Pioglitazone Hydrochloride
Tablet · Oral
Uses
Monotherapy and Combination Therapy Pioglitazone Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14) ] . Important Limitations of Use Pioglitazone Tablets exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone Tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease [see Warnings and Precautions (5.3) ] . Pioglitazone Tablets is a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. ( 1, 14) Important Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 )
Dosage and administration
Initiate Pioglitazone Tablets at 15 mg or 30 mg once daily. Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure. (2.1) If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily. (2.1) Obtain liver tests before starting Pioglitazone Tablets. If abnormal, use caution when treating with Pioglitazone Tablets, investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on Pioglitazone Tablets is not recommended in patients without liver disease. ( 5.3 ) 2.1 Recommendations for All Patients Pioglitazone Tablets should be taken once daily and can be taken without regard to meals. The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily. The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily. The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c. After initiation of Pioglitazone Tablets or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.5) ] . Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Pioglitazone Tablets. Routine periodic monitoring of liver tests during treatment with Pioglitazone Tablets is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Pioglitazone Tablets or who are found to have abnormal liver tests while taking Pioglitazone Tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . 2.2 Concomitant Use with an Insulin Secretagogue or Insulin If hypoglycemia occurs in a patient co-administered Pioglitazone Tablets and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced. If hypoglycemia occurs in a patient co-administered Pioglitazone Tablets and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response. 2.3 Concomitant Use with Strong CYP2C8 Inhibitors Coadministration of Pioglitazone Tablets and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of Pioglitazone Tablets is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].
Dosage forms and strengths
Round tablet contains pioglitazone as follows: 15 mg: White, round, beveled edged tablets, debossed with “C78” on one side and plain on other side 30 mg: White, round, beveled edged tablets, debossed with “C79” on one side and plain on other side 45 mg: White, round, beveled edged tablets, debossed with “C80” on one side and plain on other side Tablets: 15 mg, 30 mg, and 45 mg (3)
Contraindications
Initiation in patients with established NYHA Class III or IV heart failure [see Boxed Warning ]. Use in patients with known hypersensitivity to pioglitazone or any other component of Pioglitazone Tablets. Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see Boxed Warning ] . (4) Use in patients with known hypersensitivity to pioglitazone or any other component of Pioglitazone Tablets. (4)
Warnings and precautions
Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. (5.1) Hypoglycemia: When used with insulin or an insulin secretagogue, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. (5.2) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt Pioglitazone Tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone if liver injury is confirmed and no alternate etiology can be found. (5.3) Bladder cancer: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. (5.4) Edema: Dose-related edema may occur. (5.5) Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.6) Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. (5.7) Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone. ( 5.8 ) 5.1 Congestive Heart Failure Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered [see Boxed Warning , Contraindications (4) , and Adverse Reactions (6.1) ] . 5.2 Hypoglycemia Patients receiving pioglitazone in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration (2.2) ]. 5.3 Hepatic Effects There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date [see Adverse Reactions (6.1) ] . Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating pioglitazone therapy. In patients with abnormal liver tests, pioglitazone should be initiated with caution. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), pioglitazone treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone should not be restarted in these patients without another explanation for the liver test abnormalities. Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on pioglitazone. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone can be used with caution. 5.4 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1) ]. In addition, during the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59-1.72]). Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. A large prospective 10-year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89-1.26]).
