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Metformin Hydrochloride Tablets

FDA Drug Information • Also known as: Metformin Hydrochloride

Brand Names
Metformin Hydrochloride
Route
ORAL
Dosage Form
TABLET, FILM COATED, EXTENDED RELEASE
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: LACTIC ACIDOSIS Post-marketing 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) ]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.

Description

11 DESCRIPTION Metformin hydrochloride extended-release tablets contain the biguanidine antihyperglycemic agent, metformin, in the form of monohydrochloride salt. The chemical name of metformin HCl is N, N-dimethylimidodicarbonimidic diamide hydrochloride with a molecular formula of C 4 H 11 N 5

  • HCl and a molecular weight of 165.63. Its structural formula is: Metformin HCl is a white or almost white crystals powder that is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. Metformin hydrochloride extended-release tablets deliver 500 mg or 1,000 mg of metformin HCl, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. In addition to the active ingredient metformin HCl, each tablet contains the following inactive ingredients: Povidone, Sodium Lauryl Sulfate, Magnesium Stearate, Cellulose Acetate, Polyethylene Glycol (PEG 400, PEG 8000), Triacetin, Hypromellose, Titanium Dioxide, Polysorbate 80, Ferrosoferric Oxide, Shellac. Metformin Meets USP Dissolution Test 5. structure-formula.jpg

    • What Is Metformin Hydrochloride Tablets Used For?

    1 INDICATIONS AND USAGE 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. Metformin hydrochloride extended-release tablets are biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 )

    Dosage and Administration

    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 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...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling:

  • Lactic Acidosis [see Error! Hyperlink reference not valid. and Warnings and Precautions (5.1)]
  • Vitamin B 12 Deficiency [see Warnings and Precautions (5.2) ]
  • Hypoglycemia [see Warnings and Precautions (5.3) ] Common adverse reactions are diarrhea, nausea/vomiting, abdominal pain, constipation, abdomen distention, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In placebo-controlled trials, 781 patients were administered metformin HCl extended-release tablets. Adverse reactions reported in greater than 5% of the patients treated with metformin HCl extended-release tablets and that were more common than in placebo-treated patients are listed in Table 1. Table 1: Adverse Reactions from Clinical Trials of Metformin HCl Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Adverse Reaction Metformin HCl Extended-Release Tablets (n=781) Placebo (n=195) Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to the discontinuation of metformin HCl extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in 1.0% to 5.0% of patients treated with metformin HCl extended-release tablets and were more commonly reported than in placebo-treated patients: abdominal pain, constipation, abdomen distention, dyspepsia/ heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. Laboratory Tests Vitamin B 12 Concentrations In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

    • Drug Interactions

    7 DRUG INTERACTIONS Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

  • 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...

    • Contraindications

    4 CONTRAINDICATIONS 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.
  • 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 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations ]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5-times, respectively, a 2550 mg clinical dose, based on body surface area [see Data ]. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of...

    Overdosage

    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.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Metformin hydrochloride extended-release tablets are supplied as: 500 mg Bottles of 60 NDC 42806-405-60 white-colored, unscored biconvex-shaped, film-coated extended-release tablets imprinted with 0019 500 on one side. 1,000 mg Bottles of 60 NDC 42806-406-60 white-colored, unscored biconvex-shaped, film-coated extended-release tablets imprinted with 0018 1000 on one side. 16.2 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] excursions permitted to 15° to 30°C (59° to 86°F). Avoid excessive heat and humidity. Keep tightly closed (protect from moisture). Protect from light.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.