Saxagliptin And Metformin Hydrochloride

1 INDICATIONS AND USAGE Saxagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies ( 14 )]. Saxagliptin and metformin hydrochloride extended-release tablets are a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) 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 recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.1 ) 1.1 Limitations of Use Saxagliptin and metformin hydrochloride extended-release tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

2 DOSAGE AND ADMINISTRATION Administer once daily with the evening meal. ( 2.1 ) Individualize the starting dosage based on the patient’s current regimen then adjust the dosage based on effectiveness and tolerability. ( 2.1 ) Do not exceed a daily dosage of 5 mg saxagliptin/2,000 mg metformin HCl extended-release. ( 2.1 ) Swallow whole. Never crush, cut, or chew. ( 2.1 ) Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). ( 2.3 , 7.1 ) Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. ( 2.2 ) o Do not use in patients with eGFR below 30 mL/min/1.73 m 2 . o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . o Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 . o Limit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m 2 . o Discontinue if eGFR falls below 30 mL/min/1.73 m 2 . Saxagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.4 ) 2.1 Recommended Dosage and Administration Individualize the starting dosage of saxagliptin and metformin hydrochloride extended-release tablets based on the patient’s current regimen and the available strengths of saxagliptin and metformin hydrochloride extended-release tablets [see Dosage Forms and Strengths ( 3 )] . Administer saxagliptin and metformin hydrochloride extended-release tablets once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin HCl [see Adverse Reactions ( 6.1 )] The recommended starting dosage of saxagliptin and metformin hydrochloride extended-release tablets in patients who need 5 mg of saxagliptin and who are not currently treated with metformin HCl is one saxagliptin and metformin hydrochloride extended-release tablet containing 5 mg saxagliptin and 500 mg metformin HCl extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin HCl. In patients treated with metformin HCl, the recommended starting dosage of saxagliptin and metformin hydrochloride extended-release tablets should provide metformin HCl at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin HCl immediate-release to saxagliptin and metformin hydrochloride extended-release tablets, closely monitor glycemic control and adjust the dosage accordingly. Patients who need 2.5 mg saxagliptin in combination with metformin HCl extended-release may be treated with saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1,000 mg. Patients who need 2.5 mg saxagliptin who are either metformin HCl naive or who require a dose of metformin HCl higher than 1,000 mg should use the individual components. Gradually titrate the dosage of saxagliptin and metformin hydrochloride extended-release tablets, as needed, after assessing therapeutic response and tolerability, up to a maximum recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets (5 mg for saxagliptin and 2,000 mg for metformin HCl extended-release orally once daily). Inform patients that saxagliptin and metformin hydrochloride extended-release tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of saxagliptin and metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet. If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. 2.2 Recommendations for Dosage and Administration in Renal Impairment Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and then as clinically indicated [see Use in Specific Populations ( 8.6 )]. The recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/minute/1.73 m 2 is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration ( 2.1 )]. In patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily. Initiation of saxagliptin and metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR below 30 mL/minute/1.73 m 2 . Discontinue saxagliptin and metformin hydrochloride extended-release tablets 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 Dosage Modifications with Concomitant Use of Strong CYP3A4/5 Inhibitors The maximum recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets is 2.5 mg of saxagliptin and 1,000 mg of metformin HCl given orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.3 )]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue saxagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; a history of liver disease, alcoholism or heart failure; or in any patient who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart saxagliptin and metformin hydrochloride extended-release tablets if renal function is stable [see Warnings and Precautions ( 5.1 )].

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Heart Failure [see Warnings and Precautions ( 5.3 )] Vitamin B 12 Concentrations [see Warnings and Precautions ( 5.4 )] Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.5 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Severe and disabling arthralgia [see Warnings and Precautions ( 5.7 )] Bullous pemphigoid [see Warnings and Precautions ( 5.8 )] • Most common adverse reactions with metformin HCl extended-release (incidence >5% and more often than placebo) are: diarrhea and nausea/vomiting. ( 6.1 ) • Most common adverse reactions with saxagliptin (incidence ≥5% and more often than placebo) are: upper respiratory tract infection, urinary tract infection, and headache. ( 6.1 ) • Adverse reactions with coadministered saxagliptin and metformin HCl (incidence ≥5% and more often than placebo) are: headache and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 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. Adverse Reactions in Placebo-Controlled Trials in Adults with Type 2 Diabetes Mellitus Metformin HCl In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of trial medication in 0.6% of the patients treated with metformin HCl extended-release. Saxagliptin The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies ( 14 )]. These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, 10.5% other races and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60mL/min/1.73m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin. Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin 5 mg N=882 Placebo N=799 Upper respiratory tract infection 7.7 7.6 Urinary tract infection 6.8 6.1 Headache 6.5 5.9 * The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin HCl, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin HCl, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Adverse Reactions with Concomitant Use with Insulin In the add-on to insulin trial [see Clinical Studies ( 14.1 )] , the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia [see Adverse Reactions ( 6.1 )]. Adverse Reactions Associated with Saxagliptin Coadministered with Metformin HCl Immediate-Release in Treatment-Naive Patients with Type 2 Diabetes Mellitus Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin HCl in treatment-naive patients. Table 2: Coadministration of Saxagliptin and Metformin HCl Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported in ≥5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin HCl Immediate-Release (and More Commonly than in Patients Treated with Metformin HCl Immediate-Release Alone) Number (%) of Patients Saxagliptin 5 mg + Metformin HCl* N=320 Placebo + Metformin HCl* N=328 Headache 24 (7.5) 17 (5.2) Nasopharyngitis 22 (6.9) 13 4.0) * Metformin HCl immediate-release was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2,000 mg daily. In patients treated with the combination of saxagliptin and metformin HCl immediate-release, either as saxagliptin add-on to metformin HCl immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence ≥5% in any treatment group in both trials. In the saxagliptin add-on to metformin HCl immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg + metformin HCl immediate-release group and 7.3% in the placebo + metformin HCl immediate-release group. Hypoglycemia In the saxagliptin clinical trials, adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively. In the add-on to metformin HCl immediate-release trial, the incidence of reported hypoglycemia was 7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5% with placebo. When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given saxagliptin 5 mg + metformin HCl immediate-release and 4% in patients given placebo + metformin HCl immediate-release. In the active-controlled trial comparing add-on therapy with saxagliptin 5 mg to glipizide in patients inadequately controlled on metformin HCl alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was reported in none of the saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001). In the saxagliptin add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%). Among the patients using insulin in combination with metformin HCl, the incidence of confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with placebo. In the saxagliptin add-on to metformin HCl plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients [see Warnings and Precautions ( 5.5 ) ]. Hypersensitivity Reactions Saxagliptin Hypersensitivity reactions, such as urticaria and facial edema in the 5-trial pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. None of these events in patients who received saxagliptin required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema. Renal Impairment In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum creatinine compared with baseline and serum creatinine >6 mg/dL), were reported in 5.8% (483/8,280) of saxagliptin-treated patients and 5.1% (422/8,212) of placebo-treated patients. The most frequently reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%), in the saxagliptin versus placebo groups, respectively. From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73m 2 for saxagliptin-treated patients and a mean decrease of 2.4 mL/min/1.73m 2 for placebo-treated patients. More patients randomized to saxagliptin (421/5,227, 8.1%) compared to patients randomized to placebo (344/5,073, 6.8%) had downward shifts in eGFR from >50 mL/min/1.73 m 2 (i.e., normal or mild renal impairment) to ≤50 mL/min/1.73 m 2 (i.e., moderate or severe renal impairment). The proportions of patients with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment. Infections Saxagliptin In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6 (0.12%) reports of tuberculosis among the 4,959 saxagliptin-treated patients (1.1 per 1,000 patient-years) compared to no reports of tuberculosis among the 2,868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use. There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use. Vital Signs Saxagliptin No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin alone or in combination with metformin HCl. Laboratory Tests Absolute Lymphocyte Counts Saxagliptin There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical trials. Similar effects were observed when saxagliptin 5 mg and metformin HCl were coadministered in treatment-naive patients compared to placebo and metformin HCl. There was no difference observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an approved dosage. In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin relative to placebo was observed. The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤750 cells/microL was 1.6% (136/8,280) and 1% (78/8,212) on saxagliptin and placebo, respectively. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. Vitamin B 12 Concentrations Metformin HCl In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of saxagliptin and metformin hydrochloride extended-release, saxagliptin, or metformin HCl. 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. Saxagliptin Gastrointestinal Disorders : Pancreatitis Immune System Disorders : Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Musculoskeletal and Connective Tissue Disorders : Rhabdomyolysis, Severe and disabling arthralgia Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid Metformin HCl Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

12.3 Pharmacokinetics Saxagliptin and Metformin Hydrochloride Extended-release Tablets Bioequivalence and food effect of saxagliptin and metformin hydrochloride extended-release tablets was characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that saxagliptin and metformin hydrochloride extended-release combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA ® ) and metformin HCl extended-release as individual tablets under fed conditions. Saxagliptin The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The C max and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma C max values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and C max for both saxagliptin and its active metabolite was less than 25%. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg. Metformin HCl Metformin extended-release C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and C max are less than dose proportional for metformin extended-release within the range of 500 to 2,000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets. Absorption Saxagliptin The median time to maximum concentration (T max ) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Metformin HCl Following a single oral dose of metformin extended-release, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Effect of Food Saxagliptin Administration with a high-fat meal resulted in an increase in T max of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as saxagliptin and metformin hydrochloride extended-release combination tablets. Metformin HCl Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as saxagliptin and metformin hydrochloride extended-release combination tablets. Distribution Saxagliptin The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Metformin HCl Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. Elimination Metabolism Saxagliptin The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions ( 7.1 )] . Metformin HCl Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted. Excretion Saxagliptin Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14 C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t 1/2 ) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Metformin HCl Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations G eriatric Patients Saxagliptin No dosage adjustment is recommended based on age alone. Elderly subjects (65 to 80 years) had 23% and 59% higher geometric mean C max and geometric mean AUC values, respectively, for saxagliptin than young subjects (18 to 40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Metformin HCl Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Male and Female Patients Saxagliptin No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Metformin HCl Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females. Racial or Ethnic Groups Saxagliptin No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 White subjects with 105 subjects of other races (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations. Metformin HCl No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African American (n=51), and Hispanics or Latino ethnicity (n=24). Patients with Renal Impairment Saxagliptin A single-dose, open-label trial was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect C max of saxagliptin or its metabolite. In subjects with moderate renal impairment with eGFR 30 to less than 45 mL/min/1.73 m 2 , severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m 2 ) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function. Metformin HCl In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Patients with Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Body Mass Index Saxagliptin No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis. Drug Interaction Studies Specific pharmacokinetic drug interaction studies with saxagliptin and metformin hydrochloride extended-release tablets have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components. In Vitro Assessment of Drug Interactions In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate, but is not a significant inhibitor or inducer of P-gp. In Vivo Assessment of Drug Interactions Table 3: Effect of Coadministered Drug on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin Coadministered Drug Dosage of Coadministered Drug * Dosage of Saxagliptin * Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Metformin 1,000 mg 100 mg saxagliptin 5-hydroxy saxagliptin 0.98 0.99 0.79 0.88 Glyburide 5 mg 10 mg saxagliptin 5-hydroxy saxagliptin 0.98 ND 1.08 ND Pioglitazone ‡ 45 mg QD for 10 days 10 mg QD for 5 days saxagliptin 5-hydroxy saxagliptin 1.11 ND 1.11 ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days saxagliptin 5-hydroxy saxagliptin 1.05 1.06 0.99 1.02 Dapagliflozin 10 mg single dose 5 mg single dose saxagliptin 5-hydroxy saxagliptin ↓1% ↑9% ↓7% ↑6% Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days saxagliptin 5-hydroxy saxagliptin 1.12 1.02 1.21 1.08 Diltiazem 360 mg LA QD for 9 days 10 mg saxagliptin 5-hydroxy saxagliptin 2.09 0.66 1.63 0.57 Rifampin § 600 mg QD for 6 days 5 mg saxagliptin 5-hydroxy saxagliptin 0.24 1.03 0.47 1.39 Omeprazole 40 mg QD for 5 days 10 mg saxagliptin 5-hydroxy saxagliptin 1.13 ND 0.98 ND Aluminum hydroxide + magnesium hydroxide + simethicone aluminum hydroxide: 2,400 mg magnesium hydroxide: 2,400 mg simethicone: 240 mg 10 mg saxagliptin 5-hydroxy saxagliptin 0.97 ND 0.74 ND Famotidine 40 mg 10 mg saxagliptin 5-hydroxy saxagliptin 1.03 ND 1.14 ND Limit saxagliptin and metformin hydrochloride extended-release tablets dose to 2.5 mg/1,000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [see Drug Interactions ( 7.1 ) and Dosage and Administration ( 2.2 )] : Ketoconazole 200 mg BID for 9 days 100 mg saxagliptin 5-hydroxy saxagliptin 2.45 0.12 1.62 0.05 Ketoconazole 200 mg BID for 7 days 20 mg saxagliptin 5-hydroxy saxagliptin 3.67 ND 2.44 ND * Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ‡ Results exclude one patient. § The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin. ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting. Table 4: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs Coadministered Drug Dosage of Coadministered Drug* Dosage of Saxagliptin* Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Metformin 1,000 mg 100 mg metformin 1.20 1.09 Glyburide 5 mg 10 mg glyburide 1.06 1.16 Pioglitazone ‡ 45 mg QD for 10 days 10 mg QD for 5 days pioglitazone hydroxy-pioglitazone 1.08 ND 1.14 ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days digoxin 1.06 1.09 Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days simvastatin simvastatin acid 1.04 1.16 0.88 1.00 Diltiazem 360 mg LA QD for 9 days 10 mg diltiazem 1.10 1.16 Ketoconazole 200 mg BID for 9 days 100 mg ketoconazole 0.87 0.84 Ethinyl estradiol and norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days 5 mg QD for 21 days ethinyl estradiol norelgestromin norgestrel 1.07 1.10 1.13 0.98 1.09 1.17 * Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ‡ Results include all patients. ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting. Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.3)]. Cimetidine 400 mg 850 mg metformin 1.40 1.61 * All metformin and coadministered drugs were given as single doses. † AUC = AUC(INF). ‡ Ratio of arithmetic means. Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug * Dose of Metformin * Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 ‡ 0.63 ‡ Furosemide 40 mg 850 mg furosemide 0.87 ‡ 0.69 ‡ Nifedipine 10 mg 850 mg nifedipine 1.10 § 1.08 Propranolol 40 mg 850 mg propranolol 1.01 § 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 ¶ 1.01 ¶ Cimetidine 400 mg 850 mg cimetidine 0.95 § 1.01 * All metformin and coadministered drugs were given as single doses. † AUC = AUC(INF) unless otherwise noted. ‡ Ratio of arithmetic means, p-value of difference <0.05. § AUC(0-24 hr) reported. ¶ Ratio of arithmetic means.