Semaglutide / Cyanocobalamin Injection​

• Classification: Semaglutide is a synthetic glucagon-like peptide-1 receptor agonist (GLP-1 RA), a class of antidiabetic agents also known as incretin mimetics.
• Mechanism of Action: GLP-1 RAs mimic the effects of incretins, endogenous compounds that improve glycemic control by enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying.
• Uses:
  • Type 2 Diabetes Mellitus (T2DM): Semaglutide is used as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. It can be administered via subcutaneous injection or oral tablets.
  • Cardiovascular Benefits: Clinical trials show that semaglutide oral tablets are non-inferior to placebo for major adverse cardiovascular events (MACE), though they are not approved specifically for CV event reduction.
  • Weight Management: Semaglutide subcutaneous injection is used for weight loss and chronic weight management in obese or overweight adults with weight-related comorbid conditions.
• Cardiovascular and Renal Benefits: GLP-1 RAs, including semaglutide, have shown efficacy in reducing cardiovascular outcomes and progression of renal disease in patients with established cardiovascular disease or chronic kidney disease.
• Usage Recommendations: For patients with high-risk cardiovascular disease or chronic kidney disease, GLP-1 RAs or SGLT2 inhibitors with proven cardiovascular benefits are recommended. GLP-1 RAs are preferred over insulin due to better efficacy in A1C reduction, lower hypoglycemia risk, and weight loss benefits.

• Classification: Cyanocobalamin is a synthetic form of vitamin B12, used to treat or prevent vitamin B12 deficiency.
• Forms and Stability: It is the most common form used in supplements and fortified foods due to its stability, though hydroxocobalamin is more biologically active.
• Chemical Properties: Contains cyanide in its structure, which stabilizes the molecule. It is less soluble in water and more air-stable than other forms of vitamin B12.
• Uses:
  • Vitamin B12 Deficiency: Often due to conditions such as pernicious anemia, malabsorption issues, gastrointestinal pathology, or certain medication use.
  • Dosage Forms: Available as tablets, nasal spray, and injection.
• Manufacturing: Produced through bacterial fermentation and known for its stability and ease of crystallization.

• Semaglutide: Not recommended as first-line therapy but can be used in combination with other treatments for patients with high cardiovascular risk or those requiring injectable medication.
• Cyanocobalamin: Recommended for individuals with vitamin B12 deficiency due to various conditions or medication effects.

Both medications serve distinct purposes: semaglutide for diabetes and weight management, and cyanocobalamin for vitamin B12 deficiency.

• Class: Incretin mimetic, specifically a glucagon-like peptide-1 (GLP-1) receptor agonist.
• Structure: Semaglutide has 94% sequence homology to human GLP-1.
• Action:
  • GLP-1 Receptor Activation: Semaglutide binds to and activates GLP-1 receptors. GLP-1, an endogenous incretin, is released after carbohydrate or fat intake and plays a crucial role in glucose homeostasis.
  • Effects on Insulin and Glucagon:
    • Increased Insulin Secretion: Enhances glucose-dependent insulin synthesis and secretion from pancreatic beta cells.
    • Decreased Glucagon Secretion: Suppresses glucagon release, reducing glucose production by the liver.
  • Additional Effects:
    • Slowed Gastric Emptying: Delays the rate at which food exits the stomach, contributing to reduced postprandial glucose spikes.
    • Reduced Food Intake: Helps in reducing appetite and food consumption.
    • Beta-Cell Proliferation: Promotes the growth of insulin-producing beta cells in the pancreas.
  • Pharmacokinetics: Semaglutide has a long half-life due to its binding to albumin, which reduces renal clearance and protects it from metabolic degradation. It is stabilized against degradation by the DPP-4 enzyme.

• Class: Synthetic form of vitamin B12 (cobalamin).
• Role and Functions:
  • Cell Division and Growth: Essential for cellular processes, including DNA synthesis, protein metabolism, and myelin formation.
  • Enzymatic Cofactor:
    • Methionine Synthase: Catalyzes the regeneration of methionine from homocysteine, critical for methylation reactions involved in DNA, RNA, and protein synthesis.
    • Methylmalonyl-CoA Mutase: Converts methylmalonyl-CoA to succinyl-CoA, aiding in the metabolism of odd-chain fatty acids and branched-chain amino acids.
  • Binding and Transport:
    • Plasma Protein Binding: Cyanocobalamin binds to specific cobalamin-binding proteins (transcobalamin I and II) in the bloodstream, facilitating its uptake into tissues.
  • Deficiency Effects:
    • Anemia: Deficiency leads to impaired DNA synthesis and megaloblastic anemia due to the functional folate deficiency.
    • Neurological Symptoms: Inadequate vitamin B12 levels can result in neurological damage due to the accumulation of methylmalonyl-CoA.

