OSENI

Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 ) 06/2024

1 INDICATIONS AND USAGE OSENI is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. OSENI is a combination of alogliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone, a thiazolidinedione agonist of peroxisome proliferator receptor gamma, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: OSENI is not recommended for use in patients with type 1 diabetes mellitus. ( 1 ) Limitations of Use OSENI is not recommended for use in patients with type 1 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION Obtain liver tests prior to initiation. OSENI may be taken with or without food. ( 2.1 ) Individualize the starting dose of OSENI based on the patient’s current regimen and concurrent medical condition but do not exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg. ( 2.2 ) The recommended starting dosage in patients with NYHA Class I or II congestive heart failure is 25 mg of alogliptin and 15 mg of pioglitazone ( 2.4 ) Prior to initiation, assess renal function with creatinine clearance (CrCl) ( 2.3 ) Mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min): same as the recommended dosage in patients with normal renal function. Moderate renal impairment (CrCl ≥30 to <60 mL/min): 12.5 mg of alogliptin and 30 mg of pioglitazone once daily. Severe renal impairment (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min or requiring hemodialysis): not recommended. 2.1 Important Dosage and Administration Information Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating OSENI [see Warnings and Precautions (5.4) ] . Take OSENI orally once daily. Do not split tablets. OSENI may be taken with or without food [see Clinical Pharmacology (12.3) ] . If a dose is missed, do not double the next dose. 2.2 Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of OSENI based on the patient's current regimen and the available strengths of OSENI (see Table 1 ). Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of OSENI (alogliptin/pioglitazone) For dosage recommendations for patients with renal impairment and/or congestive heart failure, [see Dosage and Administration (2.3 , 2.4) ] . Not treated with either alogliptin or pioglitazone 25 mg/15 mg or 25 mg/30 mg Alogliptin 25 mg/15 mg or 25 mg/30 mg Pioglitazone 25 mg/15 mg, 25 mg/30 mg, or 25 mg/45 mg Alogliptin and pioglitazone Select a dosage that is as close as possible to the current dosage of alogliptin and pioglitazone Dosage Titration for Additional Glycemic Control Titrate the OSENI dosage gradually, as needed, after assessing therapeutic response and tolerability, up to a maximum dosage of 25 mg of alogliptin and 45 mg of pioglitazone once daily. 2.3 Recommended Dosage for Patients with Renal Impairment Assess renal function prior to initiation of OSENI and periodically thereafter [see Use in Specific Populations (8.6) ] . The recommended dosage of OSENI in patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min) is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration (2.1) ] . The recommended dosage of OSENI for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min) is 12.5 mg of alogliptin and 30 mg of pioglitazone once daily. OSENI is not recommended for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or ESRD (CrCl <15 mL/min or requiring hemodialysis) because these patients require a lower dosage of alogliptin than what is available in the fixed dose combination product, OSENI [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.4 Recommendations for Congestive Heart Failure Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone [see Boxed Warning and Warnings and Precautions (5.1) ]. Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of OSENI or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure). If congestive heart failure develops …

3 DOSAGE FORMS AND STRENGTHS Pharmaceutical form Strength (alogliptin/ pioglitazone) Color Shape Markings (on one side) film-coated tablets 12.5 mg/30 mg Pale peach Round biconvex “A/P” and “12.5/30” film-coated tablets 25 mg/15 mg Yellow Round biconvex “A/P” and “25/15” film-coated tablets 25 mg/30 mg Peach Round biconvex “A/P” and “25/30” film-coated tablets 25 mg/45 mg Red Round biconvex “A/P” and “25/45” Tablets: 25 mg alogliptin and 15 mg pioglitazone, 25 mg alogliptin and 30 mg pioglitazone, 25 mg alogliptin and 45 mg pioglitazone. ( 3 ) 12.5 mg alogliptin and 30 mg pioglitazone. ( 3 )

