alogliptin and metformin hydrochloride

RECENT MAJOR CHANGES Boxed Warning...........................................................................08/2026 Warnings and Precautions, Lactic Acidosis ( 5.1 )..............................08/2026

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 hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Should not be used in patients with type 1 diabetes mellitus. ( 1 ) Limitations of Use Alogliptin and metformin HCl tablets should not recommended for use in patients with type 1 diabetes mellitus.

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) ] .

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 )

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. History of serious hypersensitivity reaction to alogliptin or metformin or any of the excipients in alogliptin and metformin HCl tablets, 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 serious hypersensitivity to alogliptin or metformin, components of Alogliptin and metformin HCl tablets or any of the excipients. ( 4 )

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) ] Most common adverse reactions (incidence ≥4%) 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 America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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 HCl Over 2,700 patients with type 2 diabetes mellitus have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The racial distribution of patients exposed to trial medication was 65% White, 20% Asian, 7% Black or African American, 4% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 4% Multiracial or other racial groups. The ethnic distribution was 23% Hispanic or Latino and 77% was not Hispanic or Latino. The mean exposure to alogliptin coadministered with metformin was 58 weeks, with more than 1,400 subjects treated for more than one year. These included two 26 week placebo-controlled trials, one 52 week active control trial and an interim analysis of a 104 week active-controlled trial. In the alogliptin co-administered with metformin HCl arm, the mean duration of diabetes mellitus 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 co-administered with metformin HCl compared to 75% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 6.2% with alogliptin co-administered with metformin HCl 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 co-administered with metformin HCl 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 Adults with Type 2 Diabetes Mellitus Treated with Alogliptin Co-administered with Metformin HCl 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 doses 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) 6 (3) 105 (7) 3 (3) Nasopharyngitis 191 (7) 7 (3) 93 (6) 2 (2) Diarrhea 155 (6) 4 (2) 105 (7) 3 (3) Hypertension 154 (6) 5 (2) 96 (6) 6 (6) Headache 149 (5) 11 (5) 74 (5) 3 (3) Back pain 119 (4) 1 (1) 72 (5) 1 (1) Urinary tract infection 116 (4) 4 (2) 59 (4) 2 (2) Alogliptin A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with alogl …

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 HCl 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 HCl 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 HCl TABLETS. Insulin Secretagogues and Insulin Clinical Impact: Coadministration of ALOGLIPTIN WITH METFORMIN HCl 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 HCl 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 HCl 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: Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of alogliptin and metformin HCl tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.7) ].

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 pediatric patients 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 mellitus 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 mellitus 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 mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major malformations, still birth, and macrosomia related morbidity. Data Human Data Published data from postmarketing 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 HCl Metformin HCl 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, …

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.

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

10 OVERDOSAGE 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 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. In the event of an overdose, contact the Poison Help Line, (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Alogliptin and metformin HCl tablets are available in the following strengths and packages: 12.5 mg/500 mg tablet: pale yellow, oblong, film-coated tablets with "12.5/500" debossed on one side and "322M" debossed on the other side, available in: NDC 45802-169-72 Bottles of 60 tablets 12.5 mg/1000 mg tablet: pale yellow, oblong, film-coated tablets with "12.5/1000" debossed on one side and "322M" debossed on the other side, available in: NDC 45802-211-72 Bottles of 60 tablets Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.