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CLINICAL PHARMACOLOGY Mechanism Of Action Alogliptin And Metformin Hydrochloride KAZANO combines two antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes: alogliptin, a selective inhibitor of DPP-4, and metformin HCl, a member of the biguanide class. Alogliptin Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures. Metformin Hydrochloride Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances [see WARNINGS AND PRECAUTIONS] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease. Pharmacodynamics Alogliptin Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were three-to four-fold greater with alogliptin (at doses of 25 to 200 mg) than placebo. In a 16 week, double-blind, placebo-controlled study, alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an eight hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg demonstrated decreases in two-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL, respectively). Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses (25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. Pharmacokinetics Absorption And Bioavailability Alogliptin and Metformin Hydrochloride In bioequivalence studies of KAZANO, the area under the plasma concentration curve (AUC) and maximum concentration (Cmax) of both the alogliptin and the metformin component following a single dose of the combination tablet were bioequivalent to the alogliptin 12.5 mg concomitantly administered with metformin HCl 500 or 1000 mg tablets under fasted conditions in healthy subjects. Administration of KAZANO with food resulted in no change in total exposure (AUC) of alogliptin and metformin. Mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28%, respectively, when administered with food. There was no change in time to peak plasma concentrations (Tmax) for alogliptin under fed conditions, however, there was a delayed Tmax for metformin of 1.5 hours. These changes are not likely to be clinically significant. Alogliptin The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal results in no significant change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food. Metformin Hydrochloride The absolute bioavailability of metformin following administration of a 500 mg metformin HCl tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin HCl tablets 500 mg to 1500 mg and 850 mg to 2550 mg indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin HCl with food compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown. Distribution Alogliptin Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. Alogliptin is 20% bound to plasma proteins. Metformin Hydrochloride The apparent volume of distribution (V/F) of metformin following single oral doses of immediate release metformin HCl tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 mcg/mL. During controlled clinical trials, which served as the basis for approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. Metabolism Alogliptin Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine. Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, Ndemethylated, M-I (less than 1% of the parent compound), and N-acetylated alogliptin, M-II (less than 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin. Alogliptin exists predominantly as the (R)-enantiomer (more than 99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose. Metformin Hydrochloride 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. Excretion And Elimination Alogliptin The primary route of elimination of [14C] alogliptin-derived radioactivity occurs via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr. Metformin Hydrochloride 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. Special Populations Renal Impairment Metformin Hydrochloride In patients with decreased renal function (based on measured creatine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. Hepatic Impairment Alogliptin Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Metformin Hydrochloride No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment. Gender Alogliptin No dose adjustment is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Metformin Hydrochloride Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females. Geriatric Due to declining renal function in the elderly, measurement of creatinine clearance should be obtained prior to initiation of therapy. Alogliptin No dose adjustment is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Metformin Hydrochloride 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 Cmax 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. Pediatrics Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed. Race Alogliptin No dose adjustment of alogliptin is necessary based on race. Race (white, black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Metformin Hydrochloride No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24). Drug Interactions Alogliptin And Metformin Hydrochloride Administration of alogliptin 100 mg once daily with metformin HCl 1000 mg twice daily for six days had no meaningful effect on the pharmacokinetics of alogliptin or metformin. Specific pharmacokinetic drug interaction studies with KAZANO have not been performed, although such studies have been conducted with the individual components of KAZANO (alogliptin and metformin). Alogliptin In Vitro Assessment of Drug Interactions In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations. In Vivo Assessment of Drug Interactions Effects of Alogliptin on the Pharmacokinetics of Other Drugs In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1). No dose adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies. Figure 1. Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs *Warfarin was given once daily at a stable dose in the range of 1 mg to 10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR). **Caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate) and fexofenadine (P-gp substrate) were administered as a cocktail. Effects of Other Drugs on the Pharmacokinetics of Alogliptin There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described below (Figure 2). Figure 2. Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin Metformin Hydrochloride Pharmacokinetic drug interaction studies have been performed on metformin (Tables 4 and 5). Table 4. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug* Dose of Metformin HCl* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC† Cmax No dosing adjustments required for the following: Glyburide 5 mg 500 mg‡ 0.98§ 0.99§ Furosemide 40 mg 850 mg 1.09§ 1.22§ Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05§ 1.07§ Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS] Topiramate 100 mg¶ 500 mg¶ 1.25¶ 1.17 *All metformin and coadministered drugs were given as single doses †AUC = AUC0˗∞ ‡metformin hydrochloride extended-release tablets 500 mg §Ratio of arithmetic means ¶At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC012h Table 5. Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug* Dose of Metformin HCl* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC† Cmax No dosing adjustments required for the following: Glyburide 5 mg 500 mg‡ 0.78§ 0.63§ Furosemide 40 mg 850 mg 0.87§ 0.69§ Nifedipine 10 mg 850 mg 1.10‡ 1.08 Propranolol 40 mg 850 mg 1.01‡ 0.94 Ibuprofen 400 mg 850 mg 0.97¶ 1.01¶ Cimetidine 400 mg 850 mg 0.95‡ 1.01 *All metformin and coadministered drugs were given as single doses †AUC = AUC0˗∞ ‡AUC0-24 hr reported §Ratio of arithmetic means, p-value of difference <0.05 ¶Ratio of arithmetic means Clinical Studies The coadministration of alogliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone, on metformin alone or metformin in combination with a thiazolidinedione. There have been no clinical efficacy studies conducted with KAZANO; however, bioequivalence of KAZANO with coadministered alogliptin and metformin tablets was demonstrated, and efficacy of the combination of alogliptin and metformin has been demonstrated in three Phase 3 efficacy studies. A total of 2095 patients with type 2 diabetes were randomized in three double-blind, placebo-or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of KAZANO on glycemic control. The racial distribution of patients exposed to study medication was 69.2% white, 16.3% Asian, 6.5% black and 8.0% other racial groups. The ethnic distribution was 24.3% Hispanic. Patients had an overall mean age of approximately 54.4 years (range 22 to 80 years). In patients with type 2 diabetes, treatment with KAZANO produced clinically meaningful and statistically significant improvements in A1C versus comparator. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in hemoglobin A1c (A1C) with KAZANO appears to be related to the degree of A1C elevation at baseline. Alogliptin And Metformin Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Diet And Exercise In a 26 week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily, alogliptin 12.5 mg twice daily, or alogliptin 25 mg daily; alogliptin 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (alogliptin 12.5 mg + metformin HCl 500 mg and alogliptin 12.5 mg + metformin HCl 1000 mg) resulted in significant improvements in A1C (Figure 3) and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 6). Coadministration treatment arms demonstrated improvements in two-hour postprandial glucose (PPG) compared to alogliptin alone or metformin alone (Table 6). A total of 12% of patients receiving alogliptin 12.5 mg + metformin HCl 500 mg, 3% of patients receiving alogliptin 12.5 mg + metformin HCl 1000 mg, 17% of patients receiving alogliptin 12.5 mg, 23% of patients receiving metformin HCl 500 mg, 11% of patients receiving metformin HCl 1000 mg and 39% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and alogliptin when coadministered with metformin. Lipid effects were neutral. Table 6. Glycemic Parameters at Week 26 for Alogliptin and Metformin Alone and in Combination in Patients with Type 2 Diabetes Placebo Alogliptin 12.5 mg twice daily Metformin HCl 500 mg twice daily Metformin HCl 1000 mg twice daily Alogliptin 12.5 mg + Metformin HCl 500 mg twice daily Alogliptin 12.5 mg + Metformin HCl 1000 mg twice daily A1C (%)* N=102 N=104 N=103 N=108 N=102 N=111 Baseline (mean) 8.5 8.4 8.5 8.4 8.5 8.4 Change from baseline (adjusted mean†) 0.1 -0.6 -0.7 -1.1 -1.2 -1.6 Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -0.6‡ (-0.9, -0.3) -0.4‡ (-0.7, -0.2) Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - -0.7‡ (-1.0, -0.4) -1.0‡ (-1.3, -0.7) % of Patients (n/N) achieving A1C <7%§ 4% (4/102) 20% (21/104) 27% (28/103) 34% (37/108) 47%‡ (48/102) 59%‡ (66/111) FPG (mg/dL)* N=105 N=106 N=106 N=110 N=106 N=112 Baseline (mean) 187 177 180 181 176 185 Change from baseline (adjusted mean†) 12 -10 -12 -32 -32 -46 Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -20‡ (-33, -8) -14‡ (-26, -2) Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - -22‡ (-35, -10) -36‡ (-49, -24) 2-Hour PPG (mg/dL)¶ N=26 N=34 N=28 N=37 N=31 N=37 Baseline (mean) 263 272 247 266 261 268 Change from baseline (adjusted mean†) -21 -43 -49 -54 -68 -86‡ Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -19 (-49, 11) -32‡ (-58, -5) Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - -25 (-53, 3) -43‡ (-70, -16) *Intent-to-treat population using last observation on study prior to discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue †Least squares means adjusted for treatment, geographic region and baseline value ‡p<0.05 when compared to metformin and alogliptin alone §Compared using logistic regression ¶Intent-to-treat population using data available at Week 26 Figure 3. Change from Baseline A1C at Week 26 with Alogliptin andMetformin Alone and Alogliptin in Combination with Metformin Alogliptin And Metformin Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Metformin Alone In a 26 week, double-blind, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg) during the treatment period. Alogliptin 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 7). A