Innovative sports pharmaceuticals

Solution with an active ingredient concentration of 5 mg/ml. Deviations within +/-10% are acceptable in determining the quantity (pharmaceutically acceptable according to European Pharmacopoeia standards). Analysis by HPLC may exhibit multiple mixed peaks, attributed to the equilibrium state of several tertiary structures.

● Building high-quality muscle mass (muscles grow in layers).

● Regeneration of muscle, nerve, tendon, and cartilage tissues.

● Lifespan extension.

● Reduction of tissue insulin resistance.

● Rehabilitation after all types of strokes.

● Treatment of migraines.

● Enhancement of erectile function.

The uniqueness lies in a significantly higher (5 times) concentration and dosage of the active substance compared to counterparts. The IGF-1 molecule is unmodified and entirely identical to the naturally occurring substance in our bodies, preventing the formation of antibodies.

The introduction of analogs, different from our IGF-1, such as LR3 and others, is perceived by the body as foreign, leading to the formation of antibodies and making further athletic progress impossible.

Course Duration: 10 to 60 days. For trauma regeneration, 10 to 14 days; muscle mass gain, 30-60 days; multiple sclerosis, injections three times a week for 16 weeks; stroke rehabilitation, 45 days; paralysis with “pinched nerve,” up to 60 days; optic nerve restoration, 20-25 days; unclear etiology migraines, possible intranasal spray use; erectile dysfunction therapy, 14 days.

Dosages and Dependencies: Depend on body weight, existing conditions, age, and athletic goals. Dosage is measured strictly in milligrams. Do not use an insulin scale in IU, as it does not correlate with insulin. Initial guidelines: up to 70 kg – 1 mg, up to 100 kg – 2 mg, over 100 kg – up to 3 mg. Individual variations may exist, and recommended dosages may be effective within a range of +/- 50%.

Dosage Calculation: Adjust based on feelings, such as hypoglycemic sensations (reduce dosage), lethargy (also reduce), muscle fullness, and appetite. In the presence of insulin resistance, dosages may be increased by 50%. For trauma and neurological conditions, adjust based on sensations and the healing process, consulting our medical specialist in these cases.

Course Duration Factors: Primarily depends on the set objectives. Muscle mass gain typically takes 1-2 months, with possible intervals of 1-2 months between courses. For therapeutic purposes, intervals between courses can be half the course length, repeated until the issue is resolved.

The IGF-1 drug is compatible with any other medications; however, caution is advised with insulin and metformin. IGF-1 may induce hypoglycemia in 70% of individuals, so it should be used after meals (before injection, mandatory carbohydrate intake).

Additional stimulants: include all types of anabolic steroids, with IGF-1 enhancing the effects of anabolic steroids and possibly allowing a reduction in AS dosage.

For general impact, administer intramuscularly with a deep injection. Additionally, local application is highly effective when injections are made into lagging muscle groups before training using an insulin syringe! (Shoulders, arms, thighs, back, chest)

Post-cycle therapy (PCT) requirement: No need for PCT specifically after an IGF-1 course. However, the IGF-1 drug itself is an ideal tool for PCT between steroid courses, allowing the preservation and continued increase of muscle mass. IGF-1 can also be used if there are antibodies to growth hormone, and the use of growth hormone does not yield the desired effect.

Possible side effects include hypoglycemia, which can be managed by taking food or reducing the dosage. Do not use in the presence of malignant tumors.

Use of a Spoiled Product: As the product’s molecule has a natural origin and is essentially a protein, when spoiled, it will not exhibit the desired effects and will be metabolized by the body as a regular protein, broken down into amino acids.

The need for analyses and consultations BEFORE/AFTER product usage – conducting analyses is necessary.

Reasons for the necessity: for type 1 or type 2 diabetes, the product intake schedules differ, and the product cannot be used in the presence of oncological diseases.

List of analyses:

Insulin, glucose, triglycerides, thyroid hormones, prostate-specific antigen, lung cancer markers, stomach cancer marker, neuronal cancer marker.

Markers/indicators of the working product:

During the course (over 3-5 days) of administering 0.05 mg of the product per 1 kg of body weight every 1 hour, there is an increase in somatomedin C in the blood by approximately 150 ng compared to the baseline before the course of administration (submit a blood test for Insulin-like Growth Factor, IGF-I (Somatomedin C) one hour after injection). Also, indicators of “total protein” increase, and glucose decreases 1-4 hours after administration.

Deviation of indicators and their explanation:

IGF-1 in the blood may not be detected with a high level of IGFBP (IGF-binding protein). A high level of IGFBP may occur after a course of anabolic steroids, various metabolic disorders, liver diseases.

Shaking during transportation is highly undesirable.

Transport packaging: The product should be transported at +4-+8 degrees Celsius. At room temperature, not more than a day.

