Schedule H

Oral

• Tablets (Immediate-release): 250 mg, 500 mg, 850 mg, 1000 mg

• Tablets (Modified-release/Sustained-release/Extended-release): 500 mg, 750 mg, 1000 mg

• Oral solution: NOT AVAILABLE in India as monotherapy

Fixed-Dose Combinations (FDCs) Available:

• Metformin + Glimepiride

• Metformin + Gliclazide

• Metformin + Glipizide

• Metformin + Vildagliptin

• Metformin + Sitagliptin

• Metformin + Linagliptin

• Metformin + Teneligliptin

• Metformin + Empagliflozin

• Metformin + Dapagliflozin

• Metformin + Canagliflozin

• Metformin + Pioglitazone

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Type 2 Diabetes Mellitus (Monotherapy or Combination Therapy)

First-line pharmacological therapy along with lifestyle intervention as per ICMR Guidelines 2018

Immediate-Release Formulation:

Parameter Dose

Starting dose 500 mg orally once or twice daily with meals

Titration Increase by 500 mg every 7–14 days based on glycaemic response and GI tolerability

Usual maintenance dose 1500–2000 mg/day in 2–3 divided doses with meals

Maximum dose 2550 mg/day (in divided doses)

Modified-Release/Extended-Release Formulation:

Parameter Dose

Starting dose 500 mg orally once daily with evening meal

Titration Increase by 500 mg every 1–2 weeks based on glycaemic response

Usual maintenance dose 1500–2000 mg once daily with evening meal

Maximum dose 2000 mg/day (once daily)

Clinical Notes:

• Administer with meals to reduce GI side effects

• MR/SR/XR formulations should be swallowed whole; do not crush or chew

• Reduces hepatic glucose output and improves peripheral insulin sensitivity

• Does not cause hypoglycaemia when used as monotherapy

• Provides modest weight loss or weight neutrality (advantage over sulfonylureas)

• Continue metformin when adding other antidiabetic agents including insulin (unless contraindicated)

1. Polycystic Ovary Syndrome (PCOS)

For metabolic and reproductive benefits; used for insulin resistance, menstrual irregularity, and ovulation induction

Parameter Dose

Starting dose 500 mg orally once daily with food

Titration Increase by 500 mg every 1–2 weeks to improve GI tolerance

Usual maintenance dose 1500–2000 mg/day in 2–3 divided doses

Maximum dose 2550 mg/day (typically ≤2000 mg/day in practice)

Clinical Notes:

• Benefits include improved insulin sensitivity, restoration of ovulation, and menstrual regularity

• May be used alone or with clomiphene for ovulation induction

• Weight loss and lifestyle modification should accompany pharmacotherapy

• Continue for at least 3–6 months to assess efficacy

• Not a substitute for lifestyle intervention

Secondary Indications – Adults (Off-label)

Indication Dose Duration Supervision Evidence Basis

Prevention of Type 2 Diabetes in High-Risk Individuals (Prediabetes/IFG/IGT) (OFF-LABEL) Starting: 500 mg once daily; Titration: increase to 500–1000 mg twice daily as tolerated; Maintenance: 1000–1700 mg/day Long-term; indefinite if risk factors persist Specialist recommended DPP trial; Indian Diabetes Prevention Programme (IDPP) data; ICMR guidance for high-risk individuals with metabolic syndrome not responding to lifestyle alone

Gestational Diabetes Mellitus (GDM) — Alternative to Insulin (OFF-LABEL) Starting: 500 mg once or twice daily; Titration: increase by 500 mg/week; Maintenance: 1000–2500 mg/day in divided doses Duration of pregnancy Specialist only (Obstetrician/Endocrinologist) MiG trial; Indian obstetric practice; used when insulin is declined, unavailable, or as adjunct

Antipsychotic-Induced Weight Gain and Metabolic Syndrome (OFF-LABEL) 500–2000 mg/day in divided doses Long-term as needed Specialist only (Psychiatrist) RCTs showing benefit in clozapine/olanzapine-induced weight gain; Indian psychiatric practice

Non-Alcoholic Fatty Liver Disease (NAFLD) with Insulin Resistance (OFF-LABEL) 1000–2000 mg/day in divided doses Long-term Specialist recommended (Gastroenterology/Endocrinology) Limited evidence; may improve insulin resistance but no proven effect on liver histology; used in Indian practice for associated metabolic syndrome

PAEDIATRIC DOSING (Specialist Only)

⚠️ Not recommended in children below 10 years of age except under specialist endocrinology supervision.

Primary Indication: Type 2 Diabetes Mellitus (Children ≥10 years)

Immediate-Release Formulation:

Parameter Dose

Starting dose 500 mg orally once daily with meals

Titration Increase by 500 mg every 1–2 weeks based on glycaemic response and GI tolerability

Usual maintenance dose 1000–2000 mg/day in 2–3 divided doses

Maximum dose 2000 mg/day

Modified-Release/Extended-Release Formulation (Children ≥10 years):

Parameter Dose

Starting dose 500 mg orally once daily with evening meal

Titration Increase by 500 mg every 1–2 weeks

Usual maintenance dose 1000–2000 mg once daily

Maximum dose 2000 mg/day

Safety Monitoring:

• Monitor for GI intolerance (nausea, diarrhoea, abdominal pain)

• Renal function at baseline and annually

• HbA1c every 3 months

• Growth and development monitoring

• Vitamin B12 levels annually if on long-term therapy

Clinical Notes:

• Always combine with lifestyle intervention (diet, physical activity)

• Preferred first-line agent in paediatric Type 2 DM per IAP guidelines

• Start low and titrate slowly to minimise GI side effects

Secondary Indications – Paediatrics (Off-label)

Indication Age Dose Duration Supervision Evidence Basis

Polycystic Ovary Syndrome (PCOS) in Adolescent Girls (OFF-LABEL) ≥12 years Starting: 500 mg once daily; Titration: increase by 500 mg every 1–2 weeks; Maintenance: 1000–2000 mg/day in divided doses; Maximum: 2000 mg/day ≥6 months; reassess periodically Specialist only (Paediatric Endocrinology/Adolescent Gynaecology) IAP adolescent PCOS guidelines; Indian paediatric endocrinology practice

Obesity with Insulin Resistance (OFF-LABEL) ≥10 years 500–2000 mg/day in divided doses Long-term with lifestyle intervention Specialist only (Paediatric Endocrinology) Limited evidence; used as adjunct to lifestyle modification in severe obesity with metabolic complications

Age Restrictions:

• Not recommended below 10 years of age for Type 2 DM

• Use in children <10 years only under exceptional circumstances with paediatric endocrinology supervision

• Not for Type 1 Diabetes (may be considered as adjunct in insulin-resistant T1DM under specialist care — very limited evidence)

Additional Notes:

• Reassess eGFR before initiating and at least annually (more frequently if eGFR declining or risk factors present)

• Withhold metformin temporarily during acute illness with risk of dehydration or AKI (sick day rules)

• Withhold 48 hours before and after iodinated contrast administration if eGFR <60 or other risk factors for contrast-induced nephropathy

Note: Liver disease impairs lactate metabolism and increases lactic acidosis risk even without significant renal impairment.

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)

• Acute or chronic metabolic acidosis including diabetic ketoacidosis (DKA)

• Conditions predisposing to lactic acidosis:

• Severe dehydration

• Shock (cardiogenic, septic, hypovolaemic)

• Acute or decompensated heart failure

• Acute myocardial infarction

• Severe hypoxia (respiratory failure, severe COPD exacerbation)

• Severe hepatic impairment / Hepatic failure

• History of lactic acidosis

• Chronic alcohol abuse or acute alcohol intoxication

• 48 hours before and after surgery requiring general anaesthesia (due to risk of acute renal impairment)

• Known hypersensitivity to metformin

• Chronic kidney disease (eGFR 30–60) — requires dose adjustment and close monitoring

• Elderly patients — often have reduced renal reserve; assess eGFR before and during therapy

• Conditions predisposing to dehydration (diarrhoea, vomiting, fever) — temporarily withhold metformin

• Congestive heart failure (stable NYHA Class I-II may use with caution; avoid in Class III-IV)

• Excessive alcohol intake (increased lactate production)

• Planned iodinated contrast procedures — withhold 48 hours before and after; resume only after confirming stable renal function

• Concurrent use of nephrotoxic drugs

• Patients undergoing major surgery — temporarily discontinue

• Vitamin B12 deficiency risk with long-term use — monitor periodically

Parameter Information

Overall Safety Limited but reassuring human data; no confirmed teratogenicity; considered acceptable when indicated

Risk Crosses placenta; theoretical concerns about fetal effects not substantiated in clinical studies

