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Indications
Monotherapy and Combination Therapy Pioglitazone tablets are 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 exert 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 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 )
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.
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(5.2) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt pioglitazone 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 )
5.1Congestive 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) ] .
5.2Hypoglycemia
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) ].
5.3Hepatic 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.
5.4Urinary 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; [95% CI: 0.59 to 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 to 1.26]). A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22 to 2.19]).
Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10-year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. Pioglitazone may be associated with an increase in the risk of urinary bladder tumors.
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, pioglitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of bladder cancer.
5.5Edema
In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose-related [see Adverse Reactions (6.1) ] . In postmarketing experience, reports of new onset or worsening edema have been received. Pioglitazone should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, pioglitazone should be used with caution in patients at risk for congestive heart failure.
Patients treated with pioglitazone should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1) a nd Patient Counseling Information (17) ] .
5.6Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events),
5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to sta
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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) ].
7.2CYP2C8 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) ] .
7.3Topiramate
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.
Pregnancy and breastfeeding
8.1Pregnancy 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 to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 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 to 4% and 15 to 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.
Adverse reactions
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 Rising Health, LLC at 1-833-395-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9% 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
5.1Common 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
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 Headache 1.9 6 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
6.7Table
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. 16- to 24-Week Clinical Trials of Pioglitazone Add-on to Insulin 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 + Insulin than in Patients Treated with Placebo + Insulin % of Patients Placebo +Insulin N=187 Pioglitazone 15 mg + Insulin N=191 Pioglitazone 30 mg + Insulin N=188 Hypoglycemia 4.8 7.9
in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Insulin than in Patients Treated with Pioglitazone 30 mg + Insulin % of Patients Pioglitazone 30 mg + Insulin N=345 Pioglitazone 45 mg + Insulin N=345 Hypoglycemia 43.5
47.8 Edema 22
26.1 Weight Increased 7.2
13.9 Urinary Tract Infection 4.9
8.7 Diarrhea 5.5
5.8 Back Pain 3.8
6.4 Blood Creatine Phosphokinase Increased 4.6
5.5 Sinusitis 4.6
5.5 Hypertension 4.1
5.5 A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. 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. Table 5. PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients Treated with Pioglitazone and More Commonly than Placebo Mean duration of patient follow-up was 34.5 months. % of Patients Placebo N=2633 Pioglitazone N=2605 Hypoglycemia 18.8
27.3 Edema 15.3
26.7 Cardiac Failure 6.1
8.1 Pain in Extremity 5.7
6.4 Back Pain 5.1
5.5 Chest Pain 5
5.1Congestive Heart Failure
A summary of the incidence of adverse events rela
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
PIOGLITAZONE HYDROCHLORIDE EQ 45MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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