Side effects
The following serious adverse reactions are discussed elsewhere in the labeling: Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1) ] Edema [see Warnings and Precautions (5.5) ] Fractures [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥5%) are upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact CorePharma, LLC at +1 732-419-8800 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. Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years. In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo. Common Adverse Events: 16- to 26-Week Monotherapy Trials A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to pioglitazone dose. Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo N=259 Pioglitazone N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 2. 16- to 24-Week Clinical Trials of Pioglitazone Add-on to Sulfonylurea Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.” 16-Week Placebo-Controlled Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea % of Patients Placebo + Sulfonylurea N=187 Pioglitazone 15 mg + Sulfonylurea N=184 Pioglitazone 30 mg + Sulfonylurea N=189 Edema 2.1 1.6 12.7 Headache 3.7 4.3 5.3 Flatulence 0.5 2.7 6.3 Weight Increased 0 2.7 5.3 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Sulfonylurea than in Patients Treated with Pioglitazone 30 mg + Sulfonylurea % of Patients Pioglitazone 30 mg + Sulfonylurea N=351 Pioglitazone 45 mg + Sulfonylurea N=351 Hypoglycemia 13.4 15.7 Edema 10.5 23.1 Upper Respiratory Tract Infection 12.3 14.8 Weight Increased 9.1 13.4 Urinary Tract Infection 5.7 6.8 A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 3. 16- to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.” 16-Week Placebo-Controlled Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin % of Patients Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Edema 2.5 6.0 Headache 1.9 6.0 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin % of Patients Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 Upper Respiratory Tract Infection 12.4 13.5 Edema 5.8 13.9 Headache 5.4 5.8 Weight Increased 2.9 6.7 Table 4 summarizes the incidence and types of common adverse events reported in trials of pioglitazone add-on to insulin. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 4.
Drug interactions
Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone dose to 15 mg daily. (2.3 , 7.1) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2) Topiramate may decrease pioglitazone concentrations. ( 7.3 ) 7.1 Strong CYP2C8 Inhibitors An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t 1/2 ) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. 7.2 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 pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical Pharmacology (12.3) ] . 7.3 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 pioglitazone and topiramate are used concomitantly, monitor patients for adequate glycemic control.
Use in specific populations
Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) Pediatrics: Not recommended for use in pediatric patients. (8.4) 8.1 Pregnancy Risk Summary Limited data with pioglitazone in pregnant women are not sufficient to determine 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 [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, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data 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 in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pioglitazone and any potential adverse effects on the breastfed infant from pioglitazone or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions ( 5.1, 5.4, 5.5, and 5.6 ) ]. 8.5 Geriatric Use A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology (12.3) ] . Although clinical experiences have not identified differences in effectiveness and safety between the elderly ( > 65 years) and younger patients, these conclusions are limited by small sample sizes for patients > 75 years old.
Pregnancy
8.1 Pregnancy Risk Summary Limited data with pioglitazone in pregnant women are not sufficient to determine 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 [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, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data 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.
Pediatric use
8.4 Pediatric Use Safety and effectiveness of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions ( 5.1, 5.4, 5.5, and 5.6 ) ].
Geriatric use
8.5 Geriatric Use A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology (12.3) ] . Although clinical experiences have not identified differences in effectiveness and safety between the elderly ( > 65 years) and younger patients, these conclusions are limited by small sample sizes for patients > 75 years old.
Overdosage
During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.
Description
Pioglitazone tablets are a thiazolidinedione and an agonist for peroxisome proliferator activated receptor (PPAR) gamma that contains an oral antidiabetic medication: pioglitazone. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo . No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown: Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S
• HCl and a molecular weight of 392.90 daltons. 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. Pioglitazone Tablets, USP is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, and magnesium stearate. pioglitazone-str
Mechanism of action
12.1 Mechanism of Action 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. 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.
How supplied
Pioglitazone Tablets, USP are available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg tablet: White, round, beveled edged tablets, debossed with “C78” on one side and plain on other side, available in: NDC 84677-026-30 Bottles of 30 NDC 84677-026-90 Bottles of 90 NDC 84677-026-05 Bottles of 500 30 mg tablet: White, round, beveled edged tablets, debossed with “C79” on one side and plain on other side, available in: NDC 84677-027-30 Bottles of 30 NDC 84677-027-90 Bottles of 90 NDC 84677-027-05 Bottles of 500 45 mg tablet: White, round, beveled edged tablets, debossed with “C80” on one side and plain on other side, available in: NDC 84677-028-30 Bottles of 30 NDC 84677-028-90 Bottles of 90 NDC 84677-028-05 Bottles of 500 Storage Store at 20°C to 25°C (68° to 77°F); excursions permitted to 15 to 30°C (59° - 86°F) [see USP Controlled Room Temperature]. Protect from moisture and humidity. Dispense in a tightly closed, light-resistant container.
