ACTOPLUS MET SIDE EFFECTS
- Generic Name: pioglitazone hcl and metformin hcl
- Brand Name: Actoplus MET, Actoplus MET XR
SIDE EFFECTS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Congestive heart failure.
- Lactic acidosis.
- Edema.
- Fractures.
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.
Pioglitazone
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 from 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 the 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 metformin 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 Metformin
| 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 |
| Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” | ||
Common Adverse Events: 24-Week ACTOPLUS MET Clinical Trial
Table 3 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of ACTOPLUS MET dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600).
Table 3: Adverse Events ( ≥ 5% for ACTOPLUS MET) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24-Week Double-Blind Clinical Trial of ACTOPLUS MET Administered Twice Daily
| % of Patients | |||
| ACTOPLUS MET 15/850 mg Twice Daily N=201 |
Pioglitazone 15 mg Twice Daily N=190 |
Metformin 850 mg Twice Daily N=209 |
|
| Diarrhea | 9.0 | 2.6 | 15.3 |
| Headache | 5.5 | 2.6 | 4.8 |
In this 24-week trial, abdominal pain was reported in 2.0% of patients in the ACTOPLUS MET group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.
Common Adverse Events: PROactive Trial
A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 4. 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 4: PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients Treated with Pioglitazone and More Commonly than Placebo
| % 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 | 5.0 | 5.1 |
Mean duration of patient follow-up was 34.5 months.
Congestive Heart Failure
A summary of the incidence of adverse events related to congestive heart failure is provided in Table 5 for the 16-to 24-week add-on to metformin trials. None of the events were fatal.
Table 5: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin
| Number (%) of Patients | ||||
| Placebo-Controlled Trial (16 weeks) | Non-Controlled Double-Blind Trial (24 weeks) | |||
| Placebo + Metformin N=160 |
Pioglitazone 30 mg + Metformin N=168 |
Pioglitazone 30 mg + Metformin N=411 |
Pioglitazone 45 mg + Metformin N=416 |
|
| At least one congestive heart failure event | 0 | 1 (0.6%) | 0 | 1 (0.2%) |
| Hospitalized | 0 | 1 (0.6%) | 0 | 1 (0.2%) |
Table 6: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)
| Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea | |||||||
| Number (%) of Patients | |||||||
| Placebo-Controlled Trial (16 weeks) | Non-Controlled Double-Blind Trial (24 weeks) | ||||||
| Placebo + Sulfonylurea N=187 |
Pioglitazone 15 mg + Sulfonylurea N=184 |
Pioglitazone 30 mg + Sulfonylurea N=189 |
Pioglitazone 30 mg + Sulfonylurea N=351 |
Pioglitazone 45 mg + Sulfonylurea N=351 |
|||
| At least one congestive heart failure event | 2 (1.1%) | 0 | 0 | 1 (0.3%) | 6 (1.7%) | ||
| Hospitalized | 2 (1.1%) | 0 | 0 | 0 | 2 (0.6%) | ||
| Patients Treated with Pioglitazone or Placebo Added on to Insulin | |||||||
| Number (%) of Patients | |||||||
| Placebo-Controlled Trial (16 weeks) | Non-Controlled Double-Blind Trial (24 weeks) | ||||||
| Placebo + Insulin N=187 | Pioglitazone 15 mg + Insulin N=191 | Pioglitazone 30 mg + Insulin N=188 | Pioglitazone 30 mg + Insulin N=345 | Pioglitazone 45 mg + Insulin N=345 | |||
| At least one congestive heart failure event | 0 | 2 (1.0%) | 2 (1.1%) | 3 (0.9%) | 5 (1.4%) | ||
| Hospitalized | 0 | 2 (1.0%) | 1 (0.5%) | 1 (0.3%) | 3 (0.9%) | ||
| Patients Treated with Pioglitazone or Placebo Added on to Metformin | |||||||
| Number (%) of Patients | |||||||
| Placebo-Controlled Trial (16 weeks) | Non-Controlled Double-Blind Trial (24 weeks) | ||||||
| Placebo + Metformin N=160 | Pioglitazone 30 mg + Metformin N=168 | Pioglitazone 30 mg + Metformin N=411 | Pioglitazone 45 mg + Metformin N=416 | ||||
| At least one congestive heart failure event | 0 | 1 (0.6%) | 0 | 1 (0.2%) | |||
| Hospitalized | 0 | 1 (0.6%) | 0 | 1 (0.2%) | |||
Table 7: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide
| Number (%) of Subjects | ||
| Pioglitazone N=262 |
Glyburide N=256 |
|
| Death due to cardiovascular causes (adjudicated) | 5 (1.9%) | 6 (2.3%) |
| Overnight hospitalization for worsening CHF (adjudicated) | 26 (9.9%) | 12 (4.7%) |
| Emergency room visit for CHF (adjudicated) | 4 (1.5%) | 3 (1.2%) |
| Patients experiencing CHF progression during study | 35 (13.4%) | 21 (8.2%) |
Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.
Table 8: Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial
| Number (%) of Patients | ||
| Placebo N=2633 |
Pioglitazone N=2605 |
|
| At least one hospitalized congestive heart failure event | 108 (4.1%) | 149 (5.7%) |
| Fatal | 22 (0.8%) | 25 (1.0%) |
| Hospitalized, nonfatal | 86 (3.3%) | 124 (4.7%) |
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). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 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. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (HR 0.90; 95% CI: 0.80, 1.02; p=0.10).
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: PROactive Trial: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint
| Cardiovascular Events | Placebo N=2633 |
Pioglitazone N=2605 |
||
| First Events n (%) | Total events n | First Events n (%) | Total events n | |
| Any event | 572 (21.7) | 900 | 514 (19.7) | 803 |
| All-cause mortality | 122 (4.6) | 186 | 110 (4.2) | 177 |
| Nonfatal myocardial infarction (MI) | 118 (4.5) | 157 | 105 (4.0) | 131 |
| Stroke | 96 (3.6) | 119 | 76 (2.9) | 92 |
| Acute coronary syndrome | 63 (2.4) | 78 | 42 (1.6) | 65 |
| Cardiac intervention (CABG/PCI) | 101 (3.8) | 240 | 101 (3.9) | 195 |
| Major leg amputation | 15 (0.6) | 28 | 9 (0.3) | 28 |
| Leg revascularization | 57 (2.2) | 92 | 71 (2.7) | 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, 11, and 12 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, the PROactive trial, and the 24-week ACTOPLUS MET trial.
Table 10: Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials
| Control Group (Placebo) | Pioglitazone 15 mg | Pioglitazone 30 mg | ||
| Median (25th, 75th percentile) | Median (25th, 75th percentile) | Median (25th, 75th percentile) | ||
| Monotherapy (16 to 26 weeks) | -1.4 (-2.7, 0.0) N=256 | 0.9 (-0.5, 3.4) N=79 | 1.0 (-0.9, 3.4) N=188 | |
| Combination Therapy (16 to 24 weeks) | Sulfonylurea | -0.5 (-1.8, 0.7) N=187 | 2.0 (0.2, 3.2) N=183 | 3.1 (1.1, 5.4) N=528 |
| Metformin | -1.4 (-3.2, 0.3) N=160 | N/A | 0.9 (-1.3, 3.2) N=567 | |
| Insulin | 0.2 (-1.4, 1.4) N=182 | 2.3 (0.5, 4.3) N=190 | 3.3 (0.9, 6.3) N=522 |
Table 11: Median Change in Body Weight in Patients Treated with Pioglitazone Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial
| Placebo | Pioglitazone | |
| Median (25th, 75th percentile) | Median (25th, 75th percentile) | |
| Change from baseline to final visit (kg) | -0.5 (-3.3, 2.0) N=2581 | +3.6 (0.0, 7.5) N=2560 |
| Note: Median exposure for both pioglitazone and placebo was 2.7 years. | ||
Table 12: Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with ACTOPLUS MET in Patients with Inadequate Glycemic Control on Diet and Exercise
| ACTOPLUS MET 15/850 mg Twice Daily | Pioglitazone 15 mg Twice Daily | Metformin 850 mg Twice Daily | |
| Median (25th , 75th percentile) | Median (25th , 75th percentile) | Median (25th , 75th percentile) | |
| Change from baseline to final visit (kg) | 1.00 (-1.0, 3.0) N=198 | 1.35 (-0.7, 4.1) N=178 | -1.00 (-2.6, 0.4) N=203 |
| Note: Trial duration of 24 weeks. | |||
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.
In the 24-week ACTOPLUS MET trial, edema was reported in 3.0% of patients in the ACTOPLUS MET group, 4.2% in the pioglitazone monotherapy group, and 1.4% in the metformin monotherapy group.
A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 13.
Table 13: Adverse Events of Edema in Patients Treated with Pioglitazone
| Number (%) of Patients | ||||
| Placebo | Pioglitazone 15 mg | Pioglitazone 30 mg | ||
| Monotherapy (16 to 26 weeks) | 3 (1.2%) N=259 | 2 (2.5%) N= 81 | 13 (4.7%) N= 275 | |
| Combined Therapy (16 to 24 weeks) | Sulfonylurea | 4 (2.1%) N=187 | 3 (1.6%) N=184 | 61 (11.3%) N=540 |
| Metformin | 4 (2.5%) N=160 | N/A | 34 (5.9%) N=579 | |
| Insulin | 13 (7.0%) N=187 | 24 (12.6%) N=191 | 109 (20.5%) N=533 | |
| Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” | ||||
Table 14: Adverse Events of Edema in Patients in the PROactive Trial
| Number (%) of Patients | |
| Placebo N=2633 |
Pioglitazone N=2605 |
| 419 (15.9%) | 712 (27.3%) |
| Note: The preferred terms of edema peripheral, generalized edema, pitting edema, and fluid retention were combined to form the aggregate term of “edema.” | |
Hepatic Effects
There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three-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. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) 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.
In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo.
The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% versus 13.4%) and in the 24-week add-on to insulin trial (47.8% versus 43.5%).
Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) 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. In two 3-year trials in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.
Metformin Hydrochloride
In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 15. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.
Table 15: Most Common Adverse Reactions ( > 5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*
| Adverse Reaction | Metformin Monotherapy (n=141) |
Placebo (n=145) |
| % of Patients | ||
| Diarrhea | 53.2 | 11.7 |
| Nausea/Vomiting | 25.5 | 8.3 |
| Flatulence | 12.1 | 5.5 |
| Asthenia | 9.2 | 5.5 |
| Indigestion | 7.1 | 4.1 |
| Abdominal Discomfort | 6.4 | 4.8 |
| Headache | 5.7 | 4.8 |
| *Reactions that were more common in metformin than placebo-treated patients. | ||
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 four 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.
Vitamin B12 Concentrations
Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on ACTOPLUS MET and any apparent abnormalities should be appropriately investigated and managed.
Creatine Phosphokinase
During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) 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.
Postmarketing Experience
Pioglitazone
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.
- Fatal and nonfatal hepatic failure.
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.
SRC: NLM .