GLUMETZA

GLUMETZA contains the biguanide antihyperglycemic agent metformin in the form of monohydrochloride salt. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride 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 hydrochloride is 6.68. GLUMETZA tablets contain 500 mg or 1,000 mg of metformin hydrochloride, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1,000 mg tablet contains colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl dibehenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, titanium dioxide, simethicone emulsion, polysorbate and coloring. Chemical Structure-Glumetza

GLUMETZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. GLUMETZA is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

• Starting dose: 500 mg orally once daily with the evening meal ( 2.1 ) • Increase the dose in increments of 500 mg every 1 to 2 weeks, 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 GLUMETZA once daily at the same total daily dose, up to 2,000 mg once daily. ( 2.1 ) • Swallow GLUMETZA tablets whole and never crush, cut or chew. ( 2.1 ) Renal Impairment: • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) o Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 . o Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . o Assess risk/benefit of continuing GLUMETZA if eGFR falls below 45 mL/minute/1.73 m 2 . o Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 . Discontinuation for Iodinated Contrast Imaging Procedures: • GLUMETZA may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Adult Dosage and Administration • The recommended starting dose of GLUMETZA is 500 mg orally once daily with the evening meal. • Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal. • Patients receiving metformin hydrochloride (HCl) may be switched to GLUMETZA once daily at the same total daily dose, up to 2,000 mg once daily. • Swallow GLUMETZA whole and never crush, cut or chew. • 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. 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 m 2 . • Initiation of GLUMETZA in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. • In patients taking GLUMETZA whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit risk of continuing therapy. • Discontinue GLUMETZA 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 GLUMETZA at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/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 GLUMETZA if renal function is stable [see Warnings and Precautions ( 5.1 )].

GLUMETZA is contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/minute/1.73 m 2 ) [see Warnings and Precautions ( 5.1 )] . • Known hypersensitivity to metformin. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. • Severe renal impairment: (eGFR below 30 mL/minute/1.73 m 2 ) ( 4 , 5.1 ) • Known hypersensitivity to metformin ( 4 ) • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma ( 4 )

Adverse reactions occurring >5% in GLUMETZA clinical trials: hypoglycemia, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals 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 Boxed Warning and Warnings and Precautions ( 5.1 )] • Vitamin B 12 Deficiency [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 1,000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1,500 to 2,000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form. 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. 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: Adverse Reactions Reported by >5% Adverse reactions 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 14% 5% Diarrhea 13% 6% Nausea 7% 4% 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 B12 levels was observed in approximately 7% of patients. 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 have been reported with postmarketing use of metformin.

Table 2 presents clinically significant drug interactions with GLUMETZA. Table 2: Clinically Significant Drug Interactions with GLUMETZA 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 GLUMETZA may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce GLUMETZA 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 GLUMETZA. 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 GLUMETZA. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of GLUMETZA 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 GLUMETZA, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUMETZA, 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 excessive alcohol intake. ( 7 )