Usage
- Metformin + Methylcobalamin is primarily prescribed for the management of type 2 diabetes mellitus, especially in patients with diabetic peripheral neuropathy or at risk of vitamin B12 deficiency.
- Pharmacological Classification: Metformin is classified as a biguanide antidiabetic agent, and Methylcobalamin is a vitamin (vitamin B12).
- Mechanism of Action: Metformin decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Methylcobalamin is a cofactor in various metabolic processes, including nerve cell metabolism, and helps prevent and treat vitamin B12 deficiency, which can be exacerbated by metformin.
Alternate Names
- While the combination doesn’t have a specific international nonproprietary name (INN), it is often referred to simply as Metformin-Methylcobalamin.
- Brand Names: This combination is marketed under various brand names such as Rejumet, Sugamet MC, Formin Plus and others. Brand names may vary regionally.
How It Works
- Pharmacodynamics: Metformin primarily works by reducing hepatic glucose output and enhancing insulin action. Methylcobalamin is essential for myelin synthesis and nerve function, thus addressing peripheral neuropathy.
- Pharmacokinetics: Metformin is absorbed from the gastrointestinal tract and is not extensively metabolized. It is excreted primarily by the kidneys. Methylcobalamin is absorbed via passive diffusion and active transport and is widely distributed throughout the body, including the liver, where it is stored. It is primarily excreted in bile, with some renal excretion.
- Mode of Action: Metformin activates AMP-activated protein kinase (AMPK), leading to a reduction in hepatic gluconeogenesis. It also enhances insulin-stimulated glucose uptake in peripheral tissues. Methylcobalamin acts as a coenzyme in the conversion of homocysteine to methionine, which is crucial for myelin synthesis and nerve function.
- Elimination Pathways: Metformin is primarily eliminated unchanged through renal excretion. Methylcobalamin undergoes enterohepatic circulation with biliary excretion being the major route, and some renal elimination.
Dosage
Standard Dosage
Adults:
- The typical starting dosage is 500 mg of Metformin and 750 mcg or 1500 mcg of Methylcobalamin, once or twice daily, with meals. The dose can be titrated upwards based on individual patient response and blood glucose control. The maximum daily dose of metformin is generally 2550 mg, although some formulations allow for higher doses in patients with good renal function.
Children:
- Metformin use is generally recommended for children above 10 years of age with type 2 diabetes when dietary management and exercise alone are insufficient. Dosing should be individualized based on the child’s weight and blood glucose levels, starting at a low dose and titrating gradually. Methylcobalamin dosing in children with vitamin B12 deficiency should be determined based on severity and age.
Special Cases:
- Elderly Patients: Start with a lower dose due to potential age-related decline in renal function and titrate cautiously. Close monitoring of renal function is recommended.
- Patients with Renal Impairment: Metformin is contraindicated in patients with severe renal impairment (eGFR < 30 ml/min). Dosage adjustments are required in patients with moderate renal impairment (eGFR 30-45 ml/min), and close monitoring of renal function is essential. Methylcobalamin generally does not require dose adjustment in renal impairment.
- Patients with Hepatic Dysfunction: Use with caution in patients with hepatic impairment, as it may increase the risk of lactic acidosis. Close monitoring is recommended. Methylcobalamin dose adjustment may be necessary in severe liver disease.
- Patients with Comorbid Conditions: Patients with heart failure, severe infections, or dehydration should be closely monitored, as Metformin can worsen these conditions.
Clinical Use Cases
The dosage in the following cases should be determined based on the underlying condition and any comorbidities. Renal and hepatic function should be considered when determining the dose. Metformin may need to be withheld in certain clinical settings.
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations (e.g., status epilepticus, cardiac arrest)
Dosage Adjustments
- Dosage adjustments are essential in patients with renal or hepatic impairment based on estimated glomerular filtration rate (eGFR) and liver function tests.
- Consideration for drug interactions and comorbidities are important for adjusting the dosage.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea, stomach upset, changes in taste (metallic), loss of appetite, headache, weakness, and fatigue.
Rare but Serious Side Effects
- Lactic acidosis (a buildup of lactic acid in the blood). Symptoms include: severe tiredness, difficulty breathing, feeling cold, a slow heartbeat, muscle pain, abdominal pain, vomiting.
- Hypoglycemia (low blood sugar), particularly when combined with other antidiabetic agents.
