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Pioglitazone is a brand name for Pioglitazone. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE 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…
Verbatim from this product's FDA label. Tap a section to expand.
2 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. • If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily.
• 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 are not recommended in patients without liver disease.
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 ].
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 are 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 and ] .
, 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.
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 are 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see and ].
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Congestive heart failure [see Boxed Warning and ] • Edema [see Warnings and Precautions ] • Fractures [see Warnings and Precautions ] Most common adverse reactions (≥5%) are upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis.
gov/medwatch. 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.
8% for comparator-treated patients. 5%) with pioglitazone than with placebo (3%). 7% for placebo-treated patients. 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. 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.
5 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. • 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. • 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.
• 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. • Edema: Dose-related edema may occur. • Fractures: Increased incidence in female patients.
Apply current standards of care for assessing and maintaining bone health. • 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.
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone. 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 , , and ] .
4 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 ] .
• Use in patients with known hypersensitivity to pioglitazone or any other component of pioglitazone tablets.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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. ” 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. ” 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. ” 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. 5 months. Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials.
None of the events were fatal. Table 6. 2%) Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256).
A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7. Table 7. 2%) Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.
Table 8. 7%) Cardiovascular Safety In the PROactive trial, 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 standard of care.
Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). 1%. 5 months. The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events.
The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg.
1). Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone.
The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9. Table 9. 7) 115 CABG = coronary artery bypass grafting; PCI = percutaneous intervention Weight Gain Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications.
The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Tables 10 and 11 summarize the changes in body weight with pioglitazone and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials and in the PROactive trial.
Table 10. 8) N = 338 Table 11. 7 years. Edema Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure.
A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 12. Table 12. ” Hepatic Effects There has been no evidence of induced hepatotoxicity with pioglitazone in the pioglitazone controlled clinical trial database to date.
One randomized, double-blind 3-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter.
9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.
Hypoglycemia In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing. 5% with placebo. 8% with placebo.
7% vs. 8% vs. 5%). Three patients in these four trials were hospitalized due to hypoglycemia. 9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization.
These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12). Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see ].
19%) randomized to placebo were diagnosed with bladder cancer. 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.
72) [see ] . Laboratory Abnormalities Hematologic Effects Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients.
These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.
2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued pioglitazone due to the elevation.
These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pioglitazone.
Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • New onset or worsening diabetic macular edema with decreased visual acuity [see ] .
• Fatal and nonfatal hepatic failure [see ] . Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration.
In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and ] .
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 ].
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 ] .
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. 4 Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see ].
19%) randomized to placebo were diagnosed with bladder cancer. 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.
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. 26]). 19]).
, 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 Edema In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and is dose-related [see ]. 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, and Patient Counseling Information (17) ] . 6 Fractures 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 standard of care.
5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb.
1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.
7 Macular Edema Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care.
Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings [see ] . 8 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone.