with severe hepatic disease and moderate renal insufficiency, severe hyperkalemia developed during and after an arginine monohydrochloride infusion. Both patients had received spironolactone prior to the arginine infusion. Arginine shifts intracellular potassium to the extracellular compartment so caution should be used in patients with hepatic and renal failure due to decreased metabolism of arginine and decreased clearance of potassium.[9]

Use extreme caution when administering arginine injection to neonates, infants, children, and adolescents. Ensure the appropriate dose is being administered. Following high dose arginine hydrochloride administration in pediatric patients, hyperchloremic metabolic acidosis may occur. Chloride and bicarbonate levels should be monitored and bicarbonate should be administered if needed.[3] In overdosages in pediatric patients, cerebral edema and death have been reported.[2][5] In a review of adverse events reported to the FDA’s Adverse Event Reporting System (AERS), 33 reports were identified and majority of cases involved pediatric patients less than 16 years old.[10]

Arginine injection is classified as FDA pregnancy category B. Basal and post-stimulation concentrations of growth hormone are elevated in pregnant women. There are no well-controlled studies for the use of arginine injection in pregnant women. Although animal studies have provided no evidence of harm to the fetus, animal reproductive studies are not always predictive of human response; therefore, the manufacturer recommends that arginine injection not be used during pregnancy.[2]

It is not known if intravenous arginine is secreted in human milk; however, systemically administered amino acids are secreted into breast milk in quantities not likely to be harmful to the infant.[2] Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Acetaminophen; Aspirin, ASA; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aluminum Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[13][14]

Aluminum Hydroxide; Magnesium Carbonate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[13][14]

Aluminum Hydroxide; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[13][14]

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[13][14]

Aluminum Hydroxide; Magnesium Trisilicate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[13][14]

Antacids: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[13][14]

Aspirin, ASA: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Butalbital; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Butalbital; Caffeine; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Caffeine; Dihydrocodeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Carisoprodol: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Carisoprodol; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Dipyridamole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Omeprazole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Oxycodone: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Aspirin, ASA; Pravastatin: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Bismuth Subsalicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Bismuth Subsalicylate; Metronidazole; Tetracycline: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Calcium Carbonate; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[11][12]

Choline Salicylate; Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Colchicine: Colchicine is an alkaloid that is inhibited by acidifying agents. The colchicine dose may need adjustment.[15]

Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.[11][12]

Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

Methadone: As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.[16][17][18][19]

Salsalate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.[11][12]

During clinical trials of arginine injection (R-Gene 10), one patient developed a maculopapular rash with reddening and swelling of the hands and face. The rash subsided after the infusion was terminated and 50 mg of diphenhydramine was administered. Hypersensitivity reactions, including anaphylactoid reactions, have been reported during post-market surveillance of arginine injection. If serious hypersensitivity or anaphylaxis occurs during arginine therapy, discontinue the infusion and initiate appropriate medical therapy.[2]

Nausea and vomiting were reported in approximately 3% of patients during clinical trials of arginine injection. Excessive rates of infusion may cause these adverse events; consider decreasing the infusion rate if these symptoms develop. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.[2]

Flushing and headache were reported in approximately 3% of patients during clinical trials of arginine injection. Excessive rates of infusion may cause flushing; consider decreasing infusion rate if these symptoms develop. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the
pituitary and nullify the test.[2]

During clinical trials of arginine injection, thrombocytopenia was reported in one patient (decrease in platelet count from 150,000 to 60,000).[2]

Metabolic acidosis and hyperventilation may occur with an overdosage of arginine injection. Ensure the appropriate dose is being administered. In overdosages in pediatric patients, cerebral edema and death have been reported.[2][20] In a review of adverse events reported to the FDA’s Adverse Event Reporting System (AERS), 33 reports were identified. most of which were pediatric patients. The acidosis and base deficit will usually self-compensate and return to normal following cessation of the infusion. If the acidosis persists, however, the deficit should be determined and an appropriate dose of an alkalinizing agent, such as bicarbonate, administered.[2]

Hematuria has been reported in post-marketing reports of arginine injection. Some cases occurred 1—2 days after administration of arginine.[2]

Extravasation causing a third-degree chemical burn (skin necrosis) requiring surgical intervention was in a 17 year old patient during post-market surveillance of arginine injection.[10] An injection site reaction consisting of local venous irritation occurred in 3% of patients in clinical trials. Excessive rates of infusion may cause injection site reaction or skin irritation; consider decreasing infusion rate if local irritation develops. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.[2]

Paresthesias were reported in approximately 3% of patients during clinical trials of arginine injection.[2] Lethargy has also been reported with arginine administration.[10]

Arginine is a precursor of nitric oxide and accumulation of large amounts of excess arginine could lead to nitric oxide overproduction and result in vasodilation and hypotension. If hypotension is noted, reduction in arginine administration should be considered.[4]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Card 1997;80:331-333.
Arginine hydrochloride injection (R-GENE) package insert. Lake Forest, IL: Hospira Inc.; 2010 Jan.
Ammonul (sodium phenylacetate and sodium benzoate) injection package insert. Scottsdale, AZ: Ucyclyd Pharma Inc.; 2011 Jul
Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138: S30-S39.
Batshaw, ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001; 138:S46-S55
Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. Second of two parts. N Eng J Med 1998;338:107-11.
Bode-Boger SM, Boger RH, Galland A. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 1998; 46: 489-497.
Tangphao O, Grossmann M, Chalon S, et al. Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. Br J Clin Pharmacol 1999; 47: 261-266.
Bushinsky DA, Gennari J. Life-threatening hyperkalemia induced by arginine. Annals of Internal Medicine 1978; 89: 632-634.
FDA: Arginine hydrochloride injection (marketed as R-Gene 10). FDA Drug Safety Newsletter 2009;2(2):16-18.
Mudge GH, Weiner IM. Agents affecting volume and composition of body fluids. Gilman AG, Rall TW, Nies AS, Taylor P, (eds.) In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 8th ed., New York, Pergamon Press. 1990:620, 696—97.
Hamilton C. Acid-base disorders Gilman AG, Wells BG, Dipiro JT, Schwinghammer TL, et al. (eds.) In: Pharmacotherapy Handbook. 5th ed., New York, Pergamon Press. 1993:753—61.
Mudge GH, Weiner IM. Agents affecting volume and composition of body fluids. Gilman AG, Rall TW, Nies AS, Taylor P, (eds.) In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 8th ed., New York, Pergamon Press. 1990:620, 696-97.
Hamilton C. Acid-base disorders Gilman AG, Wells BG, Dipiro JT, Schwinghammer TL, et al. (eds.) In: Pharmacotherapy Handbook. 5th ed., New York, Pergamon Press. 1993:753-61.
Colchicine Tablets, USP package insert. Corona, CA: Watson Laboratories, Inc.; 2001 Jun.
Bellward GD, Warren PM, Howald W, et al. Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses. Clin Pharmacol Ther 1977;22:92—9.
Nilsson M-I, Widerlov E, Meresaar U, et al. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 1982;22:337—42.
Wolff K, Rostami-Hodjegan A, Hay AW, et al. Population-based pharmacokinetic approach for methadone monitoring of opiate addicts: potential clinical utility. Addiction 2000;95:1771—83.
Dolophine® (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; 2006 Oct.
Batshaw, ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001; 138:S46 S55

Alpha Lipoic Acid Injection

Alpha-Lipoic Acid Injection: 25 mg/mL 30 mL Vial

Alpha lipoic acid (ALA, thioctic acid) is an endogenous, potent antioxidant that is purported to be useful in the treatment of diabetes mellitus, diabetic neuropathy, dementia secondary to Alzheimer’s disease or human immunodeficiency virus (HIV) infection, glaucoma, amanita mushroom poisoning, and alcoholic liver disease. Studies supporting the use of ALA in the treatment of diabetes and diabetic neuropathy are available. The majority of studies are short in duration (e.g., 3—5 weeks) and were completed with a small number of study participants; however, small studies of both 6 months and 24 months duration have been completed in patients with diabetic neuropathy. ALA has been used extensively in the treatment of diabetic neuropathy in Germany since 1959. Studies supporting the effectiveness of ALA in other purported indications in humans are lacking or inconclusive. Further investigations of ALA in the treatment of Alzheimer’s disease, HIV-related dementia, or liver diseases are needed before it can be recommended for use for those conditions.

Endogenous alpha lipoic acid is available as both an R- and S- enantiomer; the R-enantiomer is the biologically active component, although most human clinical trials have used a racemic mixture of ALA. After oral or intraperitoneal administration, ALA is rapidly absorbed and distributed into various tissues including the heart, liver, and skeletal muscle. ALA is readily reduced to dihydrolipoic acid (DHLA) in body tissues. ALA is extensively metabolized, and very little is excreted as unchanged drug; ALA and DHLA are both water and fat soluble. ALA and DHLA are potent antioxidants that can scavenge reactive oxygen species and chelate metals (iron and copper for ALA and cadmium for DHLA), and ALA is natural cofactor of mitochondrial dehydrogenase complexes. In addition, DHLA may be able to regenerate oxidized vitamins E and C and glutathione.

Diabetes mellitus type 2: Several preliminary, short-term studies indicate that ALA may be effective in improving insulin sensitivity in patients with type 2 diabetes mellitus; administration of ALA has been shown to increase skeletal muscle glucose uptake and glucose disposal thereby improving insulin sensitivity and glucose utilization in patients with type 2 diabetes mellitus.

Diabetic neuropathy: Evidence indicates that oxidative stress and lipid peroxidation are major causes of neuropathic pain and dysfunction. Because of its antioxidant properties, ALA has been shown to improve the symptoms of neuropathy in patients with diabetes; a meta-analysis of 4 trials using intravenous ALA daily for 3 weeks reports that ALA is associated with a significant improvement in total symptoms scores including pain, burning, and numbness and neuropathic impairment scores including pin-prick sensation, touch-pressure sensation, and ankle reflexes.

Diabetes mellitus: Alpha lipoic acid may decrease blood glucose concentrations; patients with diabetes mellitus should use ALA with caution and monitor their blood glucose concentrations. Patients should also be instructed on the signs and symptoms of hypoglycemia.

Pregnancy and lactation: Evidence supporting the use of ALA in pregnancy and lactation is lacking. Women who are pregnant or breast-feeding their infants should avoid its use until information regarding safety and efficacy are available.

Antidiabetic agents: Alpha lipoic acid has been shown to increase glucose utilization and decrease insulin resistance. Patients receiving antidiabetic agents in combination with ALA may be at increased risk for hypoglycemia; dosage adjustments of antidiabetic agents may be necessary. Furthermore, patients should be instructed to monitor their blood glucose concentrations while taking ALA. In one study, some patients with type 2 diabetes mellitus receiving both ALA and sulfonylureas required a dose reduction in the sulfonylurea due to mild symptoms of hypoglycemia (Jacob et al, 1999)

Drugs that decrease the effects of antidiabetic agents: Alpha lipoic acid has been shown to increase glucose utilization and decrease insulin resistance. Patients receiving other drugs that may increase blood glucose concentrations or insulin resistance may counteract the beneficial effects of ALA. Such drugs include anti-retroviral protease inhibitors, atypical antipsychotics, beta-blockers, corticosteroids, cyclosporine, dextrothyroxine, diuretics, glucagon, isoniazid, INH, niacin, phenothiazines, somatropin, rh-GH, sympathomimetics, tacrolimus, triamterene, and thyroid hormones. NOTE: This list is not inclusive of all drugs that can decrease the effects of antidiabetic agents.

Drugs that increase the effects of antidiabetic agents: Alpha lipoic acid has been shown to increase glucose utilization and decrease insulin resistance. Patients receiving other drugs that may decrease blood glucose concentrations or insulin resistance may enhance the beneficial effects of ALA, possibly causing hypoglycemia. Such drugs include ACE inhibitors, androgens, bortezomib, chromium, disopyramide, fibric acid derivatives, garlic, Allium sativum, green tea, guanethidine, horse chestnut, Aesculus hippocastanum, MAOIs, octreotide, and orlistat. Patients with diabetes taking ALA plus any of these other drugs should be advised to monitor their blood glucose concentrations. NOTE: This list is not inclusive of all drugs that increase the effects of antidiabetic agents.

Drugs that increase or decrease the effects of antidiabetic agents: Alpha lipoic acid has been shown to increase glucose utilization and decrease insulin resistance. Patients receiving other drugs that may increase or decrease blood glucose concentrations or insulin resistance may counteract the beneficial effects of ALA or enhance its effects and increase the risk of hypoglycemia. Such drugs include clonidine, cisapride, ethanol, lithium, metoclopramide, pentamidine, and quinolones. Patients with diabetes taking any of these drugs in combination with ALA should be advised to monitor their blood glucose concentrations. NOTE: This list is not inclusive of all drugs that may increase or decrease the effects of antidiabetic agents.

Drugs that mask the signs and symptoms of hypoglycemia: Alpha lipoic acid has been shown to increase glucose utilization and decrease insulin resistance; hypoglycemia may be possible. Patients receiving other drugs that mask the signs and symptoms of hypoglycemia such as beta-blockers, clonidine, reserpine, guanethidine in combination with ALA should be advised to monitor their blood glucose concentrations. NOTE: This list is not inclusive of all drugs that may mask the signs and symptoms of hypoglycemia.

Alpha lipoic acid appears to be well-tolerated. In clinical trials of patients with diabetes, a few patients reported symptoms consistent with mild hypoglycemia. In addition, allergic skin conditions have been reported in patients taking oral ALA. In a study in patients with peripheral neuropathy, a dose-dependent increase in the incidence of nausea, vomiting and vertigo was reported with the highest incidence in those patients taking 1200 mg and 1800 mg/day PO of ALA (Ziegler et al., 2006).

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

Learn how to prepare medication for self-administered injection.

Enclomiphene Citrate Capsule 6.25 mg Each – 60 count

Semaglutide / Cyanocobalamin Injection 1/0.5 mg/mL 2.5 mL – 5 Week Supply

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Semaglutide / Cyanocobalamin Injection 1/0.5 mg/mL 1 mL – 2 Week Supply

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Metformin HCl ER Tablet 500 mg – 120 Tablets – 4 Months supply

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Lipo Burn 3 (Caffeine / Phentermine HCl / Naltrexone HCl / Methylcobalamin) (Slow Release) Capsule 100/20/8/1 mg Each — 60 count

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NAD+ Nasal Spray 300 mg/mL 15 mL

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Sermorelin Acetate Injection (Lyo) 9 mg

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Tirzepatide / Niacinamide Injection 8/2 mg/mL 2.5 mL Vial

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NAD+ Injection

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Glutathione Injection

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