- Vitamin B12 deficiency (though less likely with this combination) may lead to neurological symptoms.
- Allergic reactions
Long-Term Effects
- Prolonged metformin use may potentially cause vitamin B12 deficiency. Regular monitoring of B12 levels is recommended.
Adverse Drug Reactions (ADR)
- Lactic acidosis is a rare but serious ADR that requires immediate medical attention.
Contraindications
- Hypersensitivity to Metformin or Methylcobalamin.
- Severe renal impairment (eGFR < 30 mL/min).
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- Severe hepatic impairment.
- Congestive heart failure, acute myocardial infarction.
- Conditions predisposing to hypoxia.
Drug Interactions
- Alcohol (increases the risk of lactic acidosis).
- Cationic drugs (amiloride, digoxin, morphine, ranitidine, trimethoprim, vancomycin).
- Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide).
- Some heart medicines (ranolazine, dolutegravir).
- H2 blockers (cimetidine).
- Other antidiabetic drugs (sulfonylureas, insulin).
- Iodinated contrast media.
- Corticosteroids.
Pregnancy and Breastfeeding
- Pregnancy: Metformin is generally considered safe during pregnancy, but consult with a physician before use. Methylcobalamin is also generally considered safe.
- Breastfeeding: Metformin passes into breast milk in small amounts. While generally considered safe, monitor the infant for any adverse effects. Consult with a physician before use.
Drug Profile Summary
- Mechanism of Action: Metformin reduces hepatic glucose production and enhances insulin action. Methylcobalamin is essential for nerve function.
- Side Effects: Nausea, vomiting, diarrhea, lactic acidosis (rare), hypoglycemia.
- Contraindications: Renal failure, hepatic failure, metabolic acidosis.
- Drug Interactions: Alcohol, cationic drugs, other antidiabetics.
- Pregnancy & Breastfeeding: Generally safe, consult physician.
- Dosage: Individualized based on age, renal function, and response.
- Monitoring Parameters: Blood glucose levels, HbA1c, renal function (eGFR), vitamin B12 levels.
Popular Combinations
- Metformin is frequently combined with other antidiabetic agents like sulfonylureas (e.g., glimepiride, glipizide) or DPP-4 inhibitors (e.g., sitagliptin, linagliptin) for synergistic glucose control.
- Methylcobalamin may be combined with other B vitamins in the treatment of peripheral neuropathy.
Precautions
- General Precautions: Assess renal function, hepatic function, and vitamin B12 status before starting therapy. Monitor blood glucose and HbA1c levels regularly.
- Specific Populations: Renal and hepatic adjustments based on individual status.
- Pregnant Women: Consult a physician.
- Breastfeeding Mothers: Monitor infant for potential side effects, consult physician.
- Children & Elderly: Dosage adjustment may be necessary.
- Lifestyle Considerations: Encourage healthy diet and exercise. Avoid excessive alcohol.
FAQs (Frequently Asked Questions)
A: The initial dose is usually 500 mg metformin and 750 mcg or 1500 mcg methylcobalamin once or twice daily, taken with meals. The dose may be adjusted according to individual patient needs.
A: Metformin controls blood glucose levels, a key factor in managing neuropathy. Methylcobalamin is involved in nerve regeneration and function, helping to alleviate neuropathic symptoms.
A: Alcohol, cationic drugs, other antidiabetic medications, and iodinated contrast media can interact with this combination.
A: While considered relatively safe, it’s important to consult a doctor before using during pregnancy to assess potential benefits and risks.
A: Gastrointestinal issues like nausea, vomiting, diarrhea, stomach upset are common. Less frequent side effects include changes in taste and headache.
A: Lactic acidosis is a rare but severe side effect involving a buildup of lactic acid in the blood. It is more common in people with impaired kidney function taking metformin.
A: Take this medication orally with meals, as directed by your physician. Never crush, chew, or break sustained release tablets.
A: Excessive alcohol consumption is not advised while on this medication, as it increases the risk of lactic acidosis and can interact negatively with metformin.
A: Generally, it’s safe to drive, but be aware of possible side effects like dizziness or fatigue, especially when starting the medication or adjusting the dose. If you experience these, avoid driving until the effects subside.
Q10: What should I do if I miss a dose?
A: Take the missed dose as soon as you remember. If it’s almost time for your next dose, skip the missed one and continue with your regular schedule. Do not double the dose.