4 CONTRAINDICATIONS OSENI is contraindicated in patients with: Established NYHA Class III or IV heart failure at the time of OSENI initiation [see Boxed Warning ] . A history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in OSENI. Reactions such as anaphylaxis, angioedema and severe cutaneous adverse reactions have been reported [see Warnings and Precautions (5.3) , Adverse reactions (6.2) ] . In patients with established NYHA Class III or IV heart failure at the time of OSENI initiation. ( 4 ) In patients with a history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in OSENI. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Congestive Heart Failure [see Boxed Warning and Warnings and Precautions (5.1) ] Pancreatitis [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Hepatic Effects [see Warnings and Precautions (5.4) ] Edema [see Warnings and Precautions (5.5) ] Fractures [see Warnings and Precautions (5.6) ] Urinary Bladder Tumors [see Warnings and Precautions (5.7) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.8) ] Macular Edema [see Warnings and Precautions (5.9) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.10) ] Bullous Pemphigoid [see Warnings and Precautions (5.11) ] The most common adverse reactions (4% or greater incidence) are nasopharyngitis, back pain and upper respiratory 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 Pioglitazone Over 1,500 patients with type 2 diabetes mellitus have received alogliptin coadministered with pioglitazone in four large, randomized, double-blind, controlled clinical trials [see Clinical Studies (14) ] . The mean exposure to alogliptin and pioglitazone was 29 weeks with more than 100 subjects treated for more than one year. The studies consisted of two placebo-controlled studies of 16 to 26 weeks in duration and two active-controlled studies of 26 weeks and 52 weeks in duration. In the alogliptin and pioglitazone arm, the mean duration of diabetes was approximately six years, the mean body mass index (BMI) was 31 kg/m 2 (54% of patients had a BMI ≥30 kg/m 2 ), and the mean age was 54 years (16% of patients ≥65 years of age). In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 65% in patients treated with alogliptin and pioglitazone compared to 57% treated with placebo. Overall discontinuation of therapy due to adverse reactions was 2.5% with alogliptin and pioglitazone compared to 2.0% with placebo, 3.7% with pioglitazone or 1.3% with alogliptin. Adverse reactions reported in ≥4% of patients treated with alogliptin and pioglitazone and more frequently than in patients who received alogliptin, pioglitazone or placebo are summarized in Table 2 . Table 2. Adverse Reactions Reported in ≥4% of Patients Treated with Alogliptin and Pioglitazone and More Frequently than in Patients Receiving Either Alogliptin, Pioglitazone or Placebo Number of Patients (%) Alogliptin and pioglitazone Alogliptin and pioglitazone – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg combined with pioglitazone 15 mg, 30 mg and 45 mg Alogliptin Alogliptin – includes data pooled for patients receiving alogliptin 25 mg and 12.5 mg Pioglitazone Pioglitazone – includes data pooled for patients receiving pioglitazone 15 mg, 30 mg and 45 mg Placebo N=1533 N=446 N=949 N=153 Nasopharyngitis 75 (4.9) 21 (4.7) 37 (3.9) 6 (3.9) Back Pain 64 (4.2) 9 (2.0) 32 (3.4) 5 (3.3) Upper Respiratory Tract Infection 63 (4.1) 19 (4.3) 26 (2.7) 5 (3.3) Alogliptin Add-On Therapy to a Thiazolidinedione In a 26 week, placebo-controlled, double-blind study, patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea were treated with add-on alogliptin therapy or placebo; the adverse reactions reported in ≥5% of patients and more frequently than in patients who received placebo was influenza (alogliptin, 5.5%; placebo, 4.1%). Hyp …

7 DRUG INTERACTIONS Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit the pioglitazone dose to 15 mg daily. ( 7.2 ) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. ( 7.3 ) Topiramate may decrease pioglitazone concentrations. ( 7.4 ) 7.1 Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of OSENI with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.8) ] . 7.2 Strong CYP2C8 Inhibitors An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the concentration-time curve [AUC]) and half-life of pioglitazone. Therefore, the maximum recommended dosage of OSENI is 25 mg of alogliptin and 15 mg of pioglitazone once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 7.3 CYP2C8 Inducers An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with OSENI, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of OSENI (25 mg of alogliptin and 45 mg of pioglitazone) [see Clinical Pharmacology (12.3) ] . 7.4 Topiramate A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3) ] . The clinical relevance of this decrease is unknown; however, when OSENI and topiramate are used concomitantly, monitor patients for adequate glycemic control.

