Metformin: Important Safety Information (ISI)

Read this information carefully before starting metformin. Discuss any questions with your provider.

What Is Metformin?

Metformin is a biguanide medication FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients (10 years and older) with type 2 diabetes. It is widely used off-label for prediabetes, insulin resistance, polycystic ovary syndrome (PCOS), and as a metabolic adjunct in weight management protocols. Available as immediate-release and extended-release tablets and oral solution under multiple brand and generic names.

Boxed Warning

WARNING: LACTIC ACIDOSIS. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Risk factors include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors), age 65 or older, having a radiological study with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce risk should be taken in patients with risk factors. If lactic acidosis is suspected, discontinue metformin and institute supportive measures.

Contraindications

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Hypersensitivity to metformin

Warnings and Precautions

• Lactic Acidosis: See Boxed Warning. Monitor renal function before starting and at least annually thereafter.
• Vitamin B12 Deficiency: Long-term use may decrease vitamin B12 levels. Periodic monitoring recommended.
• Hypoglycemia: When used alone, metformin does not typically cause hypoglycemia, but risk increases with insulin, sulfonylureas, or other insulin secretagogues.
• Concomitant Use with Insulin and Insulin Secretagogues: Lower dose of insulin or insulin secretagogue may be required.
• Use with Iodinated Contrast Imaging: Discontinue metformin at the time of, or before, an iodinated contrast imaging procedure in patients with eGFR 30 to 60 mL/min/1.73 m², history of liver disease, alcoholism, or heart failure, or who will be receiving intra-arterial iodinated contrast.
• Hypoxic States: Cardiovascular collapse, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis.
• Surgical Procedures: Withhold metformin during surgical procedures (other than minor) where intake of food and fluids is restricted; do not restart until oral intake has resumed and renal function is assessed.
• Alcohol Intake: Alcohol potentiates metformin’s effect on lactate metabolism. Warn against excessive alcohol intake.

Most Common Adverse Reactions

Most common adverse reactions reported in clinical trials:

• Diarrhea
• Nausea or vomiting
• Flatulence
• Abdominal discomfort or pain
• Indigestion
• Asthenia (weakness)
• Headache
• Metallic taste

Drug Interactions

Carbonic anhydrase inhibitors (e.g., topiramate, acetazolamide) may increase the risk of lactic acidosis. Drugs that reduce metformin clearance (e.g., ranolazine, vandetanib, dolutegravir, cimetidine) may increase metformin levels. Alcohol potentiates the effect of metformin on lactate metabolism. Iodinated contrast: hold metformin per imaging guidelines.

Use in Specific Populations

• Pregnancy: Limited human data. Some clinicians use metformin in gestational diabetes; insulin remains preferred. Discuss with your provider.
• Lactation: Metformin is present in human milk in small amounts. Generally compatible with breastfeeding.
• Pediatric Use: Approved in patients 10 years and older for type 2 diabetes.
• Geriatric Use: Assess renal function before starting and during therapy. Avoid use if eGFR is below 30.
• Renal Impairment: Contraindicated if eGFR below 30. Initiation not recommended if eGFR 30 to 45.
• Hepatic Impairment: Avoid use in patients with hepatic impairment due to potential for lactic acidosis.