Alogliptin and metformin hydrochloride

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.2) ] Heart Failure [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Hepatic Effects [see Warnings and Precautions (5.5) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.8) ] Bullous Pemphigoid [see Warnings and Precautions (5.9) ] The most common adverse reactions (4% or greater incidence) are upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 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. 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 alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m 2 (56% of patients had a BMI ≥30 kg/m 2 ) 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 alogliptin and metformin HCl tablets compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 6.2% with alogliptin and metformin HCl tablets compared to 1.9% in placebo, 6.4% in metformin and 5.0% in alogliptin. Adverse reactions reported in ≥4% of patients treated with alogliptin and metformin HCl tablets 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 Alogliptin and Metformin HCl Tablets and More Frequently Than in Patients Receiving Either Alogliptin, Metformin or Placebo Number of Patients (%) Alogliptin and Metformin HCl Tablets Alogliptin and metformin HCl tablets – includes data pooled for patients receiving alogliptin 25 and 12.5 mg combined with various dose of metformin Alogliptin Alogliptin – includes data pooled for patients receiving alogliptin 25 and 12.5 mg Metformin Metformin – includes data pooled for patients receiving various doses of 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) 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/m 2 (49% of patients had a BMI ≥30 kg/m 2 ), 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 Reactions that were more common in metformin than placebo-treated patients 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 Laboratory Abnormalities Alogliptin and Metformin Hydrochloride No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results. Metformin Hydrochloride In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. 6.2 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 Gastrointestinal disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus Hepatobiliary disorders: fulminant hepatic failure Immune system disorders: hypersensitivity reactions including anaphylaxis Investigations: hepatic enzyme elevations Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis Renal and urinary disorders: tubulointerstitial nephritis Skin and subcutaneous tissue disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid Metformin Hepatobiliary disorders: Cholestatic, hepatocellular, mixed hepatocellular liver injury

4 CONTRAINDICATIONS Alogliptin and metformin HCl tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) ]. Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma. Serious hypersensitivity reaction to alogliptin or metformin or any of the exciptients, such as anaphylaxis, angioedema and severe cutaneous adverse reactions [see Warnings and Precautions (5.4) , Adverse Reactions (6.2) ] . Severe renal impairment: eGFR below 30 mL/min/1.73 m 2 . ( 4 ) Metabolic acidosis, including diabetic ketoacidosis. ( 4 ) History of a serious hypersensitivity reaction to alogliptin or metformin or any of the excipients. ( 4 )

11 DESCRIPTION Alogliptin and metformin HCl 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-[(3 R )-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C 18 H 21 N 5 O 2 ∙C 7 H 6 O 2 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. Chemical Structure 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 C 4 H 11 N 5 ∙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: Alogliptin and metformin HCl tablets are available as a tablet for oral administration containing 17 mg alogliptin benzoate equivalent to 12.5 mg alogliptin and: 500 mg metformin hydrochloride which is equivalent to 389.93 mg metformin base (12.5 mg/500 mg) or 1000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (12.5 mg/1000 mg). Alogliptin and metformin HCl 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. Chemical Structure

2 DOSAGE AND ADMINISTRATION Individualize the starting dose based on the patient's current regimen. ( 2.1 ) Give twice daily with food. ( 2.1 ) Adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl. ( 2.1 ) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) Do not use in patients with eGFR below 60 mL/min/1.73 m 2 . Alogliptin and metformin HCl tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Recommendations for All Patients Healthcare providers should individualize the starting dose of alogliptin and metformin HCl tablets based on the patient's current regimen. Alogliptin and metformin HCl tablets should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. Do not split tablets. 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 hydrochloride (HCl). The following doses are available: 12.5 mg alogliptin and 500 mg metformin HCl 12.5 mg alogliptin and 1000 mg metformin HCl 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of alogliptin and metformin HCl tablets and periodically thereafter. Alogliptin and metformin HCl tablets is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Contraindications (4) and Warnings and Precautions (5.1) ] . Alogliptin and metformin HCl tablets are not recommended in patients with an eGFR between 30 and 59 mL/min/1.73 m 2 because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product. Alogliptin and metformin HCl tablets require no dose adjustment in patients with an eGFR of 60 mL/min/1.73 m 2 or greater. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue alogliptin and metformin HCl tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart alogliptin and metformin HCl tablets if renal function is stable [see Warnings and Precautions (5.1) ] .

