Sitagliptin

1 INDICATIONS AND USAGE Sitagliptin Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Sitagliptin Tablets is not recommended in patients with type 1 diabetes mellitus. Sitagliptin Tablets have 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 Sitagliptin Tablets. [see Warnings and Precautions (5.1) ]. Sitagliptin Tablets are a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Sitagliptin Tablets are not recommended in patients with type 1 diabetes mellitus. ( 1 ) Sitagliptin Tablets has not been studied in patients with a history of pancreatitis. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of Sitagliptin Tablets is 100 mg orally once daily. Sitagliptin Tablets can be taken with or without food. ( 2.1 ) Dosage adjustment is recommended for patients with eGFR less than 45 mL/min/1.73 m 2 . ( 2.2 ) Dosage Adjustment in Patients with Renal Impairment ( 2.2 ) eGFR greater than or equal to 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 eGFR less than 30 mL/min/1.73 m 2 (including patients with end stage renal disease [ESRD] on dialysis) 50 mg once daily 25 mg once daily 2.1 Recommended Dosage The recommended dosage of Sitagliptin Tablets is 100 mg orally once daily. Sitagliptin Tablets can be taken with or without food. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of Sitagliptin Tablets and periodically thereafter. For patients with an estimated glomerular filtration rate [eGFR] greater than or equal to 45 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 , no dosage adjustment for Sitagliptin Tablets is required. For patients with moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 ), the dosage of Sitagliptin Tablets is 50 mg once daily. For patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dosage of Sitagliptin Tablets is 25 mg once daily. Sitagliptin Tablets may be administered without regard to the timing of dialysis.

5 WARNINGS AND PRECAUTIONS Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue Sitagliptin Tablets. ( 5.1 ) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of Sitagliptin Tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.2 ) Acute Renal Failure: Has been reported postmarketing, sometimes requiring dialysis. Assessment of renal function is recommended prior to initiating Sitagliptin Tablets and periodically thereafter. ( 5.3 ) Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required. ( 5.4 ) Hypersensitivity Reactions: There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Promptly stop Sitagliptin Tablets, assess for other potential causes, institute appropriate monitoring and treatment. ( 5.5 ) Severe and Disabling Arthralgia: Has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.6 ) Bullous Pemphigoid: There have been postmarketing reports requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue Sitagliptin Tablets. ( 5.7 ) 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin. After initiation of Sitagliptin Tablets, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Sitagliptin Tablets should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Sitagliptin Tablets. 5.2 Heart Failure An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of Sitagliptin Tablets prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of Sitagliptin Tablets. 5.3 Acute Renal Failure There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal impairment, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal impairment has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating Sitagliptin Tablets if another etiology is deemed likely to have precipitated the acute worsening of renal function. Assessment of renal function is recommended prior to initiating Sitagliptin Tablets and periodically thereafter. A dosage adjustment is recommended in patients with moderate …

4 CONTRAINDICATIONS Sitagliptin Tablets is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin or any of the excipients in Sitagliptin Tablets. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with sitagliptin. [see Warnings and Precautions (5.5) ; Adverse Reactions (6.2) ]. History of a serious hypersensitivity reaction to sitagliptin or any of the excipients in Sitagliptin Tablets, such as anaphylaxis or angioedema ( 4 )

7 DRUG INTERACTIONS 7.1 Insulin Secretagogues or Insulin Sitagliptin lowers blood glucose in patients with type 2 diabetes mellitus. Coadministration of sitagliptin 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. [see Warnings and Precautions (5.4) ].

8.1 Pregnancy Risk Summary The limited available data with sitagliptin in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. 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 [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, pre-eclampsia, 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 Animal Data 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.

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.1) ] Heart Failure [see Warnings and Precautions (5.2) ] Acute Renal Failure [see Warnings and Precautions (5.3) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.6) ] Bullous Pemphigoid [see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence ≥5%) are: upper respiratory tract infection, nasopharyngitis and headache. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with sitagliptin compared to placebo. ( 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 In controlled clinical trials as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with sitagliptin were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo. Two placebo-controlled monotherapy trials, one of 18- and one of 24-week duration, included patients treated with sitagliptin 100 mg daily, sitagliptin 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy trials were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dosage of the background therapy were randomized to add-on therapy with sitagliptin 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported in ≥5% of patients treated with sitagliptin 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3. Table 1: Placebo-Controlled Clinical Trials of Sitagliptin Monotherapy or Add-on Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/-Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo Intent-to-treat population Number of Patients (%) Monotherapy (18 or 24 weeks) Sitagliptin 100 mg Placebo N = 443 N = 363 Nasopharyngitis 23 (5.2) 12 (3.3) Combination with Pioglitazone (24 weeks) Sitagliptin 100 mg + Pioglitazone Placebo + Pioglitazone N = 175 N = 178 Upper Respiratory Tract Infection 11 (6.3) 6 (3.4) Headache 9 (5.1) 7 (3.9) Combination with Metformin + Rosiglitazone (18 weeks) Sitagliptin 100 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone N = 181 N = 97 Upper Respiratory Tract Infection 10 (5.5) 5 (5.2) Nasopharyngitis 11 (6.1) 4 (4.1) Combination with Glimepiride (+/- Metformin) (24 weeks) Sitagliptin 100 mg + Glimepiride (+/- Metformin) Placebo + Glimepiride (+/- Metformin) N = 222 N = 219 Nasopharyngitis 14 (6.3) 10 (4.6) Headache 13 (5.9) 5 (2.3) In the 24-week trial of patients rece…