total of 8% of patients receiving alogliptin 25 mg and 24% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race, baseline BMI or baseline metformin dose. The mean decrease in body weight was similar between alogliptin 25 mg and placebo when given in combination with metformin. Lipid effects were also neutral. Table 7. Glycemic Parameters at Week 26 in a Placebo-Controlled Study of Alogliptin as Add-on Therapy to Metformin* Alogliptin 25 mg + Metformin Placebo + Metformin A1C (%) N=203 N=103 Baseline (mean) 7.9 8.0 Change from baseline (adjusted mean†) -0.6 -0.1 Difference from placebo (adjusted mean† with 95% confidence interval) -0.5‡ (-0.7, -0.3) - % of patients (n/N) achieving A1C ≤7%‡ 44% (92/207)‡ 18% (19/104) FPG (mg/dL) N=204 N=104 Baseline (mean) 172 180 Change from baseline (adjusted mean†) -17 0 Difference from placebo (adjusted mean† with 95% confidence interval) -17‡ (-26, -9) - *Intent-to-treat population using last observation on study. †Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose. ‡p<0.001 compared to placebo. Alogliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On The Combination Of Metformin And Pioglitazone In a 52 week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin were randomized to either receive the addition of once-daily alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four-week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52 week treatment period received glycemic rescue therapy. In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 to 45 mg at Week 26 and at Week 52 (Table 8). A total of 11% of patients in the alogliptin 25 mg in combination with pioglitazone 30 mg and metformin treatment group and 22% of patients in the up titration of pioglitazone in combination with metformin treatment group required glycemic rescue. Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral. Table 8. Glycemic Parameters at Week 52 in an Active-Controlled Study of Alogliptin as Add-On Combination Therapy to Metformin and Pioglitazone* Alogliptin 25 mg + Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin A1C (%) N=397 N=394 Baseline (mean) 8.2 8.1 Change from baseline (adjusted mean†) -0.7 -0.3 Difference from pioglitazone 45 mg + metformin* (adjusted mean† with 95% confidence interval) -0.4‡ (-0.5, -0.3) - % of Patients (n/N) achieving A1C ≤7% 33% (134/404)§ 21% (85/399) Fasting Plasma Glucose (mg/dL)‡ N=399 N=396 Baseline (mean) 162 162 Change from baseline (adjusted mean†) -15 -4 Difference from pioglitazone 45 mg + metformin (adjusted mean† with 95% confidence interval) -11§ (-16, -6) - *Intent-to-treat population using last observation on study †Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose ‡Noninferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided significance level §p<0.001 compared to pioglitazone 45 mg + metformin Cardiovascular Safety Trial A randomized, double-blind, placebo-controlled cardiovascular outcomes trial (EXAMINE) was conducted to evaluate the cardiovascular risk of alogliptin. The trial compared the risk of major adverse cardiovascular events (MACE) between alogliptin (N=2701) and placebo (N=2679) when added to standard of care therapies for diabetes and atherosclerotic vascular disease (ASCVD). The trial was event driven and patients were followed until a sufficient number of primary outcome events accrued. Eligible patients were adults with type 2 diabetes who had inadequate glycemic control at baseline (e.g., HbA1c >6.5%) and had been hospitalized for an acute coronary syndrome event (e.g., acute myocardial infarction or unstable angina requiring hospitalization) 15 to 90 days prior to randomization. The dose of alogliptin was based on estimated renal function at baseline per dosage and administration recommendations. The average time between an acute coronary syndrome event and randomization was approximately 48 days. The mean age of the population was 61 years. Most patients were male (68%), Caucasian (73%), and were recruited from outside of the United States (86%). Asian and Black patients contributed 20% and 4% of the total population, respectively. At the time of randomization patients had a diagnosis of type 2 diabetes mellitus for approximately 9 years, 87% had a prior myocardial infarction and 14% were current smokers. Hypertension (83%) and renal impairment (27% with an eGFR ≤60 ml/min/1.73 m2) were prevalent co-morbid conditions. Use of medications to treat diabetes (e.g., metformin 73%, sulfonylurea 54%, insulin 41%), and ASCVD (e.g., statin 94%, aspirin 93%, reninangiotensin system blocker 88%, beta-blocker 87%) was similar between patients randomized to alogliptin and placebo at baseline. During the trial, medications to treat diabetes and ASCVD could be adjusted to ensure care for these conditions adhered to standard of care recommendations set by local practice guidelines. The primary endpoint in EXAMINE was the time to first occurrence of a MACE defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. The study was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to study drug was 526 days and 95% of the patients were followed to study completion or death. Table 9 shows the study results for the primary MACE composite endpoint and the contribution of each component to the primary MACE endpoint. The upper bound of the confidence interval was 1.16 and excluded a risk margin larger than 1.3. Table 9. Patients with MACE in EXAMINE Alogliptin Placebo Hazard Ratio Number of Patients (%) Rate per 100 PY* Number of Patients (%) Rate per 100 PY* (98% CI) N=2701 N=2679 Composite of first event of CV death, nonfatal MI or nonfatal stroke (MACE) 305 (11.3) 7.6 316 (11.8) 7.9 0.96 (0.80, 1.16) CV Death 89 (3.3) 2.2 111 (4.1) 2.8 Non-fatal MI 187 (6.9) 4.6 173 (6.5) 4.3 Non-fatal stroke 29 (1.1) 0.7 32 (1.2) 0.8 *Patient Years (PY) The Kaplan-Meier based cumulative event probability is presented in Figure 4 for the time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for placebo and alogliptin overlap throughout the duration of the study. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (14.8 MACE per 100 PY), decreased from day 60 to the end of the first year (8.4 per 100 PY) and was lowest after 1 year of follow-up (5.2 per 100 PY). Figure 4. Observed Cumulative Rate of MACE in EXAMINE The rate of all cause death was similar between treatment arms with 153 (3.6 per 100 PY) recorded among patients randomized to alogliptin and 173 (4.1 per 100 PY) among patients randomized to placebo. A total of 112 deaths (2.9 per 100 PY) among patients on alogliptin and 130 among patients on placebo (3.5 per 100 PY) were adjudicated as cardiovascular deaths.