Preferred Alternatives Insulin is first-line for GDM and pre-existing T2DM in Indian obstetric guidelines

When Use May Be Justified GDM when insulin is declined, unavailable, or as adjunct to insulin for insulin resistance; PCOS-related infertility (may continue through first trimester with specialist guidance)

Monitoring Maternal blood glucose (FBG, PPBG, HbA1c); fetal growth by serial ultrasound; monitor for neonatal hypoglycaemia after delivery

Parameter Information

Compatibility Compatible with breastfeeding

Expected Drug Level in Milk Very low (approximately 0.5–1% of weight-adjusted maternal dose reaches infant)

Risk to Infant Minimal; no significant adverse effects reported in breastfed infants

Preferred Alternatives None — metformin is preferred over sulfonylureas for glycaemic control in breastfeeding mothers with T2DM

Infant Monitoring Feeding adequacy, weight gain (routine monitoring sufficient)

Parameter Recommendation

Starting dose 500 mg orally once daily with food

Titration Increase slowly (every 2 weeks); assess tolerability and renal function frequently

Maximum recommended Based on renal function; often limited to 1500–2000 mg/day

Increased Risks Lactic acidosis (age-associated decline in renal function); GI intolerance; vitamin B12 deficiency

Additional Precautions Assess eGFR before initiation and at least every 3–6 months; avoid in frail elderly with multiple comorbidities predisposing to lactic acidosis; use MR/XR formulations to improve GI tolerability; educate on sick day rules

Interacting Drug Mechanism Effect Management

Iodinated Contrast Media Contrast-induced nephropathy may impair metformin excretion Increased risk of lactic acidosis Withhold metformin 48 hours before and after contrast administration if eGFR <60 or other risk factors; resume only after confirming stable renal function

Excessive Alcohol Alcohol increases lactate production and impairs gluconeogenesis Significantly increased risk of lactic acidosis; risk of hypoglycaemia Avoid excessive/binge alcohol consumption; moderate intake acceptable with caution

Cimetidine Competes for renal tubular secretion Increased metformin plasma levels (up to 50%) Avoid combination or monitor closely; consider alternative H2 blocker (ranitidine, famotidine) or PPI

Dolutegravir Inhibits renal tubular secretion of metformin (OCT2/MATE inhibition) Increased metformin levels Monitor for metformin adverse effects; consider dose reduction if GI intolerance develops

Interacting Drug Effect Management

ACE Inhibitors / ARBs May impair renal function; potential for acute kidney injury Monitor eGFR; adjust metformin dose if renal function declines

Loop Diuretics / Thiazides Risk of dehydration and prerenal AKI; diuretics may worsen glucose tolerance Monitor hydration status, renal function, and glycaemic control

NSAIDs Risk of acute kidney injury, especially in dehydrated patients Use with caution; ensure adequate hydration; monitor renal function

Corticosteroids (systemic) Oppose glycaemic effects of metformin; may cause hyperglycaemia Monitor blood glucose; may need temporary increase in metformin dose or addition of other antidiabetic agents

Beta-blockers May mask hypoglycaemia symptoms (relevant when metformin combined with insulin/sulfonylureas) Counsel patient on hypoglycaemia awareness; less relevant with metformin monotherapy

Carbonic Anhydrase Inhibitors (topiramate, acetazolamide) May increase risk of lactic acidosis Use with caution; monitor for acidosis symptoms

Vancomycin Potential for additive nephrotoxicity Monitor renal function closely

Rifampicin Induces OCT1 transporter; may increase metformin uptake into hepatocytes May enhance metformin effect; monitor for GI side effects and hypoglycaemia

• Nausea (very common initially; usually transient)

• Diarrhoea

• Abdominal discomfort, bloating

• Flatulence

• Metallic taste (dysgeusia)

• Anorexia, decreased appetite

• Headache

Note: GI adverse effects are usually transient (first 2–4 weeks) and can be minimized by starting at low dose, slow titration, and taking with meals. MR/XR formulations may improve GI tolerability.

