Metformin

Brand names: FORTAMET, GLUCOPHAGE, Glyburide and Metformin Hydrochloride, KOMBIGLYZE, Metformin Hydrochloride, Pioglitazone and Metformin Hydrocholride, Pioglitazone and metformin, metformin hydrochloride, Metformin

Boxed warning

WARNING: LACTIC ACIDOSIS WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin- associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 ) 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 only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin- associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [ see Warnings and Precautions (5.1) ]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [ see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [ see Warnings and Precautions (5.1) ].

Warnings

BOXED WARNING - LACTIC ACIDOSIS: Postmarketing cases of metformin-associated lactic acidosis have caused death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Risk factors include renal impairment, certain drug combinations, age over 65, contrast imaging procedures, surgery, hypoxic states, excessive alcohol, and hepatic impairment. If lactic acidosis is suspected, discontinue immediately and seek prompt hemodialysis. Additional Warnings: - Vitamin B12 deficiency may occur; monitor hematologic parameters annually and B12 levels every 2-3 years - Increased hypoglycemia risk when combined with insulin or insulin secretagogues - No conclusive evidence of macrovascular risk reduction

Contraindications

4 CONTRAINDICATIONS Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 , 5.1 ) Hypersensitivity to metformin ( 4 ) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. ( 4 ) Metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [ see Warnings and Precautions (5.1) ]. Hypersensitivity to metformin. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

Overdose

10 OVERDOSAGE Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [ see Warnings and Precautions (5.1) ]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Drug interactions

7 DRUG INTERACTIONS Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7 ) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use ( 7 ) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake ( 7 ) Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets.

Uses

Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Dosage forms & strengths

Tablet Tablet, Extended Release Tablet, Film Coated Tablet, Film Coated, Extended Release POWDER TABLET, FILM COATED, EXTENDED RELEASE TABLET, EXTENDED RELEASE

GLYBURIDE 1.25 mg METFORMIN HYDROCHLORIDE 250 mg GLYBURIDE 2.5 mg METFORMIN HYDROCHLORIDE 500 mg METFORMIN HYDROCHLORIDE 1000 mg METFORMIN HYDROCHLORIDE 750 mg METFORMIN HYDROCHLORIDE 850 mg PIOGLITAZONE HYDROCHLORIDE 15 mg metformin hydrochloride 850 mg pioglitazone hydrochloride 15 mg saxagliptin hydrochloride 5 mg metformin hydrochloride 1000 mg METFORMIN HYDROCHLORIDE 1 kg/kg METFORMIN HYDROCHLORIDE 500 mg/1 METFORMIN HYDROCHLORIDE 1000 mg/1

2 DOSAGE AND ADMINISTRATION Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew ( 2.1 ) Starting dose: 500 mg orally once daily with the evening meal ( 2.1 ) Increase the dose in increments of 500 mg weekly, up to a maximum of 2,000 mg once daily with the evening meal ( 2.1 ) Patients receiving metformin hydrochloride (HCl) tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily ( 2.1 ) Renal Impairment: Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 ( 2.2 ) Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 ( 2.2 ) Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m 2 ( 2.2 ) Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 ( 2.2 ) Discontinuation for Iodinated Contrast Imaging Procedures: Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.3 ) 2.1 Adult Dosage and Administration Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg orally once daily with the evening meal. Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal. If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2,000 mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1,000 mg twice daily. Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter. Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride extended-release tablets if the patient's eGFR later falls below 30 mL/minute/1.73 m 2 [ see Contraindications (4) and Warnings and Precautions (5.1) ]. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable.