Benformin

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM)
  – As monotherapy or in combination with other antidiabetic agents (e.g., insulin, sulfonylureas, DPP-4 inhibitors) to improve glycemic control in adults and children (≥10 years).
• Polycystic Ovary Syndrome (PCOS) (off-label but widely accepted)
  – Improves insulin resistance, regulates ovulation, and may assist in restoring menstrual regularity.
• Prevention of Type 2 Diabetes (in high-risk individuals)
  – Delays or prevents T2DM in patients with impaired glucose tolerance, impaired fasting glucose, or a history of gestational diabetes.

Route of Administration: Oral
Formulations: Immediate-release (IR), Extended-release (ER/XR)

Adults (Type 2 Diabetes Mellitus):

• Immediate-release (IR):
• Initial: 500 mg orally twice daily or 850 mg once daily with meals.
• Maintenance: Increase by 500 mg weekly or 850 mg every 2 weeks, as tolerated.
• Max dose: 2,550 mg/day (divided into 2–3 doses).
• Extended-release (ER):
• Initial: 500–1,000 mg once daily with evening meal.
• Titration: Increase by 500 mg every week.
• Max dose: 2,000 mg once daily (or 1,000 mg twice daily if needed).

Pediatrics (≥10 years):

• IR: Start at 500 mg twice daily with meals; max 2,000 mg/day.
• ER: Start at 500 mg once daily; max 2,000 mg/day.

Elderly:

• Use with caution due to age-related decline in renal function.
• Monitor renal function before and during treatment.

Renal Impairment:

• eGFR ≥60 mL/min/1.73 m²: No dose adjustment.
• eGFR 45–59: Max 2,000 mg/day; monitor renal function every 3–6 months.
• eGFR 30–44: Max 1,000 mg/day; avoid starting metformin.
• eGFR <30: Contraindicated.

Hepatic Impairment:

• Use is not recommended due to increased risk of lactic acidosis.

Metformin acts primarily by decreasing hepatic glucose production (gluconeogenesis). It also enhances insulin sensitivity in peripheral tissues such as muscle and fat, leading to increased glucose uptake and utilization. Furthermore, it delays intestinal glucose absorption. Metformin does not increase insulin secretion from pancreatic β-cells, hence carries a low risk of hypoglycemia when used alone.

• Absorption: Oral bioavailability ~50–60% (IR); delayed with food but overall exposure is similar.
• Peak Plasma Time: IR: ~2–3 hours; ER: ~6–8 hours.
• Distribution: Not protein-bound; volume of distribution ~654 L.
• Metabolism: Not metabolized by liver.
• Elimination: Primarily renal (90% unchanged); excreted via active tubular secretion.
• Half-life: ~6.2 hours (plasma); ~17.6 hours (in blood due to RBC uptake).

• Pregnancy:
• FDA Pregnancy Category B (old classification); human studies have not demonstrated fetal harm. Often used in PCOS or gestational diabetes when insulin is not suitable.
• Lactation:
• Metformin is excreted in breast milk in small amounts. Considered compatible with breastfeeding with minimal risk to the infant. Monitor infant for gastrointestinal upset or hypoglycemia.

• Primary Class: Biguanide Antidiabetic Agent
• Subclass: Insulin Sensitizer

• Known hypersensitivity to metformin or any excipient
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Acute or chronic metabolic acidosis (e.g., lactic acidosis, ketoacidosis)
• Conditions predisposing to hypoxia (e.g., cardiac/respiratory failure, recent myocardial infarction)
• Hepatic failure or significant liver disease
• Alcoholism or binge drinking

• Lactic Acidosis:
• Rare but serious; monitor renal function regularly. Avoid in patients with high risk (e.g., sepsis, hypoperfusion, severe dehydration).
• Radiologic Procedures:
• Discontinue metformin temporarily before iodinated contrast imaging in patients with eGFR 30–60 mL/min/1.73 m²; restart after 48 hours if renal function is stable.
• Renal Monitoring:
• Baseline and periodic assessment of eGFR is essential.
• Vitamin B12 Deficiency:
• Long-term use may reduce B12 absorption. Monitor annually in long-term users.

Common (≥1%):

• Gastrointestinal: Nausea, vomiting, diarrhea, flatulence, abdominal discomfort (especially during initiation)
• Neurological: Headache, metallic taste
• Metabolic: Weight loss or neutral effect

Less Common but Serious:

• Lactic acidosis (rare but fatal)
• Vitamin B12 deficiency
• Hepatotoxicity (rare)

Onset: GI side effects usually occur within the first few weeks; often transient.

• Cationic drugs (e.g., ranolazine, dolutegravir): May increase metformin levels via renal tubular competition.
• Alcohol: Increases risk of lactic acidosis.
• Iodinated contrast media: Risk of acute kidney injury and lactic acidosis.
• Diuretics (e.g., furosemide): May increase risk of dehydration and renal impairment.
• Beta-blockers: May mask hypoglycemic symptoms.
• CYP450: Metformin is not metabolized by CYP enzymes.

• ADA 2024 & EASD 2023 Guidelines:
• Metformin remains first-line therapy for T2DM unless contraindicated.
• In patients with high CV or renal risk, GLP-1 RAs or SGLT2 inhibitors may be considered early.
• FDA Update:
• Reinforced guidance on safe use with contrast agents and monitoring of renal function.
• NICE (UK):
• Recommends use in prediabetes and PCOS when lifestyle modifications are insufficient.

• Tablets (IR/ER):
• Store at 20°C to 25°C (68°F to 77°F).
• Excursions allowed to 15°C–30°C.
• Protect from moisture and heat.
• Keep tightly closed in original container.
• Handling:
• Do not split or crush ER tablets.
• Use only if packaging is intact and tablets are undamaged.