Find Lowest Prices on KAZANO (alogliptin and metformin HCl) Tablets WARNING LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metforminassociated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see WARNINGS AND PRECAUTIONS]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and Use In Specific Populations]. If metformin-associated lactic acidosis is suspected, immediately discontinue KAZANO and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see WARNINGS AND PRECAUTIONS]. DESCRIPTION KAZANO tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and metformin hydrochloride. Alogliptin Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4). Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18H21N5O2•C7H6O2 and a molecular weight of 461.51 daltons; the structural formula is: Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate. Metformin Hydrochloride Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown: KAZANO is available as a tablet for oral administration containing 17 mg alogliptin benzoate equivalent to 12.5 mg alogliptin and: 500 mg metformin hydrochloride (12.5 mg/500 mg) or 1000 mg metformin hydrochloride (12.5 mg/1000 mg). KAZANO tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, povidone, crospovidone, and magnesium stearate; the tablets are film-coated with hypromellose 2910, talc, titanium dioxide and ferric oxide yellow.

INDICATIONS Monotherapy And Combination Therapy KAZANO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both alogliptin and metformin is appropriate [see Clinical Studies]. Important Limitations Of Use KAZANO is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings. DOSAGE AND ADMINISTRATION Recommendations For All Patients Healthcare providers should individualize the starting dose of KAZANO based on the patient's current regimen. KAZANO should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. KAZANO tablets must not be split before swallowing. Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. The following doses are available: 12.5 mg alogliptin and 500 mg metformin HCl 12.5 mg alogliptin and 1000 mg metformin HCl Recommendations For Use In Renal Impairment Assess renal function prior to initiation of KAZANO and periodically thereafter. KAZANO is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m² because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination KAZANO product. Discontinuation For Iodinated Contrast Imaging Procedures Discontinue KAZANO 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 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure; restart KAZANO if renal function is stable [see WARNINGS AND PRECAUTIONS]. HOW SUPPLIED Dosage Forms And Strengths 12.5 mg/500 mg tablets are pale yellow, oblong, film-coated tablets with “12.5/500” debossed on one side and “322M” debossed on the other side 12.5 mg/1000 mg tablets are pale yellow, oblong, film-coated tablets with “12.5/1000” debossed on one side and “322M” debossed on the other side Storage And Handling KAZANO tablets are available in the following strengths and packages: 12.5 mg/500 mg tablet: pale yellow, oblong, film-coated tablets with “12.5/500” debossed on one side and “322M” debossed on the other side, available in: NDC 64764-335-60 Bottles of 60 tablets NDC 64764-335-80 Bottles of 180 tablets NDC 64764-335-77 Bottles of 500 tablets 12.5 mg/1000 mg tablet: pale yellow, oblong, film-coated tablets with “12.5/1000” debossed on one side and “322M” debossed on the other side, available in: NDC 64764-337-60 Bottles of 60 tablets NDC 64764-337-80 Bottles of 180 tablets NDC 64764-337-77 Bottles of 500 tablets Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015. Revised: Dec 2016

PATIENT INFORMATION KAZANO (Kah-ZAHN-oh) (alogliptin and metformin HCl) Tablets Read this Medication Guide carefully before you start taking KAZANO and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about KAZANO, ask your doctor or pharmacist. What is the most important information I should know about KAZANO? KAZANO can cause serious side effects, including: 1. Lactic Acidosis. Metformin, one of the medicines in KAZANO, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: you feel cold in your hands or feet you feel dizzy or lightheaded you have a slow or irregular heartbeat you feel very weak or tired you have unusual (not normal) muscle pain you have trouble breathing you feel sleepy or drowsy you have stomach pains, nausea or vomiting Most people who have had lactic acidosis with metformin have other things that, combined with metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with KAZANO if you: have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye have liver problems drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids have surgery have a heart attack, severe infection, or stroke The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems listed above. You doctor may decide to stop KAZANO for a while if you have any of these things. KAZANO can have other serious side effects. See “What are the possible side effects of KAZANO?” 2. Inflammation of the pancreas (pancreatitis). Alogliptin, one of the medicines in KAZANO, may cause pancreatitis, which may be severe. Certain medical conditions make you more likely to get pancreatitis. Before you start taking KAZANO: Tell your doctor if you have ever had: pancreatitis kidney problems liver problems Stop taking KAZANO and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. 3. Heart failure: Before you start taking KAZANO: Tell your healthcare provider if you have ever had heart failure or have problems with your kidneys. Contact your healthcare provider right away if you have any of the following symptoms: increasing shortness of breath or an unusually fast increase in swelling of feet, ankles, or legs trouble breathing especially when weight lying down These may be symptoms of heart failure. What is KAZANO? KAZANO contains 2 prescription diabetes medicines, alogliptin (NESINA) and metformin hydrochloride. KAZANO is a prescription medicine used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes. KAZANO is not for people with type 1 diabetes. KAZANO is not for people with diabetic ketoacidosis (increased ketones in blood or urine). It is not known if KAZANO is safe and effective in children under the age of 18. Who should not take KAZANO? Do not take KAZANO if you: have severe kidney problems have a condition called metabolic acidosis or have had diabetic ketoacidosis (increased ketones in your blood or urine) are going to get an injection of dye or contrast agents for an x-ray procedure, KAZANO may need to be stopped for a short time. Talk to your doctor about when you should stop KAZANO and when you should start KAZANO again are allergic to alogliptin (NESINA) or metformin or any of the ingredients in KAZANO or have had a serious allergic (hypersensitivity) reaction to alogliptin or metformin. See the end of this Medication Guide for a complete list of the ingredients in KAZANO Symptoms of a serious allergic reaction to KAZANO may include: swelling of your face, lips, throat and other areas on your skin difficulty with swallowing or breathing raised, red areas on your skin (hives) skin rash, itching, flaking or peeling If you have any of these symptoms, stop taking KAZANO and contact your doctor or go to the nearest hospital emergency room right away. What should I tell my doctor before and during treatment with KAZANO? Before you take KAZANO, tell your doctor if you: have or have had inflammation of your pancreas (pancreatitis) have severe kidney or liver problems have heart problems, including congestive heart failure are going to get an injection of dye or contrast agents for an x-ray procedure, KAZANO may need to be stopped for a short time. Talk to your doctor about when you should stop KAZANO and when you should start KAZANO again drink alcohol very often or drink a lot of alcohol in short-term “binge” drinking have other medical conditions are pregnant or plan to become pregnant. It is not known if KAZANO will harm your unborn baby. Talk with your doctor about the best way to control your blood sugar while you are pregnant or if you plan to become pregnant are breastfeeding or plan to breastfeed. It is not known whether KAZANO passes into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking KAZANO Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist before you start any new medicine. KAZANO may affect the way other medicines work, and other medicines may affect how KAZANO works. Contact your doctor before you start or stop other types of medicines. How should I take KAZANO? Take KAZANO exactly as your doctor tells you to take it. Take KAZANO 2 times each day. Take KAZANO with food to lower your chances of having an upset stomach. Do not break or cut KAZANO tablets before swallowing. Your doctor may need to change your dose of KAZANO to control your blood glucose. Do not change your dose unless told to do so by your doctor. If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose, and take the next dose at your regular time. Do not take 2 doses of KAZANO at the same time. If you take too much KAZANO, call your doctor or go to the nearest hospital emergency room right away. If your body is under stress, such as from fever, infection, accident or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away. Stay on your diet and exercise programs and check your blood sugar as your doctor tells you to. Your doctor may do certain blood tests before you start KAZANO and during treatment as needed. Your doctor may ask you to stop taking KAZANO based on the results of your blood tests due to how well your kidneys are working. Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. What are the possible side effects of KAZANO? KAZANO can cause serious side effects, including: See “What is the most important information I should know about KAZANO?” Allergic (hypersensitivity) reactions, such as: swelling of your face, lips, throat and other areas on your skin difficulty swallowing or breathing raised, red areas on your skin (hives) skin rash, itching, flaking or peeling If you have these symptoms, stop taking KAZANO and contact your doctor right away. Liver problems. Call your doctor right away if you have unexplained symptoms, such as: nausea or vomiting stomach pain unusual or unexplained tiredness loss of appetite dark urine yellowing of your skin or the whites of your eyes Low blood sugar (hypoglycemia). If you take KAZANO with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take KAZANO. If you have symptoms of low blood sugar, you should check your blood sugar and treat if low, and then call your doctor. Signs and symptoms of low blood sugar may include: shaking or feeling jittery fast heartbeat hunger change in mood dizziness sweating change in vision headache confusion Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in KAZANO, may develop joint pain that can be severe. Call your doctor if you have severe joint pain. Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in KAZANO, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking The most common side effects of KAZANO include: cold-like symptoms (upper respiratory tract infection) stuffy or runny nose and sore throat diarrhea increase in blood pressure headache back pain urinary tract infection Taking KAZANO with food can help lessen the common stomach side effects of metformin that usually happen at thebeginning of treatment. If you have unexplained stomach problems, tell your doctor. Stomach problems that start later,during treatment, may be a sign of something more serious. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of KAZANO. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store KAZANO? Store KAZANO at room temperature between 68°F to 77°F (20°C to 25°C). Keep the container of KAZANO tightly closed. Keep KAZANO and all medicines out of the reach of children. General information about the safe and effective use of KAZANO Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not take KAZANO for a condition for which it was not prescribed. Do not give KAZANO to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about KAZANO. If you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for information about KAZANO that is written for health professionals. For more information go to www.kazano.com or call 1-877-TAKEDA-7 (1-877-825-3327). What are the ingredients in KAZANO? Active ingredients: alogliptin and metformin hydrochloride Inactive ingredients: mannitol, microcrystalline cellulose, povidone, crospovidone and magnesium stearate; the tablets are film-coated with hypromellose 2910, talc, titanium dioxide and ferric oxide yellow.

SIDE EFFECTS The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see WARNINGS AND PRECAUTIONS] Heart Failure [see WARNINGS AND PRECAUTIONS] Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS] Hepatic Effects [see WARNINGS AND PRECAUTIONS] Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS] Bullous Pemphigoid [see WARNINGS AND PRECAUTIONS] 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. Alogliptin And Metformin Hydrochloride Over 2700 patients with type 2 diabetes have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The mean exposure to KAZANO was 58 weeks, with more than 1400 subjects treated for more than one year. These included two 26 week placebo-controlled studies, one 52 week active control study and an interim analysis of a 104 week active-controlled study. In the KAZANO arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m2 (56% of patients had a BMI ≥30 kg/m2) and the mean age was 55 years (18% of patients ≥65 years of age). In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with KAZANO compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 6.2% with KAZANO compared to 1.9% in placebo, 6.4% in metformin and 5.0% in alogliptin. Adverse reactions reported in ≥4% of patients treated with KAZANO and more frequently than in patients who received alogliptin, metformin or placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Patients Treated with KAZANO and More Frequently Than in Patients Receiving Either Alogliptin, Metformin or Placebo Number of Patients (%) KAZANO* Alogliptin† Metformin‡ Placebo N=2794 N=222 N=1592 N=106 Upper respiratory tract infection 224 (8.0) 6 (2.7) 105 (6.6) 3 (2.8) Nasopharyngitis 191 (6.8) 7 (3.2) 93 (5.8) 2 (1.9) Diarrhea 155 (5.5) 4 (1.8) 105 (6.6) 3 (2.8) Hypertension 154 (5.5) 5 (2.3) 96 (6.0) 6 (5.7) Headache 149 (5.3) 11 (5.0) 74 (4.6) 3 (2.8) Back pain 119 (4.3) 1 (0.5) 72 (4.5) 1 (0.9) Urinary tract infection 116 (4.2) 4 (1.8) 59 (3.7) 2 (1.9) *KAZANO – includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various dose of metformin †Alogliptin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg ‡Metformin – includes data pooled for patients receiving various doses of metformin Hypoglycemia In a 26 week, double-blind, placebo-controlled study of alogliptin in combination with metformin, the number of patients reporting hypoglycemia was 1.9% in the alogliptin 12.5 mg with metformin HCl 500 mg, 5.3% in the alogliptin 12.5 mg with metformin HCl 1000 mg, 1.8% in the metformin HCl 500 mg and 6.3% in the metformin HCl 1000 mg treatment groups. In a 26 week placebo-controlled study of alogliptin 25 mg administered once daily as add-on to metformin regimen, the number of patients reporting hypoglycemic events was 0% in the alogliptin with metformin and 2.9% in the placebo treatment groups. In a 52 week, active-controlled, double-blind study of alogliptin once daily as add-on therapy to the combination of pioglitazone 30 mg and metformin compared to the titration of pioglitazone 30 mg to 45 mg and metformin, the number of patients reporting hypoglycemia was 4.5% in the alogliptin 25 mg with pioglitazone 30 mg and metformin group versus 1.5% in the pioglitazone 45 mg with metformin group. In an interim analysis conducted in a 104-week, double-blind, active-controlled study of alogliptin 25 mg in combination with metformin, the number of patients reporting hypoglycemia was 1.4% in the alogliptin 25 mg with metformin group versus 23.8% in the glipizide with metformin group. Alogliptin A total of 14,778 patients with type 2 diabetes participated in 14 randomized, double-blind, controlled clinical trials of whom 9052 subjects were treated with alogliptin, 3469 subjects were treated with placebo and 2257 were treated with an active comparator. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m2 (49% of patients had a BMI ≥30 kg/m2), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to alogliptin was 49 weeks with 3348 subjects treated for more than one year. In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse reactions was 6.8% with alogliptin 25 mg compared to 8.4% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2. Table 2. Adverse Reactions Reported in ≥4% Patients Treated with Alogliptin 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies Number of Patients (%) Alogliptin 25 mg Placebo Active Comparator N=6447 N=3469 N=2257 Nasopharyngitis 309 (4.8) 152 (4.4) 113 (5.0) Upper Respiratory Tract Infection 287 (4.5) 121 (3.5) 113 (5.0) Headache 278 (4.3) 101 (2.9) 121 (5.4) Hypoglycemia Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia. In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with alogliptin compared to 1.6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with