Semaglutide / Cyanocobalamin Injection

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.

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2. 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
3. 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
4. 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
5. 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
6. 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.
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23. Hale TW, Kristensen JH, Hackett LP, et al. Transfer of metformin into human milk. Diabetologia 2002;45:1509-14.
24. Gardiner SJ, Kirkpatrick CMJ, Begg EJ, et al. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.
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27. Feig DS, Donat DJ, Briggs GG, et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care 2005;28:1851-5.
28. Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breastfeeding mother. Am Fam Physician 2001; 64:119-126.
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