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 have not been established. ( 8.4 ) 8.1 Pregnancy Risk Summary Limited data with OSENI in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ]. In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5 and 35 times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180 and 149 times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC) [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 a 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 birth 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 birth defects, still birth, and macrosomia related morbidity. Data Animal Data Alogliptin and Pioglitazone Co-administration of 100 mg/kg alogliptin and 40 mg/kg pioglitazone (39 and 10 times the 25 mg and 45 mg clinical doses, respectively, based on body surface area) to pregnant rats during organogenesis slightly augmented pioglitazone-related fetal effects of delayed development and reduced fetal weights but did not result in embryofetal mortality or teratogenicity. 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 (~95 times the 25 mg clinical dose, based on AUC). Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. 8.2 Lactation Risk Summary There is no information regarding the presence of pioglitazone or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and alogliptin are present in rat milk; however, due to sp …

12.1 Mechanism of Action OSENI combines two antihyperglycemic agents: alogliptin and pioglitazone. 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 mellitus, 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. Pioglitazone Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

11 DESCRIPTION OSENI tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes mellitus: alogliptin and pioglitazone. 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. Pioglitazone Chemically, pioglitazone is prepared as hydrochloride (HCl) salt, which is identified as (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride. It has a molecular formula of C 19 H 20 N 2 O 3 S∙HCl and a molecular weight of 392.90 daltons. The structural formula is: Pioglitazone HCl is an odorless white crystalline powder that contains one asymmetric carbon in the thiazolidinedione moiety. The synthetic compound is a racemate and the two enantiomers of pioglitazone interconvert in vivo . It is soluble in N,N dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water and insoluble in ether. OSENI is available as a fixed-dose combination tablet for oral administration containing 34 mg alogliptin benzoate equivalent to 25 mg alogliptin and any of the following strengths of pioglitazone HCl: 16.53 mg pioglitazone HCl equivalent to 15 mg pioglitazone (25 mg/15 mg) 33.06 mg pioglitazone HCl equivalent to 30 mg pioglitazone (25 mg/30 mg) 49.59 mg pioglitazone HCl equivalent to 45 mg pioglitazone (25 mg/45 mg) OSENI is also available as a fixed-dose combination tablet for oral administration containing 17 mg alogliptin benzoate equivalent to 12.5 mg alogliptin for the following strength of pioglitazone HCl: 33.06 mg pioglitazone HCl equivalent to 30 mg pioglitazone (12.5 mg/30 mg) OSENI tablets contain the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose; the tablets are film-coated with ferric oxide (yellow and/or red), hypromellose, polyethylene glycol, talc, titanium dioxide, and are marked with printing ink (Red A1 or Gray F1). Chemical Structure Chemical Structure

10 OVERDOSAGE 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. 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 OSENI tablets are available in the following strengths and packages: 25 mg/15 mg tablet: yellow, round, biconvex and film-coated with both “A/P” and “25/15” printed on one side, available in: NDC 64764-251-03 Bottles of 30 tablets NDC 64764-251-04 Bottles of 90 tablets NDC 64764-251-05 Bottles of 500 tablets 25 mg/30 mg tablet: peach, round, biconvex and film-coated with both “A/P” and “25/30” printed on one side, available in: NDC 64764-253-03 Bottles of 30 tablets NDC 64764-253-04 Bottles of 90 tablets NDC 64764-253-05 Bottles of 500 tablets 25 mg/45 mg tablet: red, round, biconvex, film-coated and with both “A/P” and “25/45” printed on one side, available in: NDC 64764-254-03 Bottles of 30 tablets NDC 64764-254-04 Bottles of 90 tablets NDC 64764-254-05 Bottles of 500 tablets 12.5 mg/30 mg tablet: pale peach, round, biconvex and film-coated with both “A/P” and “12.5/30” printed on one side, available in: NDC 64764-123-03 Bottles of 30 tablets NDC 64764-123-04 Bottles of 90 tablets NDC 64764-123-05 Bottles of 500 tablets Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture and humidity.