Patient information
See FDA-Approved Patient Labeling (Medication Guide). It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Pioglitazone Tablets should immediately report these symptoms to a physician. Tell patients to promptly stop taking Pioglitazone Tablets and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity. Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer. Tell patients to take Pioglitazone Tablets once daily. Pioglitazone can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. Inform female patients that treatment with Pioglitazone Tablets, like other thiazolidinediones, may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3) ]. Distributed by: GSMS, Incorporated Camarillo, CA 93012 USA Revised: 04/2026 40414
Label text from the FDA structured product label by GSMS, Incorporated (revised Jun 19, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Pioglitazone Hydrochloride in 21 products
Pioglitazone Hydrochloride NDC products (21)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50090-6386 | Pioglitazone Hydrochloride 15 mg/1 Tablet | A-S Medication Solutions | ANDA |
| 50090-6393 | Pioglitazone Hydrochloride 30 mg/1 Tablet | A-S Medication Solutions | ANDA |
| 50090-7846 | Pioglitazone Hydrochloride 30 mg/1 Tablet | A-S Medication Solutions | ANDA |
| 50090-6384 | Pioglitazone Hydrochloride 45 mg/1 Tablet | A-S Medication Solutions | ANDA |
| 65862-512 | Pioglitazone Hydrochloride 15 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 65862-513 | Pioglitazone Hydrochloride 30 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 65862-514 | Pioglitazone Hydrochloride 45 mg/1 Tablet | Aurobindo Pharma Limited | ANDA |
| 71335-9664 | Pioglitazone Hydrochloride 30 mg/1 Tablet | Bryant Ranch Prepack | ANDA |
| 62135-804 | Pioglitazone Hydrochloride 15 mg/1 Tablet | Chartwell RX, LLC | ANDA |
| 62135-805 | Pioglitazone Hydrochloride 30 mg/1 Tablet | Chartwell RX, LLC | ANDA |
| 62135-806 | Pioglitazone Hydrochloride 45 mg/1 Tablet | Chartwell RX, LLC | ANDA |
| 84677-028 | Pioglitazone Hydrochloride 45 mg/1 Tablet | GSMS, Incorporated | ANDA |
| 84677-027 | Pioglitazone Hydrochloride 30 mg/1 Tablet | GSMS, Incorporated | ANDA |
| 84677-026 | Pioglitazone Hydrochloride 15 mg/1 Tablet | GSMS, Incorporated | ANDA |
| 82009-103 | Pioglitazone Hydrochloride 15 mg/1 Tablet | QUALLENT PHARMACEUTICALS HEALTH LLC | ANDA |
| 82009-104 | Pioglitazone Hydrochloride 30 mg/1 Tablet | QUALLENT PHARMACEUTICALS HEALTH LLC | ANDA |
| 82009-105 | Pioglitazone Hydrochloride 45 mg/1 Tablet | QUALLENT PHARMACEUTICALS HEALTH LLC | ANDA |
| 70518-4519 | Pioglitazone Hydrochloride 45 mg/1 Tablet | REMEDYREPACK INC. | ANDA |
| 76385-180 | Pioglitazone Hydrochloride 45 mg/1 Tablet | Unichem Pharmaceuticals (USA), Inc. | ANDA |
| 76385-179 | Pioglitazone Hydrochloride 30 mg/1 Tablet | Unichem Pharmaceuticals (USA), Inc. | ANDA |
| 76385-178 | Pioglitazone Hydrochloride 15 mg/1 Tablet | Unichem Pharmaceuticals (USA), Inc. | ANDA |
Frequently asked questions
What is Pioglitazone Hydrochloride used for?
Monotherapy and Combination Therapy Pioglitazone Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14) ] . Important Limitations of Use Pioglitazone Tablets exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone Tablets should not be…
What are the side effects of Pioglitazone Hydrochloride?
The following serious adverse reactions are discussed elsewhere in the labeling: Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1) ] Edema [see Warnings and Precautions (5.5) ] Fractures [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥5%) are upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. (6.1) To report… See the full label for the complete list.
Who makes Pioglitazone Hydrochloride?
Pioglitazone Hydrochloride is listed by 8 labelers in the FDA NDC directory, including A-S Medication Solutions, Aurobindo Pharma Limited, Bryant Ranch Prepack, Chartwell RX, LLC.