Adverse Effect Clinical Action

Lactic Acidosis (rare but potentially fatal; incidence ~3–10 per 100,000 patient-years) Medical emergency — discontinue metformin immediately; symptoms include malaise, myalgia, respiratory distress, abdominal pain, hypothermia, hypotension; check arterial lactate, pH, bicarbonate; supportive care; haemodialysis may be required in severe cases

Vitamin B12 Deficiency (with long-term use; incidence 5–10% after >4 years) Monitor serum B12 annually in long-term users; supplement if deficient; presents as macrocytic anaemia, peripheral neuropathy

Hepatotoxicity (very rare) Monitor LFTs if symptoms of hepatic dysfunction; discontinue if significant elevation

Hypoglycaemia (rare as monotherapy; occurs with insulin/sulfonylureas) Reduce dose of concomitant hypoglycaemic agent; patient education on recognition and management

Long-term (every 3–6 months) HbA1c (every 3–6 months); eGFR (at least annually; more frequently if eGFR <60 or declining); vitamin B12 (annually if on therapy >12 months); LFTs (periodically if hepatic concerns)

Special Situations Check renal function before and 48 hours after iodinated contrast procedures; withhold during acute illness with dehydration risk

Immediate-Release Tablets:

• Glyciphage™ (Franco-Indian) — 250 mg, 500 mg, 850 mg, 1000 mg

• Glycomet™ (USV) — 250 mg, 500 mg, 850 mg

• Gluformin™ (Abbott) — 500 mg, 850 mg

• Obimet™ (Corona Remedies) — 500 mg

• Bigomet™ (Aristo) — 500 mg, 850 mg

• Formin™ (Sanofi) — 500 mg

Modified-Release/Sustained-Release Tablets:

• Glyciphage SR™ (Franco-Indian) — 500 mg, 1000 mg

• Glycomet SR™ (USV) — 500 mg, 1000 mg

• Gluformin XR™ (Abbott) — 500 mg, 1000 mg

• Metlong™ (USV) — 500 mg SR

Fixed-Dose Combinations (Examples):

• Glyciphage G™ (Metformin + Glimepiride)

• Glycomet Trio™ (Metformin + Glimepiride + Pioglitazone/Voglibose)

• Galvus Met™ (Metformin + Vildagliptin)

• Janumet™ (Metformin + Sitagliptin)

• Trajenta Duo™ (Metformin + Linagliptin)

• Jardiance Met™ (Metformin + Empagliflozin)

⚠️ Note on FDCs: When using FDCs, ensure total metformin dose is calculated correctly to avoid under- or overdosing. FDCs may limit dose flexibility during titration.

Regulatory: Listed under NLEM 2022 (500 mg, 850 mg tablets); NPPA price controlled for scheduled strengths; widely available in government supply

1. First-line agent for Type 2 DM — Continue metformin unless contraindicated when adding other agents; proven cardiovascular benefit (UKPDS); no weight gain; no hypoglycaemia as monotherapy

1. GI tolerability strategy — Start low (500 mg once daily), titrate slowly (every 1–2 weeks), take with meals; if IR formulation not tolerated, switch to MR/SR/XR formulation for better GI tolerance

1. Sick day rules — Educate patients to temporarily withhold metformin during acute illness with dehydration risk (vomiting, diarrhoea, fever, reduced oral intake) or when undergoing procedures with contrast media; resume when eating and drinking normally and renal function stable

1. Contrast media protocol — Withhold 48 hours before and after iodinated contrast procedures if eGFR <60 or other AKI risk factors; confirm stable renal function before resuming

1. Vitamin B12 deficiency — Screen annually in long-term users (>3–4 years); higher risk in vegetarians, elderly, and those on higher doses; supplement if deficient to prevent irreversible neuropathy

1. PCOS and fertility — May improve ovulation rates; can be continued through conception and early pregnancy (discuss with obstetrician); transition to insulin for GDM if glycaemic targets not met

type-2-diabetes; biguanide; first-line-antidiabetic; PCOS; insulin-sensitiser; renal-caution; lactic-acidosis-risk; NLEM-India; pregnancy-acceptable; lactation-safe; paediatric-approved-≥10-years; cardiovascular-benefit; Schedule-H

RxIndia v1.0 — 29 Apr 2025

• CDSCO Product Information

• Indian Pharmacopoeia (IP)

• National List of Essential Medicines (NLEM) 2022

• API Textbook of Medicine

• ICMR Guidelines for Management of Type 2 Diabetes 2018

• AIIMS Drug Formulary and Treatment Protocols

• IAP Paediatric Endocrinology Guidelines

• IAP Adolescent PCOS Guidelines

• Harrison's Principles of Internal Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Indian Diabetes Prevention Programme (IDPP) Study

• MiG Trial (Metformin in Gestational Diabetes)

• WHO Essential Medicines List (paediatric support)