1 INDICATIONS AND USAGE Alogliptin and metformin HCl tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Alogliptin and metformin HCl tablets are a combination of alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor and metformin, 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: Should not be used in patients with type 1 diabetes mellitus. ( 1 ) Limitations of Use Alogliptin and metformin HCl tablets should not be used in patients with type 1 diabetes mellitus.

10 OVERDOSAGE Alogliptin Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1) ] . In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract. Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis. Metformin Hydrochloride Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. To contact the poison control center, call 1-800-222-1222.

7 DRUG INTERACTIONS Carbionic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 ) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. ( 7 ) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 ) Metformin Hydrochloride Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ALOGLIPTIN WITH METFORMIN HYDROCHLORIDE TABLETS may increase the risk of lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide Drugs that Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ] . Intervention: Consider the benefits and risks of concomitant use. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving ALOGLIPTIN WITH METFORMIN HYDROCHLORIDE TABLETS. Insulin Secretagogues and Insulin Clinical Impact: Coadministration of ALOGLIPTIN WITH METFORMIN HYDROCHLORIDE TABLETS with an insulin secretagogue (e.g., sulfonylurea) or with insulin may increase the risk of hypoglycemia. Intervention: Patients may require a lower dose of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving ALOGLIPTIN WITH METFORMIN HYDROCHLORIDE TABLETS, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ALOGLIPTIN WITH METFORMIN HYDROCHLORIDE TABLETS, the patient should be observed closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and isoniazid Alogliptin Cytochrome (CYP) P450, CYP-Substrates or Inhibitors Clinical Impact: 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 (12.3) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alogliptin and Metformin Hydrochloride Alogliptin and metformin HCl tablets combine 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease. 12.2 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. 12.3 Pharmacokinetics Absorption and Bioavailability Alogliptin and Metformin Hydrochloride In bioequivalence studies of alogliptin and metformin HCl tablets, the area under the plasma concentration curve (AUC) and maximum concentration (C max ) 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 alogliptin and metformin HCl tablets 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 (T max ) for alogliptin under fed conditions, however, there was a delayed T max 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 (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T max ) 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. 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 [ 14 C] alogliptin, N -demethylated, 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 [ 14 C] 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 (4) , Warnings and Precautions (5.1) ]. 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 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. 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 alogliptin and metformin HCl tablets have not been performed, although such studies have been conducted with the individual components of alogliptin and metformin HCl tablets (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. Figure 1 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 Figure 2 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 All metformin and coadministered drugs were given as single doses Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC AUC = AUC 0˗∞ C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg metformin hydrochloride extended-release tablets 500 mg 0.98 Ratio of arithmetic means 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 (5) and Drug Interactions (7) ]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7) ] Topiramate 100 mg At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 500 mg 1.25 1.17 Table 5. Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC AUC = AUC 0˗∞ C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg AUC 0-24 hr reported 0.78 Ratio of arithmetic means, p-value of difference <0.05 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 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg 0.95 1.01

12.1 Mechanism of Action Alogliptin and Metformin Hydrochloride Alogliptin and metformin HCl tablets combine 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

12.2 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.