• Semaglutide: Effective in improving glycemic control and promoting weight loss. Useful for patients with Type 2 diabetes and those needing weight management.
• Cyanocobalamin: Rapidly corrects megaloblastic anemia and mitigates gastrointestinal and neurological symptoms of vitamin B12 deficiency. Essential for individuals with absorption issues or increased needs for vitamin B12.

• Contraindications:
  • Hypersensitivity Reactions: Contraindicated in individuals with a history of angioedema, anaphylaxis, or other severe hypersensitivity reactions to semaglutide or other GLP-1 receptor agonists. Discontinue use if a serious hypersensitivity reaction occurs.
  • Thyroid Cancer: Not recommended for patients with a personal or family history of thyroid C-cell tumors (e.g., medullary thyroid carcinoma) or multiple endocrine neoplasia syndrome type 2 (MEN 2). There is a risk of thyroid C-cell tumors observed in animal studies, though its relevance to humans is not fully established.
  • Type 1 Diabetes: Should not be used for treating type 1 diabetes mellitus.
  • Pregnancy: Not recommended during pregnancy due to potential harm to the fetus. Discontinue if pregnancy occurs, and use effective contraception during treatment.
• Precautions:
  • Hypoglycemia: Monitor for hypoglycemia, especially in combination with sulfonylureas or insulin. Educate patients on recognizing and managing hypoglycemia, and consider dose adjustments of other antidiabetic agents.
  • Pancreatitis: Use with caution in patients with a history of pancreatitis. Monitor for symptoms of pancreatitis and discontinue if confirmed.
  • Gallbladder Disease: Caution in patients with a history of gallbladder disease. Monitor for signs of cholelithiasis and cholecystitis, and consider preventive measures for patients at high risk.
  • Diabetic Retinopathy: Closely monitor patients with a history of diabetic retinopathy, as there is an increased risk of diabetic retinopathy complications.
  • Renal Impairment: Use with caution in patients with renal impairment or end-stage renal disease, and monitor renal function regularly.
  • Suicidal Ideation: Be cautious in patients with a history of depression or suicidal ideation. Monitor for changes in mood or behavior and discontinue if suicidal thoughts or behaviors develop.
  • Lactation: Caution is advised during lactation. Oral semaglutide is not recommended during breastfeeding due to potential risks.
  • Elderly: Special care should be taken to prevent hypoglycemia in elderly patients due to increased risk. Regular monitoring and possible adjustments of treatment regimens are necessary.

• Contraindications:
  • Hypersensitivity: Contraindicated in individuals with hypersensitivity to cobalt or cobalamin due to the risk of severe allergic reactions.
• Warnings:
  • Leber’s Disease: Use with caution in patients with early Leber’s disease due to risk of severe optic atrophy.
  • Severe Megaloblastic Anemia: Intense treatment may lead to hypokalemia and potential sudden death. Careful monitoring is essential.
  • Renal Impairment: Use cautiously in patients with renal impairment, including premature neonates, due to the risk of aluminum toxicity.
  • Benzyl Alcohol: Avoid formulations containing benzyl alcohol in premature neonates and those with hypersensitivity due to the risk of “gasping syndrome.”
• Monitoring:
  • Allergy Testing: Conduct an intradermal test dose for suspected hypersensitivity to cobalt or other components of cobalamin.
  • Laboratory Tests: Monitor serum vitamin B12, folate, iron, hematocrit, and reticulocyte count before and during treatment. Regular monitoring of potassium levels and platelet count is also required.
  • Additional Factors: Consider factors that may affect therapeutic response, such as age, concurrent medical conditions (e.g., renal insufficiency, diabetes), and interaction with other medications.

• Hypoglycemia:
  • Monotherapy Trials:
    • Severe hypoglycemia (requiring assistance) not reported.
    • Symptomatic hypoglycemia (glucose ≤70 mg/dL) in 1.6% to 3.8% of patients.
  • Combination with Insulin:
    • Severe hypoglycemia reported in 1.5%.
    • Symptomatic hypoglycemia in 16.7% to 29.8%.
  • Combination with Sulfonylurea:
    • Severe hypoglycemia in 0.8% to 1.2%.
    • Symptomatic hypoglycemia in 17.3% to 24.4%.
  • Oral Tablets:
    • Severe hypoglycemia in 1% (7 mg) and 0% (14 mg) of patients.
    • Blood glucose ≤54 mg/dL in 6% (14 mg) and 3% (placebo).
• Gastrointestinal (GI) Events:
  • Common: Nausea (11%-44%), vomiting (5%-24%), diarrhea (8.5%-30%).
  • Less common: Abdominal pain, distention, constipation, dyspepsia, etc.
  • Appendicitis: Reported in 0.5% of patients receiving semaglutide for weight management.
• Gallbladder Disease:
  • Cholelithiasis: 1.5% (0.5 mg), 0.4% (1 mg), 1% (oral 7 mg), 1.6% (weight management).
  • Cholecystitis: 0.6% (weight management).
• Other Adverse Reactions:
  • Fatigue, dysgeusia, dizziness.
  • Injection site reactions: 0.2% (T2DM), 1.4% (weight management).
  • Antibody formation: 1% to 2.9% of patients developed anti-semaglutide antibodies.
  • Acute renal failure: Increased risk with severe GI reactions.
  • Hyperamylasemia and hyperlipasemia observed.
  • Acute pancreatitis: 0.3 to 0.33 cases per 100 patient-years.
  • Sinus tachycardia: Mean increase in heart rate of 1 to 4 bpm.
  • Hair loss (alopecia): 3% (weight management).
  • Diabetic retinopathy: Increased risk with rapid glucose control.
• Thyroid Tumors: Potential risk based on rodent studies; human risk is unclear.

• Generalized: Anaphylaxis and rare cases of death.
• Cardiovascular:
  • Pulmonary edema and heart failure during early treatment.
  • Peripheral vascular thrombosis.
• Hematological: Polycythemia vera (rare blood cancer).
• Gastrointestinal: Mild, transient diarrhea.
• Dermatological: Itching and transient rash.
• Miscellaneous: Feeling of swelling of the entire body.

• Pregnancy:
  • Weight Management: Semaglutide is contraindicated during pregnancy for weight management. Weight loss offers no benefit to pregnant women and may harm the fetus. The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines recommend contraception for women of childbearing potential using semaglutide for weight loss. Discontinue semaglutide if pregnancy occurs.
  • Type 2 Diabetes Mellitus (T2DM): No adequate data or clinical studies are available to assess the risk for adverse developmental outcomes. Animal studies show embryofetal mortality, structural abnormalities, and growth alterations at doses below the maximum recommended human dose (MRHD). In rabbits and monkeys, early pregnancy losses and structural abnormalities were observed at lower doses than the MRHD. Salcaprozate sodium (SNAC), an absorption enhancer in oral semaglutide, crosses the placenta and affects fetal development. Insulin is the recommended treatment for diabetes in pregnancy as it does not cross the placenta.
• Breastfeeding:
  • Injectable Semaglutide: Use with caution; no data on human milk, effects on the infant, or milk production. In lactating rats, semaglutide was found in milk at lower levels than in maternal plasma.
  • Oral Semaglutide: Not recommended. SNAC is also present in rat milk, and its effects on human infants are unknown. Alternatives like insulin or other oral hypoglycemics with a known safety profile may be considered during breastfeeding. Monitor the infant for hypoglycemia if alternative medications are used.

• Pregnancy:
  • Category C: No well-controlled studies in humans or animals. Normal daily intake during pregnancy is not associated with maternal or fetal harm. Vitamin B12 requirements increase during pregnancy. Parenteral administration should be considered if benefits outweigh the risks.
• Breastfeeding:
  • Compatibility: Cyanocobalamin is excreted in breast milk at levels similar to maternal plasma. The American Academy of Pediatrics considers it compatible with breastfeeding. Normal daily intake is not associated with adverse effects, and lactating women are recommended to consume 4 mcg daily.

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