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Alogliptin Benzoate And Pioglitazone Hydrochloride

FDA Drug Information • Also known as: Alogliptin And Pioglitazone

Brand Names
Alogliptin And Pioglitazone
Dosage Form
TABLET, FILM COATED
Product Type
DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: CONGESTIVE HEART FAILURE Thiazolidinediones, including pioglitazone, which is a component of alogliptin and pioglitazone tablets, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1) ] . After initiation of alogliptin and pioglitazone tablets and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If congestive heart failure develops while taking alogliptin and pioglitazone tablets, consider discontinuation of alogliptin and pioglitazone tablets or dosage reduction of pioglitazone in alogliptin and pioglitazone tablets [see Warnings and Precautions (5.1) ] . Alogliptin and pioglitazone tablets are not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1) ] . Initiation of alogliptin and pioglitazone tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ] . WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning Thiazolidinediones, including pioglitazone, which is a component of alogliptin and pioglitazone tablets, cause or exacerbate congestive heart failure in some patients. ( 5.1 ) After initiation of alogliptin and pioglitazone tablets and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If congestive heart failure develops while taking alogliptin and pioglitazone tablets, consider discontinuation of alogliptin and pioglitazone tablets or dosage reduction of pioglitazone in alogliptin and pioglitazone tablets. ( 5.1 ) Alogliptin and pioglitazone tablets are not recommended in patients with symptomatic heart failure. ( 5.1 ) Initiation of alogliptin and pioglitazone tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. ( 4 , 5.1 )

Description

11 DESCRIPTION Alogliptin and pioglitazone 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. Chemical Structure 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. Alogliptin and pioglitazone tablets are 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...

What Is Alogliptin Benzoate And Pioglitazone Hydrochloride Used For?

1 INDICATIONS AND USAGE Alogliptin and pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Alogliptin and pioglitazone tablets are 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: Alogliptin and pioglitazone tablets are not recommended for use in patients with type 1 diabetes mellitus. ( 1 ) Limitations of Use Alogliptin and pioglitazone tablets are not recommended for use in patients with type 1 diabetes mellitus.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Obtain liver tests prior to initiation. Alogliptin and pioglitazone tablets may be taken with or without food. ( 2.1 ) Individualize the starting dose of alogliptin and pioglitazone tablets 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 alogliptin and pioglitazone tablets [see Warnings and Precautions (5.4) ] . Take alogliptin and pioglitazone tablets orally once daily. Do not split tablets. Alogliptin and pioglitazone tablets 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 alogliptin and pioglitazone tablets based on the patient's current regimen and the available strengths of alogliptin and pioglitazone tablets (see Table 1 ). Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of Alogliptin and Pioglitazone Tablets 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 alogliptin and pioglitazone tablets 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 alogliptin and pioglitazone tablets and periodically thereafter [see Use in Specific Populations (8.6) ] . The recommended dosage of alogliptin and pioglitazone tablets in patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min) is the same as the recommended...

Side Effects (Adverse Reactions)

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%)....

Drug Interactions

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 alogliptin and pioglitazone tablets 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 alogliptin and pioglitazone tablets 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 alogliptin and pioglitazone tablets, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of alogliptin and pioglitazone tablets (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 alogliptin and pioglitazone tablets and topiramate are used concomitantly, monitor patients for adequate glycemic control.

Contraindications

4 CONTRAINDICATIONS Alogliptin and pioglitazone tablets are contraindicated in patients with: Established NYHA Class III or IV heart failure at the time of alogliptin and pioglitazone tablets initiation [see Boxed Warning ] . A history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in alogliptin and pioglitazone tablets. 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 alogliptin and pioglitazone tablets initiation. ( 4 ) In patients with a history of serious hypersensitivity reaction to alogliptin, pioglitazone, or any of the excipients in alogliptin and pioglitazone tablets. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Limited data with alogliptin and pioglitazone tablets 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...

Overdosage

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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Alogliptin and pioglitazone 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 45802-351-65 Bottles of 30 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 45802-402-65 Bottles of 30 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 45802-499-65 Bottles of 30 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 45802-260-65 Bottles of 30 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.