12.3 Pharmacokinetics Absorption and Bioavailability Alogliptin and Metformin Hydrochloride In bioequivalence studies of alogliptin and metformin HCl tablets, the area under the plasma concentration curve (AUC) and maximum concentration (C max ) 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 alogliptin and metformin HCl tablets 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 (T max ) for alogliptin under fed conditions, however, there was a delayed T max 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 (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T max ) 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. 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 [ 14 C] alogliptin, N -demethylated, 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 [ 14 C] 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 (4) , Warnings and Precautions (5.1) ]. 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 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. 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 alogliptin and metformin HCl tablets have not been performed, although such studies have been conducted with the individual components of alogliptin and metformin HCl tablets (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. Figure 1 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 Figure 2 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 All metformin and coadministered drugs were given as single doses Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC AUC = AUC 0˗∞ C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg metformin hydrochloride extended-release tablets 500 mg 0.98 Ratio of arithmetic means 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 (5) and Drug Interactions (7) ]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7) ] Topiramate 100 mg At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 500 mg 1.25 1.17 Table 5. Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00 AUC AUC = AUC 0˗∞ C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg AUC 0-24 hr reported 0.78 Ratio of arithmetic means, p-value of difference <0.05 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 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg 0.95 1.01

20231031

5

3 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 Tablets: 12.5 mg alogliptin and 500 mg metformin HCl, 12.5 mg alogliptin and 1000 mg metformin HCl. ( 3 )

alogliptin and metformin hydrochloride alogliptin and metformin hydrochloride ALOGLIPTIN BENZOATE ALOGLIPTIN METFORMIN HYDROCHLORIDE METFORMIN mannitol microcrystalline cellulose POVIDONE, UNSPECIFIED CROSPOVIDONE (15 MPA.S AT 5%) magnesium stearate talc titanium dioxide ferric oxide yellow HYPROMELLOSE 2910 (6 MPA.S) pale yellow oblong 12;5;1000;322M

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Alogliptin and Metformin Hydrochloride No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with alogliptin and metformin HCl tablets. 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Alogliptin and Metformin Hydrochloride No carcinogenicity, mutagenicity or impairment of fertility studies have been conducted with alogliptin and metformin HCl tablets. 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.

NDA203414

Alogliptin and metformin hydrochloride

alogliptin and metformin hydrochloride

50090-5993

HUMAN PRESCRIPTION DRUG

ORAL

ALOGLIPTIN AND METFORMIN HYDROCHLORIDE Label Image

ALK334 R7 6T200 RCJ6 Rev 05-22

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue alogliptin and metformin HCl tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving alogliptin with metformin tablets. Instruct patients to inform their doctor that they are taking alogliptin with metformin tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1) ]. Pancreatitis Inform patients that acute pancreatitis has been reported during use of alogliptin. should be Educate patients 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. Instruct patients to promptly discontinue alogliptin and metformin HCl tablets and contact their physician if persistent severe abdominal pain occurs. [see Warnings and Precautions (5.2) ]. Heart Failure Inform patients of the signs and symptoms of heart failure. Before initiating alogliptin and metformin HCl tablets, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients 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. [see Warnings and Precautions (5.3) ]. Hypersensitivity Reactions Inform patients that allergic reactions have been reported during use of alogliptin and metformin. Insturct patients 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 instructed discontinue alogliptin and metformin HCl tablets and seek medical advice promptly. [see Warnings and Precautions (5.4) ]. Hepatic Effects Inform patients that postmarketing reports of liver injury, sometimes fatal, have been reported during use of alogliptin. Instruct patients that if signs or symptoms of liver injury occur, patients should be instructed to discontinue alogliptin and metformin HCl tablets and seek medical advice promptly. [see Warnings and Precautions (5.5) ]. Vitamin B12 Levels Inform patients about the importance of regular hematological parameters while receiving treatment with metformin. [see Warnings and Precautions (5.6) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Inform patients that hypoglycemia can occur, particularly when an insulin secretagogue or insulin is used in combination with alogliptin with metformin HCl tablets. Educate patients about the risks, symptoms and appropriate management of hypoglycemia. [see Warnings and Precautions (5.7) ]. Severe and Disabling Arthralgia 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. [see Warnings and Precautions (5.8) ]. Bullous Pemphigoid Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.9) ]. Dosage Instruct patients to take alogliptin with metformin hydrochloride tablets only as prescribed twice daily and that it should be taken with food. Instruct patients if a dose is missed, not to double their next dose. Instruct patients that the tablets must never be split. Females of Reproductive Age Inform female patients that treatment with metformin may result in an unintended pregnancy in some premenopausal anovulatory females due to its effects on ovulation [see Use in Specific Populations (8.3) ] .

MEDICATION GUIDE alogliptin and metformin hydrochloride tablets Read this Medication Guide carefully before you start taking alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets, ask your doctor or pharmacist. What is the most important information I should know about alogliptin with metformin hydrochloride tablets? Alogliptin with metformin hydrochloride tablets can cause serious side effects, including: 1. Lactic Acidosis. Metformin, one of the medicines in alogliptin with metformin hydrochloride tablets, 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 alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets for a while if you have any of these things. Alogliptin with metformin hydrochloride tablets can have other serious side effects. See " What are the possible side effects of alogliptin with metformin hydrochloride tablets? " 2. Inflammation of the pancreas (pancreatitis). Alogliptin, one of the medicines in alogliptin with metformin hydrochloride tablets, may cause pancreatitis, which may be severe. Certain medical conditions make you more likely to get pancreatitis. Before you start taking alogliptin with metformin hydrochloride tablets: Tell your doctor if you have ever had: pancreatitis high blood triglyceride levels kidney problems stones in your gallbladder (gall stones) liver problems history of alcoholism Stop taking alogliptin with metformin hydrochloride tablets 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: Heart failure means your heart does not pump blood well enough. Before you start taking alogliptin with metformin hydrochloride tablets: 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 trouble breathing especially when lying down an unusually fast increase in weight unusual tiredness swelling of feet, ankles, or legs These may be symptoms of heart failure. What is alogliptin with metformin hydrochloride tablets? alogliptin with metformin hydrochloride tablets contain 2 prescription diabetes medicines, alogliptin and metformin hydrochloride. alogliptin with metformin hydrochloride tablets is a prescription medicine used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes. alogliptin with metformin hydrochloride tablets is not for people with type 1 diabetes. It is not known if alogliptin with metformin hydrochloride tablets is safe and effective in children under the age of 18. Who should not take alogliptin with metformin hydrochloride tablets? Do not take alogliptin with metformin hydrochloride tablets 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. Alogliptin with metformin hydrochloride tablets may need to be stopped for a short time. Talk to your doctor about when you should stop alogliptin with metformin hydrochloride tablets and when you should start alogliptin with metformin hydrochloride tablets again are allergic to alogliptin or metformin or any of the ingredients in alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets Symptoms of a serious allergic reaction to alogliptin with metformin hydrochloride tablets may include: swelling of your face, lips, throat and other areas on your skin raised, red areas on your skin (hives) difficulty with swallowing or breathing skin rash, itching, flaking or peeling If you have any of these symptoms, stop taking alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets? Before you take alogliptin with metformin hydrochloride tablets, 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, alogliptin with metformin hydrochloride tablets may need to be stopped for a short time. Talk to your doctor about when you should stop alogliptin with metformin hydrochloride tablets and when you should start alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets 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 if alogliptin with metformin hydrochloride tablets passes into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking alogliptin with metformin hydrochloride tablets 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. alogliptin with metformin hydrochloride tablets may affect the way other medicines work, and other medicines may affect how alogliptin with metformin hydrochloride tablets works. Contact your doctor before you start or stop other types of medicines. How should I take alogliptin with metformin hydrochloride tablets? Take alogliptin with metformin hydrochloride tablets exactly as your doctor tells you to take it. Take alogliptin with metformin hydrochloride tablets 2 times each day. Take alogliptin with metformin hydrochloride tablets with food to lower your chances of having an upset stomach. Do not break or cut alogliptin with metformin hydrochloride tablets before swallowing. Your doctor may need to change your dose of alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets at the same time. If you take too much alogliptin with metformin hydrochloride tablets, call your doctor or your poison control center right away at 1-800-222-1222. 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 alogliptin with metformin hydrochloride tablets and during treatment as needed. Your doctor may ask you to stop taking alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets? alogliptin with metformin hydrochloride tablets can cause serious side effects, including: See " What is the most important information I should know about alogliptin with metformin hydrochloride tablets? " Serious allergic (hypersensitivity) reactions, such as: swelling of your face, lips, throat and other areas on your skin raised, red areas on your skin (hives) difficulty swallowing or breathing skin rash, itching, flaking or peeling If you have these symptoms, stop taking alogliptin with metformin hydrochloride tablets and contact your doctor right away or go to the nearest hospital emergency room. Liver problems. Call your doctor right away or go to the nearest hospital emergency room if you have unexplained symptoms, such as: nausea or vomiting loss of appetite stomach pain dark urine unusual or unexplained tiredness yellowing of your skin or the whites of your eyes Low Vitamin B 12 levels. Some people taking metformin one of the medicines in alogliptin with metformin hydrochloride tablets had low levels of Vitamin B 12. Your doctor should do blood tests every year and check your Vitamin B 12 levels every 2 to 3 years while you are taking alogliptin with metformin hydrochloride tablets. Low blood sugar (hypoglycemia). If you take alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets. 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 sweating fast heartbeat change in vision hunger headache change in mood confusion dizziness Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in alogliptin with metformin hydrochloride tablets, 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 alogliptin with metformin hydrochloride tablets, 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 alogliptin with metformin hydrochloride tablets. The most common side effects of alogliptin with metformin hydrochloride tablets include: cold-like symptoms (upper respiratory tract infection) increase in blood pressure urinary tract infection stuffy or runny nose and sore throat headache diarrhea back pain Taking alogliptin with metformin hydrochloride tablets with food can help lessen the common stomach side effects of metformin that usually happen at the beginning 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 alogliptin with metformin hydrochloride tablets. 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 alogliptin with metformin hydrochloride tablets? Store alogliptin with metformin hydrochloride tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep the container of alogliptin with metformin hydrochloride tablets tightly closed. Keep alogliptin with metformin hydrochloride tablets and all medicines out of the reach of children. General information about the safe and effective use of alogliptin with metformin hydrochloride tablets Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not take alogliptin with metformin hydrochloride tablets for a condition for which it was not prescribed. Do not give alogliptin with metformin hydrochloride tablets 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 alogliptin with metformin hydrochloride tablets. if you would like to know more information, talk with your doctor. You can ask your doctor or pharmacist for information about alogliptin with metformin hydrochloride tablets that is written for health professionals. For more information go to www.padagis.com or call 1-877-TAKEDA-7 (1-877-825-3327). What are the ingredients in alogliptin with metformin hydrochloride tablets? 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. Distributed by: Padagis ™ Allegan, MI 49010 • www.padagis.com All trademarks are the property of their respective owners ALK334 R7 This Medication Guide has been approved by the U.S. Food and Drug Administration. 03/2022

14 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 alogliptin and metformin HCl tablets; however, bioequivalence of alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets 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 alogliptin and metformin HCl tablets 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 (%) 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 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 Least squares means adjusted for treatment, geographic region and baseline value ) 0.1 -0.6 -0.7 -1.1 -1.2 -1.6 Difference from metformin (adjusted mean with 95% confidence interval) - - - - -0.6 p<0.05 when compared to metformin and alogliptin alone (-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% Compared using logistic regression 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) Intent-to-treat population using data available at Week 26 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) Figure 3. Change from Baseline A1C at Week 26 with Alogliptin and Metformin Alone and Alogliptin in Combination with Metformin Figure 3 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 Intent-to-treat population using last observation on study. Alogliptin 25 mg + Metformin Placebo + Metformin A1C (%) N=203 N=103 Baseline (mean) 7.9 8.0 Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose. ) -0.6 -0.1 Difference from placebo (adjusted mean with 95% confidence interval) -0.5 p<0.001 compared to placebo. (-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) ˗ 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 Intent-to-treat population using last observation on study 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 Least squares means adjusted for treatment, baseline value, geographic region and baseline metformin dose ) -0.7 -0.3 Difference from pioglitazone 45 mg + metformin (adjusted mean with 95% confidence interval) -0.4 Noninferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided significance level (-0.5, -0.3) ˗ % of Patients (n/N) achieving A1C ≤7% 33% (134/404) p<0.001 compared to pioglitazone 45 mg + metformin 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) ˗ 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 m 2 ) 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%, renin-angiotensin 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 Composite of first event of CV death, nonfatal MI or nonfatal stroke (MACE) Alogliptin Placebo Hazard Ratio Number of Patients (%) Rate per 100 PY Patient Years (PY) Number of Patients (%) Rate per 100 PY (98% CI) N=2701 N=2679 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 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. Figure 4

8.5 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 (5.1) and Clinical Pharmacology (12.3) ] . 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 (4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

8.4 Pediatric Use Safety and effectiveness of alogliptin and metformin HCl tablets in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Limited available data with alogliptin and metformin HCl tablets or alogliptin in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data ] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ]. Concomitant administration of alogliptin and metformin in pregnant rats during the period of organogenesis did not cause adverse developmental effects in offspring at maternal exposures up to 28 times and two times the 25 mg and 2000 mg clinical doses, respectively [see Data ]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20-25% in women with HbA1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major malformations, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Alogliptin and Metformin Concomitant administration of alogliptin and metformin in pregnant rats during the period of organogenesis did not cause adverse developmental effects in offspring at a dose of 100 mg/kg alogliptin and 150 mg/kg metformin, or approximately 28 and two times the clinical dose of alogliptin (25 mg) and metformin (2000 mg), respectively based on plasma drug exposure (AUC). Alogliptin Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (approximately 95 times the 25 mg clinical dose, based on AUC). Metformin Hydrochloride Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about two to six times a clinical dose of 2000 mg based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy.( 8.3 ) Pediatrics: Safety and effectiveness of alogliptin and metformin HCl tablets in patients below the age of 18 have not been established. ( 8.4 ) Geriatric Use: Assess renal function more frequently. ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary Limited available data with alogliptin and metformin HCl tablets or alogliptin in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data ] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ]. Concomitant administration of alogliptin and metformin in pregnant rats during the period of organogenesis did not cause adverse developmental effects in offspring at maternal exposures up to 28 times and two times the 25 mg and 2000 mg clinical doses, respectively [see Data ]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20-25% in women with HbA1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major malformations, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Alogliptin and Metformin Concomitant administration of alogliptin and metformin in pregnant rats during the period of organogenesis did not cause adverse developmental effects in offspring at a dose of 100 mg/kg alogliptin and 150 mg/kg metformin, or approximately 28 and two times the clinical dose of alogliptin (25 mg) and metformin (2000 mg), respectively based on plasma drug exposure (AUC). Alogliptin Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats. No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (approximately 95 times the 25 mg clinical dose, based on AUC). Metformin Hydrochloride Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about two to six times a clinical dose of 2000 mg based on body surface area (mg/m 2 ) for rats and rabbits, respectively. 8.2 Lactation Risk Summary There is no information regarding the presence of alogliptin and metformin or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production . Alogliptin is present in rat milk. Limited published studies report that metformin is present in human milk [see Data ]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for alogliptin and metformin HCl tablets and any potential adverse effects on the breastfed infant from alogliptin and metformin HCl tablets or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio (based on AUC) ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential There is the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some premenopausal anovulatory women. 8.4 Pediatric Use Safety and effectiveness of alogliptin and metformin HCl tablets in pediatric patients have not been established. 8.5 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 (5.1) and Clinical Pharmacology (12.3) ] . 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 (4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 8.6 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. Alogliptin and metformin HCl tablets is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m 2 [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Alogliptin and metformin HCl tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-5993 NDC: 50090-5993-0 90 TABLET, FILM COATED in a BOTTLE

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated 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 (5.1) ] . 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 (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7) ] . If metformin-associated lactic acidosis is suspected, immediately discontinue alogliptin and metformin HCl tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. ( 5.1 ) If lactic acidosis is suspected, discontinue alogliptin and metformin HCl tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )