Yes — fatigue has been reported as a side effect of Pioglitazone in FDA adverse-event reports (FAERS) and product labeling. It is among the more frequently reported events for this medication. These are voluntary reports, so they show what's been reported, not how often it happens.
Boxed warning
WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS FULL PRESCRIBING INFORMATION WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS Congestive Heart Failure • Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions ( 5.1 )]. • After initiation of pioglitazone and metformin hydrochloride, 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 pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride [see Warnings and Precautions ( 5.1 )]. • Pioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure [ see Warnings and Precautions ( 5.1 ) ]. • Initiation of pioglitazone and metformin hydrochloride 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 )]. Lactic Acidosis • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions ( 5.2 )]. • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )]. • If metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.2 )]. WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS See full prescribing information for complete boxed warning Congestive Heart Failure • Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and metformin hydrochloride tablets, cause or exacerbate congestive heart failure in some patients. ( 5.1 ) • After initiation of pioglitazone and metformin hydrochloride 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 pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets. ( 5.1 ) • Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure. ( 5.1 ) • Initiation of pioglitazone and metformin hydrochloride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. ( 4 , 5.1 ) Lactic Acidosis • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate: pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. ( 5.2 ) • Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.2 ) • If lactic acidosis is suspected, discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.2 )
Reported adverse reactions
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 Quallent Pharmaceuticals Health LLC at 1-877-605-7243 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%). 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 5.1 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 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 6.7 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. 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 15.4 Edema 7 12.6 17.6 Upper Respiratory Tract Infection 9.6 8.4 14.9 Headache 3.2 3.1 6.9 Weight Increased 0.5 5.2 6.4 Back Pain 4.3 2.1 5.3 Dizziness 3.7 2.6 5.3 Flatulence 1.6 3.7 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 + 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 5.1 Congestive Heart Failure A summary of the incidence of adve
Warnings
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 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; [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. 5.5 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 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) ] . 5.6 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 stand
Yes — fatigue has been reported as a side effect of Pioglitazone in FDA adverse-event reports (FAERS) and/or its labeling. These are voluntary reports, so they show what's been reported, not how often it happens.
How common is fatigue with Pioglitazone?
fatigue is among the more frequently reported events for Pioglitazone in FAERS. Reporting volume isn't a true incidence rate — check the prescribing information for documented frequencies.
What should I do if I have fatigue while taking Pioglitazone?
Don't stop a prescribed medication on your own. Tell your prescriber or pharmacist — they can tell you whether it's expected, whether it needs attention, and what to do next.
Informational only, drawn from FDA adverse-event reporting (FAERS) and labeling — not medical advice, and not proof a medication caused an effect. Talk to your clinician or pharmacist about any side effect.
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