Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 01 April 2018

Indication(s)

1 INDICATIONS AND USAGE GLUMETZA® (metformin hydrochloride extended-release tablets) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use GLUMETZA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. GLUMETZA is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) Important limitations of use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS GLUMETZA is contraindicated in patients with: •Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]. •Known hypersensitivity to metformin hydrochloride. •Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin. •Severe renal impairment: (eGFR below 30 mL/min/1.73 m2) (4) •Known hypersensitivity to metformin hydrochloride (4) •Metabolic acidosis, including diabetic ketoacidosis (4)
Adverse reactions
6 ADVERSE REACTIONS The incidence and type of adverse reactions reported by >5% of patients for the combined GLUMETZA group versus placebo group are hypoglycemia, diarrhea, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions are discussed in more detail in other sections of the labeling: • Lactic acidosis [see Warnings and Precautions (5.1)] • Vitamin B12 Levels [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.3)] 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 clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1500 to 2000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form. In the 24-week monotherapy trial comparing GLUMETZA to immediate-release metformin, serious adverse reactions were reported in 3.6% (19/528) of the GLUMETZA-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA and glyburide and 144 patients received placebo and glyburide. A serious adverse reaction was reported in 2.1% (9/431) of the GLUMETZA and glyburide-treated patients compared to 1.4% (2/144) of the placebo and glyburide-treated patients. When the data from the monotherapy and add-on to sulfonylurea clinical trials were combined, the most frequently (incidence ≥0.5%) reported serious adverse reactions classified by system organ class were gastrointestinal disorders (1.0% of GLUMETZA-treated patients compared to 0% of patients not treated with GLUMETZA) and cardiac disorders (0.4% of GLUMETZA-treated patients compared to 0.5% of patients not treated with GLUMETZA). Only 2 serious adverse reactions (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one GLUMETZA-treated patient. Adverse reactions reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA and glyburide group than in the placebo and glyburide group are shown in Table 1. In 0.7% of patients treated with GLUMETZA and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group. Table 1: Treatment-Emergent Adverse Reactions Reported by >5%ARs that were more common in the GLUMETZA-treated than in the placebo-treated patients. of Patients for the Combined GLUMETZA Groups Versus Placebo Group Adverse Reaction GLUMETZA + Glyburide (n=431) Placebo + Glyburide (n=144) Hypoglycemia 13.7% 4.9% Diarrhea 12.5% 5.6% Nausea 6.7% 4.2% Laboratory Tests Vitamin B12 Concentrations Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on GLUMETZA, and any apparent abnormalities should be appropriately investigated and managed. [See Warnings and Precautions (5.2 ).] 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of GLUMETZA. 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Starting dose is 500 mg daily with evening meal. (2.1) •Individualize dose based on effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg. (2.1) •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 m2. •Initiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m2. •Assess risk/benefit of continuing GLUMETZA if eGFR falls below 45 mL/minute/1.73 m2. •Discontinue if eGFR falls below 30 mL/minute/1.73 m2. •GLUMETZA may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.4) •Swallow whole. Never split, crush or chew. (2.5) 2.1 Recommended Dosage The starting dose of GLUMETZA in patients who are not currently taking metformin is 500 mg orally, once daily with the evening meal. Increase the dose in 500 mg increments every 1-2 weeks if a higher dose of GLUMETZA is needed and there are no gastrointestinal (GI) adverse reactions. The dosage of GLUMETZA must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of GLUMETZA and periodically thereafter. GLUMETZA is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. Initiation of GLUMETZA in patients with an eGFR between 30–45 mL/minute/1.73 m2 is not recommended. In patients taking GLUMETZA whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy. Discontinue GLUMETZA if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)]. 2.3 Switching from Immediate-Release Metformin to GLUMETZA If switching from immediate-release metformin to GLUMETZA, initiate GLUMETZA once daily at the same total dose, up to 2000 mg once daily. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue GLUMETZA 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 m2; 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 GLUMETZA if renal function is stable [see Warnings and Precautions (5.1)]. 2.5 Important Administration Instructions Administer GLUMETZA orally, once daily with the evening meal. GLUMETZA tablets must be swallowed whole and never split, crushed or chewed. If a dose of GLUMETZA is missed, instruct patients not to take two doses the same day and to resume their usual dose of GLUMETZA with the next schedule dose [see Patient Counseling Information (17)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Pediatric Use: Safety and effectiveness in children younger than 18 years of age have not been established. (8.4) •Geriatric Use: Assess renal function more frequently. (8.5) •Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed. 8.2 Labor and Delivery The safety and effectiveness of GLUMETZA used during labor and delivery has not been evaluated in human studies. 8.3 Nursing Mothers Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin HCl Oral Solution may exist. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. GLUMETZA is not recommended in pediatric patients below the age of 18 years. 8.5 Geriatric Use Clinical studies of GLUMETZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients. [See Dosage and Administration (2.2) and Warnings and Precautions (5.1).] 8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUMETZA is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. [See Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3).] 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUMETZA is not recommended in patients with hepatic impairment. [See Warnings and Precautions (5.1).]

Interactions

7 DRUG INTERACTIONS •Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7.1) •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. (7.2) •Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7.3) 7.1 Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GLUMETZA may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients. 7.2 Drugs that Reduce Metformin Clearance 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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Consider the benefits and risks of concomitant use. 7.3 Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving GLUMETZA. 7.4 Insulin Secretagogues or Insulin Coadministration of GLUMETZA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. 7.5 Drugs Affecting Glycemic Control Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving GLUMETZA, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUMETZA, the patient should be observed closely for hypoglycemia.

More information

Category Value
Authorisation number NDA021748
Agency product number 786Z46389E
Orphan designation No
Product NDC 68012-004,68012-003,68012-002
Date Last Revised 20-03-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Santarus, Inc.
Warnings 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 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 in the full prescribing information [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )]. If metformin-associated lactic acidosis is suspected, immediately discontinue GLUMETZA 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. • 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 GLUMETZA and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)