sitagliptin hydrochloride oral

1 INDICATIONS & USAGE BRYNOVIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use BRYNOVIN is not recommended in patients with type 1 diabetes. BRYNOVIN 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 BRYNOVIN. [see Warnings and Precautions ] . BRYNOVIN is 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. Limitations of Use:

• BRYNOVIN is not recommended in patients with type 1 diabetes.
• BRYNOVIN has not been studied in patients with a history of pancreatitis.

The recommended dose of BRYNOVIN is 100 mg orally once daily (4 mL). BRYNOVIN can be taken with or without food. Dosage adjustment is recommended for patients with eGFR less than 45 mL/min/1.73 m 2 . Dosage Adjustment in Patients with 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 eGFR less than 30 mL/min/1.73 m 2 (including patients with end stage renal disease [ESRD] on dialysis) 50 mg once daily (2 mL) 25 mg once daily (1 mL) 2.1 Recommended Dosage and Administration Measure the BRYNOVIN dose using a calibrated oral syringe or oral dosing cup scored using metric units of measurements (i.e., mL). The recommended dosage of BRYNOVIN is 100 mg (4 mL) taken orally once daily. BRYNOVIN can be taken with or without food [see Clinical Pharmacology ] . 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of BRYNOVIN and periodically thereafter [see Use in Specific Populations ] . 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 BRYNOVIN 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 BRYNOVIN is 50 mg (2 mL) 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 BRYNOVIN is 25 mg (1 mL) once daily. BRYNOVIN may be administered without regard to the timing of dialysis.

12.1 Mechanism of Action Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic dosages.

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

• Pancreatitis [ see Warnings and Precautions ]
• Heart Failure [ see Warnings and Precautions ]
• Acute Renal Failure [ see Warnings and Precautions ]
• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [ see Warnings and Precautions ]
• Hypersensitivity Reactions [ see Warnings and Precautions ]
• Severe and Disabling Arthralgia [ see Warnings and Precautions ]
• Bullous Pemphigoid [ see Warnings and Precautions ] 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 trials, hypoglycemia was also more commonly reported in patients treated with sitagliptin compared to placebo. To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc., at 1-800-461-7449 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. The safety of BRYNOVIN has been established for glycemic control in patients with type 2 diabetes mellitus based in adequate and well-controlled trials of sitagliptin tablets, referenced below as “sitagliptin” [see Clinical Studies ] . 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, 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* Number of Patients (%) Monotherapy (18 or 24 weeks) Sitagliptin 100 mg Placebo N = 443 N = 363 Nasopharyngitis 23 12 Combination with Pioglitazone (24 weeks) Sitagliptin 100 mg + Pioglitazone Placebo + Pioglitazone N = 175 N = 178 Upper Respiratory Tract Infection 11 6 Headache 9 7 Combination with Metformin + Rosiglitazone (18 weeks) Sitagliptin 100 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone N = 181 N = 97 Upper Respiratory Tract Infection 10 5 Nasopharyngitis 11 4 Combination with Glimepiride (+/- Metformin) (24 weeks) Sitagliptin 100 mg + Glimepiride (+/- Metformin) Placebo + Glimepiride (+/- Metformin) N = 222 N = 219 Nasopharyngitis 14 10 Headache 13 5 * Intent-to-treat population In the 24-week trial of patients receiving sitagliptin as add-on combination therapy with metformin, there were no adverse reactions reported in patients and more commonly than in patients given placebo. In the 24-week trial of patients receiving sitagliptin as add-on therapy to insulin (with or without metformin), there were no adverse reactions reported in patients and more commonly than in patients given placebo, except for hypoglycemia (see Table 3). In the trial of sitagliptin as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions in patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%). In an additional, 24-week, placebo-controlled factorial trial of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported in ≥5% of patients are shown in Table 2. Table 2:Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo)* Number of Patients (%) Placebo Sitagliptin 100 mg QD Metformin HCl 500 or 1,000 mg bid † Sitagliptin 50 mg bid + Metformin HCl 500 or 1,000 mg bid † N = 176 N = 179 N = 364 † N = 372 † Upper Respiratory Infection 9 8 19 23 Headache 5 2 14 22 * Intent-to-treat population. † Data pooled for the patients given the lower and higher dosages of metformin. In a 24-week trial of initial therapy with sitagliptin in combination with pioglitazone, there were no adverse reactions reported in ≥5% of patients and more commonly than in patients given pioglitazone alone. Other Adverse Reactions Hypoglycemia In the above trials (N=9), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When sitagliptin was coadministered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3). Table 3:Incidence and Rate of Hypoglycemia* in Placebo-Controlled Clinical Trials when Sitagliptin was used as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin) Add-On to Glimepiride (+/- Metformin) (24 weeks) Sitagliptin 100 mg + Glimepiride (+/- Metformin) Placebo + Glimepiride (+/- Metformin) N = 222 N = 219 Overall (%) 27 4 Rate (episodes/patient-year) † 0.59 0.24 Severe (%) ‡ 0 0 Add-On to Insulin (+/- Metformin) (24 weeks) Sitagliptin 100 mg + Insulin (+/- Metformin) Placebo + Insulin (+/- Metformin) N = 322 N = 319 Overall (%) 50 25 Rate (episodes/patient-year)† 1.06 0.51 Severe (%)‡ 2 1 * Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population. † Based on total number of events (i.e., a single patient may have had multiple events). ‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. In a pooled analysis of the two monotherapy trials, the add-on to metformin trial, and the add-on to pioglitazone trial, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with sitagliptin 100 mg and 0.9% in patients treated with placebo. In the trial of sitagliptin as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1% in patients given add-on placebo. In the 24-week, placebo-controlled factorial trial of initial therapy with sitagliptin in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in combination with metformin. In the trial of sitagliptin as initial therapy with pioglitazone, one patient taking sitagliptin experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other trials except in the trial involving coadministration with insulin. In an additional, 30-week placebo-controlled, trial of patients with type 2 diabetes mellitus inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo groups. Gastrointestinal Adverse Reactions In a pooled analysis of the two monotherapy trials, the add-on to metformin trial, and the add-on to pioglitazone trial, the incidence of selected gastrointestinal adverse reactions in patients treated with sitagliptin was as follows: abdominal pain (sitagliptin 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3%, 2.3%). Pancreatitis In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control). Vital Sign and Electrocardiogram (ECG) Changes No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with sitagliptin. Laboratory Tests Across clinical trials, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical trials, with a mean baseline WBC count of approximately 6,600 cells/microL) is not considered to be clinically relevant. In a 12-week trial of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin (0.12 mg/dL [0.04]) and in patients treated with placebo (0.07 mg/dL [0.07]). The clinical significance of this added increase in serum creatinine relative to placebo is not known. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of sitagliptin as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Reactions : anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, and exfoliative skin conditions including Stevens-Johnson syndrome Hepatobiliary disorders : hepatic enzyme elevations Gastrointestinal disorders : acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis, constipation; vomiting, mouth ulceration, and stomatitis Renal and urinary disorders : worsening renal function, including acute renal failure (sometimes requiring dialysis), and tubulointerstitial nephritis Musculoskeletal and connective tissue disorders : severe and disabling arthralgia; myalgia; pain in extremity; back pain; pruritus; rhabdomyolysis Nervous system disorders : headache

7.1 Concomitant Use with Insulin or Insulin Secretagogues BRYNOVIN lowers blood glucose in patients with type 2 diabetes mellitus. Coadministration of BRYNOVIN with insulin or an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. [See Warnings and Precautions ].

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 6-10% in women with pre-gestational diabetes with a hemoglobin A1C >7% and has been reported to be as high as 20-25% in women with a hemoglobin 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 trials, 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. 8.2 Lactation Risk Summary There is no information regarding the presence of sitagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Sitagliptin is present in rat milk and therefore possibly present in human milk [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sitagliptin and any potential adverse effects on the breastfed infant from sitagliptin or from the underlying maternal condition. Data Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. 8.4 Pediatric Use The safety and effectiveness of BRYNOVIN have not been established in pediatric patients. Three 20-week double-blind, placebo-controlled trials each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus, with or without insulin therapy (HbA1C 6.5-10% for patients not on insulin, HbA1C 7-10% for patients on insulin). At trial entry, patients in trial 1 were not treated with oral antihyperglycemic agents; patients in trials 2 and 3 were on maximally tolerated metformin therapy. The primary efficacy endpoint was the change from baseline in HbA1C after 20 weeks of therapy. The pre-specified primary efficacy analyses included data from trial 1 and pooled data from trials 2 and 3, regardless of glycemic rescue or treatment discontinuation. In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo. In trial 1, the mean baseline HbA1C was 7.5%, and 12% of patients were on insulin therapy. At week 20, the change from baseline in HbA1C in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI: -0.62, 0.28). In trials 2 and 3, the mean baseline HbA1C was 8%, 15% of patients were on insulin and 72% were on metformin HCl dosages of greater than 1,500 mg daily. At week 20, the change from baseline in HbA1C in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05). 8.5 Geriatric Use Of the total number of subjects (N=3,884) in pre-approval clinical safety and efficacy trials of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness have been observed between patients 65 years and over and younger patients. Because sitagliptin is substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients [see Dosage and Administration , Warnings and Precautions ] . 8.6 Renal Impairment Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m 2 (moderate and severe renal impairment, as well as in ESRD patients requiring dialysis). [See Dosage and Administration ; Clinical Pharmacology ] .