ZITUVIMET XR

1 INDICATIONS AND USAGE ZITUVIMET XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ZITUVIMET XR is not recommended in patients with type 1 diabetes mellitus. ZITUVIMET XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ZITUVIMET XR [see Warnings and Precautions ( 5.2 )]. ZITUVIMET XR is a combination of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not for the treatment of type 1 diabetes mellitus. ( 1 ) Has not been studied in patients with a history of pancreatitis. ( 1 )

2 DOSAGE AND ADMINISTRATION Take ZITUVIMET XR orally once daily with a meal. Patients taking two ZITUVIMET XR tablets should take the tablets together. ( 2.1 ) Individualize the dosage of ZITUVIMET XR on the basis of the patient's current regimen, effectiveness, and tolerability. ( 2.1 ) The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin HCl extended-release. ( 2.1 ) The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin HCl once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin. ( 2.1 ) The starting dose in patients already treated with metformin should provide sitagliptin dosed as 100 mg and the dose of metformin already being taken once daily. For patients taking metformin HCl 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of ZITUVIMET XR is two 50 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets once daily. ( 2.1 ) Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin immediate-release or sitagliptin and metformin extended-release and ZITUVIMET XR. ( 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/min/1.73 m 2 . ZITUVIMET XR is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . Limit dose of sitagliptin to 50 mg once daily if eGFR falls below 45 mL/min/1.73 m 2 . ZITUVIMET XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Recommended Dosage and Administration Take ZITUVIMET XR orally once daily with a meal. Patients taking two ZITUVIMET XR tablets should take the two tablets together once daily. Individualize the dosage of ZITUVIMET XR on the basis of the patient's current regimen, effectiveness, and tolerability. The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release. The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin HCl extended-release once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin. The starting dose in patients already treated with metformin should provide 100 mg sitagliptin and the previously prescribed dose of metformin. For patients taking metformin HCl immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of ZITUVIMET XR is two 50 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets taken together once daily. Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin HCl immediate-release or sitagliptin and metformin extended-release and ZITUVIMET XR. Do not split, crush or chew ZITUVIMET XR tablets. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of ZITUVIMET XR and periodically thereafter. ZITUVIMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Initiation of ZITUVIMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 is not recommended. In patients taking ZITUVIMET XR whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue ZITUVIMET XR 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 iodin …

3 DOSAGE FORMS AND STRENGTHS Tablets: sitagliptin 100 mg and metformin HCl 1,000 mg extended-release tablets are reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side. sitagliptin 50 mg and metformin HCl 500 mg extended-release tablets are light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side. sitagliptin 50 mg and metformin HCl 1,000 mg extended-release tablets are yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side. ZITUVIMET XR Tablets: sitagliptin 100 mg and metformin HCl 1,000 mg extended-release sitagliptin 50 mg and metformin HCl 500 mg extended-release sitagliptin 50 mg and metformin HCl 1,000 mg extended-release ( 3 )

4 CONTRAINDICATIONS ZITUVIMET XR is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions ( 5.1 )] . Acute or chronic metabolic acidosis, including diabetic ketoacidosis. A history of a serious hypersensitivity reaction to sitagliptin , metformin, or any of the excipients in ZITUVIMET XR. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.2 )]. Severe renal impairment: eGFR below 30 mL/min/1.73 m 2 . ( 4 ) Metabolic acidosis, including diabetic ketoacidosis. ( 4 ) History of a serious hypersensitivity reaction to ZITUVIMET XR, sitagliptin, or metformin, such as. anaphylaxis or angioedema) ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the prescribing information: Lactic Acidosis [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Heart Failure [see Warnings and Precautions ( 5.3 )] Acute Renal Failure [see Warnings and Precautions ( 5.4 )] Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.5 )] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Severe and Disabling Arthralgia [see Warnings and Precautions ( 5.8 )] Bullous Pemphigoid [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Common Adverse Reactions Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise Table 1 summarizes the most common (≥5% of patients) adverse reactions reported in a 24-week placebo-controlled factorial trial in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Table 1: Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) Intent-to-treat population. Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg twice daily + Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily N = 176 N = 179 N = 364 N = 372 Diarrhea 7 (4) 5 (2.8) 28 (7.7) 28 (7.5) Upper Respiratory Tract Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2) Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9) Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%). Gastrointestinal Adverse Reactions The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone. See Table 2. Table 2: Pre-selected Gastrointestinal Adverse Reactions Reported in Patients with Type 2 Diabetes Mellitus Receiving Sitagliptin and Metformin Immediate-Release Number of Patients (%) Trial of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise Trial of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone Placebo Sitagliptin 100 mg once daily Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily Data p …

7 DRUG INTERACTIONS Table 4 presents clinically significant drug interactions with ZITUVIMET XR: Table 4: Clinically Significant Drug Interactions with ZITUVIMET XR 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 ZITUVIMET XR 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 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 [OCT 2 ] / 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 ZITUVIMET XR. 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 alcohol intake while receiving ZITUVIMET XR. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of ZITUVIMET XR 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 ZITUVIMET XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ZITUVIMET XR, 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 )

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) Geriatric Use: Assess renal function more frequently. ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary The limited available data with ZITUVIMET XR in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and 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 in pregnancy [see Clinical Considerations] . No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and 6-times, respectively, a 2,000 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 with a hemoglobin A1c (A1c) >7% and has been reported to be as high as 20 to 25% in women with a A1C >10%. 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 in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Sitagliptin and Metformin No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin. Sitagliptin In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100-times the clinical dose, based on AUC. Placental transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1,000 mg/kg. Metformin Metformin did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of ZITUVIMET XR in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data] . There are no reports of adverse effects on breastfed infants …

11 DESCRIPTION ZITUVIMET XR tablets for oral use contain two antihyperglycemic medications: sitagliptin and metformin hydrochloride. Sitagliptin Sitagliptin is an orally-active inhibitor of the DPP-4 enzyme. Sitagliptin free base drug substance is used to manufacture ZITUVIMET XR. Sitagliptin free base is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine with an empirical formula of C 16 H 15 F 6 N 5 O and a molecular weight of 407.31. The structural formula is: Sitagliptin free base is a white to off-white, non-hygroscopic powder. It is soluble in methanol and slightly soluble in water. Metformin HCl Metformin HCl ( N , N -dimethylimidodicarbonimidic diamide HCl) is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin HCl is freely soluble in water, slightly soluble in ethanol (95%), practically insoluble in acetone and in methylene chloride. The pK a of metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown: ZITUVIMET XR ZITUVIMET XR is available as film-coated tablets containing: 50 mg sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin HCl (ZITUVIMET XR 50/500). 50 mg sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin HCl (ZITUVIMET XR 50/1,000). 100 mg sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin HCl (ZITUVIMET XR 100/1,000). All doses of ZITUVIMET XR contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate anhydrous, ferric oxide yellow, hypromellose, magnesium stearate, malic acid, microcrystalline cellulose, povidone, pregelatinized starch (maize) and sodium stearyl fumarate. In addition, the film-coating for all doses contains the following inactive ingredients: polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, iron oxide yellow, talc and titanium dioxide. Additionally, ZITUVIMET XR 50 mg/500 mg and 100 mg/1,000 mg tablets film-coating contain the inactive ingredient red iron oxide and 50 mg/1,000 mg and 100 mg/1,000 mg tablets film-coating contain the FD&C yellow#6 Aluminum Lake. Image Image

10 OVERDOSAGE In the event of overdose with ZITUVIMET XR, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ supportive measures dictated by the patient's clinical status. Per clinical judgement, consider removal of unabsorbed material from the gastrointestinal tract, and clinical monitoring (including obtaining an ECG). Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis. Overdose of metformin 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets supplied as follows: Contents Description How Supplied NDC 50 mg sitagliptin and 500 mg metformin HCl extended-release tablets Light orange to beige colored, oval shaped, film-coated tablets debossed with "1804" on one side and plain on the other side. Bottles of 60 tablets with child-resistant closure NDC 70710-1804-6 50 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets Yellow to beige colored, oval shaped, film-coated tablets debossed with "1805" on one side and plain on the other side. Bottles of 60 tablets with child-resistant closure NDC 70710-1805-6 100 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets Reddish brown to brown colored, oval shaped, film-coated tablets debossed with "1806" on one side and plain on the other side. Bottles of 30 tablets with child-resistant closure NDC 70710-1806-3 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a dry place with cap tightly closed. Keep ZITUVIMET XR in the original container to protect it from moisture. Use ZITUVIMET XR within 1 month of opening the bottle.