alogliptin compared to 26% with glipizide. In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving alogliptin and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with alogliptin and in 0.6% of patients treated with placebo. Metformin Hydrochloride Table 3. Most Common Adverse Reactions (≥5%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy* Adverse Reaction Metformin Monotherapy (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal discomfort 6.4 4.8 Headache 5.7 4.8 *Reactions that were more common in metformin than placebo-treated patients Laboratory Abnormalities Alogliptin And Metformin Hydrochloride No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results. Metformin Hydrochloride Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on KAZANO, and any apparent abnormalities should be appropriately investigated and managed [see WARNINGS AND PRECAUTIONS]. Postmarketing Experience The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Alogliptin Acute pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and bullous pemphigoid, diarrhea, constipation, nausea, and ileus [see WARNINGS AND PRECAUTIONS]. Metformin Cholestatic, hepatocellular, and mixed hepatocellular liver injury. DRUG INTERACTIONS Alogliptin Alogliptin is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs [see CLINICAL PHARMACOLOGY]. Metformin Hydrochloride Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with KAZANO may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients. Drugs That Reduce Metformin Clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see CLINICAL PHARMACOLOGY]. Consider the benefits and risks of concomitant use. Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KAZANO. Insulin Secretagogues And Insulin When used in an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. The Use Of Metformin With Other Drugs Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid. When such drugs are administered to a patient receiving KAZANO, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving KAZANO, the patient should be observed closely for hypoglycemia.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metforminassociated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of KAZANO. In KAZANO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KAZANO and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney [see CLINICAL PHARMACOLOGY]. Before initiating KAZANO, obtain an eGFR. KAZANO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m². KAZANO is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m² because these patients require a lower dosage of alogliptin than what is available in the fixed combination KAZANO product. Obtain an eGFR at least annually in all patients taking KAZANO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions The concomitant use of KAZANO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see DRUG INTERACTIONS]. Therefore, consider more frequent monitoring of patients. Age 65 Or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations]. Radiological Studies With Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop KAZANO 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 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart KAZANO if renal function is stable. Surgery And Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. KAZANO should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue KAZANO. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving KAZANO. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of KAZANO in patients with clinical or laboratory evidence of hepatic disease. Pancreatitis Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. In glycemic control trials in patients with type 2 diabetes, acute pancreatitis was reported in 6 (0.2%) patients treated with alogliptin 25 mg and 2 ( < 0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) of patients treated with alogliptin and in 7 (0.3%) of patients treated with placebo. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using KAZANO. After initiation of KAZANO, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should promptly be discontinued and appropriate management should be initiated. Heart Failure In the EXAMINE trial which enrolled patients with type 2 diabetes and recent acute coronary syndrome, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure. Consider the risks and benefits of KAZANO 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. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KAZANO. Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue KAZANO, assess for other potential causes for the event and institute alternative treatment for diabetes [see ADVERSE REACTIONS]. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with KAZANO. Hepatic Effects There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause [see ADVERSE REACTIONS]. In glycemic control trials in patients with type 2 diabetes, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with alogliptin 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with alogliptin and in 1.8% of patients treated with placebo. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, KAZANO should be interrupted and investigation done to establish the probable cause. KAZANO should not be restarted in these patients without another explanation for the liver test abnormalities. Vitamin B12 Levels In controlled, 29-week clinical trials of immediate-release metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on KAZANO, and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful. Use With Medications Known To Cause Hypoglycemia Alogliptin Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with KAZANO. Metformin Hydrochloride Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β- adrenergic blocking drugs. Severe And Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KAZANO or any other antidiabetic drug. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide) Inform patients of the potential risks and benefits of KAZANO. The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue KAZANO immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of KAZANO, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Patients should be informed that acute pancreatitis has been reported during use of alogliptin. Patients should be informed that persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue KAZANO and contact their physician if persistent severe abdominal pain occurs. Patients should be informed of the signs and symptoms of heart failure. Before initiating KAZANO, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Patients should be instructed to contact their healthcare providers as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight, or swelling of the feet. Patients should be informed that allergic reactions have been reported during use of alogliptin and metformin. If symptoms of allergic reactions (including skin rash, hives and swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing) occur, patients should be instructed to discontinue KAZANO and seek medical advice promptly. Patients should be informed that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin. If signs or symptoms of liver injury occur, patients should be instructed to discontinue KAZANO and seek medical advice promptly. Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with KAZANO. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving KAZANO. Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with KAZANO. Explain the risks, symptoms and appropriate management of hypoglycemia. Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs. Instruct patients to take KAZANO only as prescribed twice daily. KAZANO should be taken with food. If a dose is missed, advise patients not to double their next dose. Patients should be informed that the tablets must never be split. Instruct patients to read the Medication Guide before starting KAZANO therapy and to reread each time the prescription is refilled. Instruct patients to inform their healthcare provider if an unusual symptom develops or if a symptom persists or worsens. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Alogliptin and Metformin Hydrochloride No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with KAZANO. The following data are based on findings in studies performed with alogliptin or metformin individually. Alogliptin Rats were administered oral doses of 75, 400 and 800 mg/kg alogliptin for two years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on area under the plasma concentration curve (AUC) exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150 or 300 mg/kg alogliptin for two years, or up to approximately 51 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study. In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating or fertility, at doses up to 500 mg/kg, or approximately 172 times the clinical dose based on plasma drug exposure (AUC). Metformin Hydrochloride Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg and 1500 mg/kg, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons. Use In Specific Populations Pregnancy Pregnancy Category B Alogliptin and Metformin Hydrochloride There are no adequate and well-controlled studies in pregnant women with KAZANO or its individual components. Based on animal data, KAZANO is not predicted to increase the risk of developmental abnormalities. Because animal reproduction studies are not always predictive of human risk and exposure, KAZANO, like other antidiabetic medications, should be used during pregnancy only if clearly needed. No treatment-related fetal abnormalities occurred following concomitant administration of 100 mg/kg alogliptin with 150 mg/kg metformin to pregnant rats, or approximately 28 and two times the clinical dose of alogliptin (25 mg) and metformin (2000 mg), respectively (based on AUC). Alogliptin Alogliptin administered to pregnant rabbits and rats during the period of organogenesis was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, respectively, the clinical dose based on plasma drug exposure (AUC). Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the developing embryo or adversely affect growth and development of offspring. Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. Metformin Hydrochloride Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg, which represents an exposure of about two and six times the MRHD dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Metformin HCl should not be used during pregnancy unless clearly needed. Nursing Mothers No studies have been conducted with the combined components of KAZANO. In studies performed with the individual components, both alogliptin and metformin are secreted in the milk of lactating rats. It is not known whether alogliptin and/or metformin are secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KAZANO is administered to a nursing woman. Pediatric Use Safety and effectiveness of KAZANO in pediatric patients have not been established. Geriatric Use Alogliptin and Metformin Hydrochloride Elderly patients are more likely to have decreased renal function. Monitor renal function in the elderly more frequently [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].  Of the total number of patients (N = 2095) in clinical safety and efficacy studies, 343 (16.4%) patients were 65 years and older and 37 (1.8%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded. Alogliptin Of the total number of patients (N=9052) in clinical safety and efficacy studies treated with alogliptin, 2257 (24.9%) patients were 65 years and older and 386 (4.3%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Metformin Hydrochloride Controlled studies of metformin did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal and cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. KAZANO is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m² [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. KAZANO is not recommended in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].