Actos Side Effects

Generic name: pioglitazone

Please note - some side effects for Actos may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Actos - for the consumer

Actos

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Actos:

Headache; muscle aches; sore throat; weight gain.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision or other vision changes; symptoms of heart failure (eg, shortness of breath; sudden unexplained weight gain; swelling of the hands, ankles, or feet); symptoms of liver problems (eg, dark urine; stomach pain; unexplained nausea, vomiting, or loss of appetite; yellowing of the skin or eyes; sweating); symptoms of low blood sugar (eg, anxiety; chills, increased hunger, headache; increased dizziness or drowsiness; tremors); unusual bone pain; unusual tiredness or weakness.

For the professional

Actos

Over 8500 patients with type 2 diabetes have been treated with Actos in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with Actos from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received Actos for at least 2 years. 

      The overall incidence and types of adverse events reported in placebo-controlled clinical trials of Actos monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7.

      For most clinical adverse events the incidence was similar for groups treated with Actos monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with Actos and insulin compared to insulin alone.

      In a 16-week, placebo-controlled Actos plus insulin trial (n=379), 10 patients treated with Actos plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group.

      The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or Actos (3.3%).

      In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported.

      In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with Actos plus sulfonylurea, metformin or insulin.

      In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with Actos versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with Actos and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone. Most of these events were considered mild or moderate in intensity.

      In one 16-week clinical trial of insulin plus Actos combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone.

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) 

      In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with Actos (n=2605), force-titrated up to 45 mg daily or placebo (n=2633) in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean HbA1c 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of Actos 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 the cardiovascular composite endpoint. Although there was no statistically significant difference between Actos and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with Actos.

      Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received.

Laboratory Abnormalities

Hematologic: Actos may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with Actos appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with Actos. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with Actos therapy and have rarely been associated with any significant hematologic clinical effects.

Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with Actos had ALT values ≥ 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with Actos, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with Actos were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

      In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive Actos, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to Actos therapy is unknown.

By body system

General side effects

Pioglitazone has been generally well tolerated with the incidence of adverse effects similar to placebo. Upper respiratory tract infections, headache, sinusitis, myalgia, tooth disorder and pharyngitis were reported slightly more frequently than placebo in clinical trials.

The types of side effects reported when pioglitazone was used in combination with sulfonylurea, metformin or insulin were generally similar to those reported during pioglitazone monotherapy with the exception of an increase in the occurrence of edema in the insulin combination study.

Endocrine side effects

Endocrine side effects have included mild to moderate hypoglycemia which was reported during combination therapy with a sulfonylurea or insulin.

Hematologic side effects

Hematologic side effects have included anemia which was reported in 1% of pioglitazone patients and none of the placebo patients. Pioglitazone may cause decreases in hemoglobin and hematocrit. Across all clinical studied, mean hemoglobin values declined by 2 to 4%. Anemia was reported more frequently when pioglitazone was combined with insulin, a sulfonylurea or metformin.

Cardiovascular side effects

Cardiovascular side effects have included edema which was reported in 4.8% of pioglitazone patients versus 1.2% of placebo patients. In combination studies, edema was reported for 7.2% of patients treated with pioglitazone and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone.

A case of angioneurotic edema, characterized as a sore throat followed by dyspnea and swelling of the lips and tongue, has been reported.

Hepatic side effects

Hepatic side effects have included reports of liver damage associated with pioglitazone therapy.

Ocular side effects

Ocular side effects have included postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity.

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