Storage:

Shelf life of the sealed product is 1 year at +4-+8 degrees Celsius, and 5 days at room temperature.

Shelf life of the opened product is: 30 days at +4-+8 degrees Celsius.

Storage temperatures: +4-+8 degrees Celsius.

1. Why do some individuals not experience an increase in somatomedin-C in the blood after IGF-1 injections, and how can one explain to them that the medication is effective?

IGF-1 in the blood may not be detected when there is a high level of IGFBP (Insulin-Like Growth Factor Binding Protein). Elevated IGFBP levels can occur after a course of anabolic steroids, in various metabolic disorders, and liver diseases. The determination of the product is also influenced by kidney function. Genetic factors, such as IGF-1 receptor polymorphism, can lead to rapid binding with a higher number of IGF receptors, preventing it from remaining in free form in the blood. The effectiveness of the medication is typically gauged by muscle hypertrophy, reduction in fat deposits (e.g., in the waist), increased endurance, or improved strength.

2. Are there other blood indicators that change with the consumption of IGF-1?

Blood glucose, total protein, and hematocrit levels are among the indicators that may change with the use of IGF-1.

3. Can diabetes develop as a result of IGF-1 usage?

No, the medication may even help prevent the development of diabetes.

4. Is there a health risk if a person uses spoiled IGF-1?

The molecule of the product has a natural origin and is essentially a protein. If spoiled, it will not exert the intended effects and will be metabolized by the body as a regular protein, broken down into amino acids. Therefore, there is no health risk.

5. Are there recommendations for other medications to be used alongside IGF-1 during a course?

Any type of anabolic steroids is recommended. Additionally, it is essential to include vitamins and amino acids in the regimen.

• Anabolic effect causes muscle growth.
• Anti-catabolic effect – inhibits the destruction of muscles.
• Reduces the adipose tissue.
• Regulates the use of energy.
• Accelerates the healing of wounds.
• Demonstrates a rejuvenating effect.
• Stimulates the re-growth of internal organs (atrophied with age).
• Causes bone growth and increases growth in young people up to 26 years (before closing the growth zones), strengthens bone tissue.
• Increases the level of glucose in the blood.
• Strengthen immunity.

Absorption and distribution

In both healthy individuals and patients with growth hormone deficiency, approximately 80% of subcutaneously administered Somatropin JFC LAB® is absorbed. After subcutaneous administration of the drug at a dose of 0.1 IU/kg of body weight, Cmax is 13-35 ng/ml which is reached in 3-6 hours. Vd is 0.5-2.1 l/kg.

Metabolism and excretion

Biotransformed in the kidneys and liver. While the intramuscular administration of the drug T1/2 is reached in 2-3 hours. While the subcutaneous administration of the drug, T1/2 is reached in 3-4 hours. The observed difference is probably due to slower absorption of the drug during subcutaneous injection. About 0.1% of the administered drug is excreted directly with bile.

Pharmacokinetics in particular medical cases 

Absolute bioavailability of Somatropin JFC LAB® for subcutaneous administration is the same for men and women.

Rejuvenating effect:

Dosages vary from 1 to 4 IU/day (0.01-0.04 IU/kg/day).

The duration of the course of administration takes from 3 to 6 months, then a break (3-6 months) is made and the course is repeated.

The daily dosage is recommended to be divided into 2 injections, the first in the morning under fasting condition, at least an hour before meals and the second 30-60 minutes before bedtime, at least 2 hours after the last meal (at a time of low blood sugar concentration). Injections are to be subcutaneous, in the abdominal area or intramuscular, made with an insulin syringe in small muscle groups.

For women, as a rule, dosages can be reduced by 2 times relative to men.

Weight loss effect:

Dosages vary from 4 to 8 IU/day (0.04-0.08 IU/kg/day).

The duration of the course of administration takes from 60 to 90 days, then a break is made for 60-90 days and the course may be repeated.

The daily dosage is recommended to be divided into 2 injections, the first in the morning under fasting condition, at least an hour before meals and the second 30-60 minutes before bedtime, at least 2 hours after the last meal (at a time of low blood sugar concentration). Injections are to be subcutaneous, in the abdominal area or intramuscular, made with an insulin syringe in small muscle groups. 

For women, as a rule, dosages may be reduced by 2 times relative to men.

Additionally, the combination of somatotropin with other fat-burning drugs is strictly under the supervision of the attending physician.

Muscle gain:

Dosages vary from 5 to 10 IU/day (0.05-0.1 IU/kg/day) The duration of the course of administration takes 6 months, then a break is made for 6 months and the course may be repeated.

The daily dosage is recommended to be divided into 2 injections, the first in the morning under fasting condition, at least an hour before meals and the second 30-60 minutes before bedtime, at least 2 hours after the last meal (at a time of low blood sugar concentration). Injections are to be subcutaneous, in the abdominal area or intramuscular, made with an insulin syringe in small muscle groups.

The same scheme is used for taking somatotropin not only every day, but also intermittently (in order to reduce tolerance for long-term use of the drug). For example, 5/2 and 6/1 (apply 5 days and 2 days of rest, and apply 6 days and 1 day of rest, respectively). In this case, the daily dosage may be slightly increased, on average by 15-30%. The use of dosages over 10 IU/day is strictly under the supervision of the attending physician. For women, as a rule, dosages may be reduced by 2 times relative to men.

It is highly recommended to undergo tests for cancer markers before starting the treatment course: CA19-9, CA72-4, Cyfra 21-1, AFP (alpha-fetoprotein), CEA (carcinoembryonic antigen). If there are deviations in the cancer marker values, the course of growth hormone administration is prohibited, you need an oncologist consultation.

Hypersensitivity to any component of the drug.

Signs of active malignant tumor (at the start of treatment the intracranial tumor must be inactive and antitumor therapy completed). Treatment should be discontinued if signs of tumor growth appear. Acute conditions (including after cardiac, abdominal surgery, acute respiratory failure, multiple injuries from accidents). Prader-Willi syndrome (PWS) in cases of severe obesity and respiratory impairment. Stimulation of longitudinal growth in children with closed epiphyseal growth plates. In children with chronic kidney failure, the course of treatment with the drug Somatropin JFC LAB® should be interrupted during kidney transplantation. Caution: hypothyroidism, diabetes, breastfeeding.

Patients with growth hormone deficiency often suffer from a volume depletion. With the beginning of treatment with somatotropin, this deficit is corrected. More often, fluid retention in the form of peripheral edema occurs in adults. Mild arthralgia, myalgia, and paresthesia may also occur, which usually do not require additional treatment. Symptoms are transient, dose-dependent, and may require a temporary dose reduction.

DATA GAINED FROM CLINICAL TRIALS

The dose is selected individually based on the individual clinical and biochemical response to therapy.

It is usually recommended to make one subcutaneous injection of the drug. In order to prevent the development of lipoatrophy, it is necessary to change the injection sites.

ADULTS:

Substitution therapy:

The dose is prescribed based on the individual needs of the patient. Adult patients with growth hormone deficiency are recommended to start treatment with low doses of the drug: 0.1-0.3 mg/day (0.3-0.9 IU/day) and gradually increase the dose each month based on the clinical response and tolerability of the drug. The concentration of IGF-1 in the blood serum can be used as a control indicator when titrating the dose. Women may need a higher dose of the drug than men, because men have increased sensitivity to IGF-1 over time. This means that women (especially those who receive oral estrogen replacement therapy) are at risk of using low doses of the drug, and men overestimated.

As the patient ages, the need for growth hormone decreases. The maintenance dose of the drug is selected individually, but rarely exceeds 1 mg/day (which corresponds to 3 IU/day).

OVERDOSE:

Symptoms of acute overdose: first hypoglycemia, then hyperglycemia. Such reduced glucose levels were determined only biochemically without clinical symptoms of hypoglycemia. With prolonged overdose, signs and symptoms that are characteristic of an excess of human growth hormone (acromegaly and/or gigantism) may appear, as well as hypothyroidism (suppression of thyroid function) and a decrease in serum cortisol levels. With a significant accumulation of fluid, edema, tunnel syndrome,

and arterial hypertension are possible.

Treatment: drug withdrawal, symptomatic therapy.

By prescription.

At a temperature of 2-8 °C (in the refrigerator), but not near the freezer. Do not freeze. Keep in the original packaging, in child-resistant closure.

3 years.

After opening 3 weeks (at a temperature below 25 °C), 4 months (at a temperature of 2-8 °C). Do not use after the expiration date indicated on the package.

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 (Ozempic) and oral tablets (Rybelsus) 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.2345 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.78 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.78910

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.1113

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.1617

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.1617 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.10131619

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.1920

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 (Ozempic), 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.232425 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.313233

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.1931

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.163234

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.1931
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.1935 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

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 (Ozempic), 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.232425 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.313233

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.1931

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.163234

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.1931
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.1935 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

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 (Ozempic), 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.232425 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.313233

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.1931

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.163234

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.1931
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.1935 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

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 (Ozempic) and oral tablets (Rybelsus) 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.2345 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.78 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.78910

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.1113

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.1617

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.1617 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.10131619

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.1920

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 (Ozempic), 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.232425 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.313233

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.1931

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.163234

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.1931
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.1935 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

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 (Ozempic), 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.232425 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.313233

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.1931

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.163234

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.1931
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.1935 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

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 (Ozempic), 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.232425 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.313233

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.1931

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.163234

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.1931
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.1935 Therefore, these factors should be taken into consideration and regular monitoring should be performed in these conditions while treating vitamin B12 deficiency with cyanocobalamin.