Actos (Page 2 of 7)
5.4 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 ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for ACTOS versus 2.5% (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. No increase in the incidence of fracture was observed in men treated with ACTOS (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with ACTOS and attention should be given to assessing and maintaining bone health according to current standards of care.
5.5 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 two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. 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 ACTOS and two (0.05%) cases on placebo.
A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure, a duration of ACTOS therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking ACTOS longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without ACTOS] to approximately 10 in 10,000 [with ACTOS]).
There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOS should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOS should be considered in patients with a prior history of bladder cancer.
5.6 Hypoglycemia
Patients receiving ACTOS in combination with insulin or other anti-diabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant anti-diabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration (2.2)].
5.7 Macular Edema
Macular edema has been reported in postmarketing experience in diabetic patients who were taking ACTOS 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 Adverse Reactions (6.1)].
5.8 Ovulation
Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS [see Use in Specific Populations (8.1)]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with ACTOS is recommended.
5.9 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS or any other anti-diabetic drug.
6 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 (5.2)]
- Fractures [see Warnings and Precautions (5.4)]
6.1 Clinical Studies 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 ACTOS in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with ACTOS in the PROactive clinical trial. In these trials, over 6000 patients have been treated with ACTOS for 6 months or longer, over 4500 patients have been treated with ACTOS for one year or longer, and over 3000 patients have been treated with ACTOS for at least 2 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 ACTOS 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 ACTOS than with placebo (3.0%).
In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with ACTOS 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 ACTOS 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 ACTOS 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 ACTOS than in patients who received placebo. None of these adverse events were related to ACTOS dose.
% of Patients | ||
---|---|---|
PlaceboN=259 | ACTOSN=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 ACTOS 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 ACTOS.
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 TrialAdverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with ACTOS 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea | |||
% of Patients | |||
Placebo+ SulfonylureaN=187 | ACTOS 15 mg+ SulfonylureaN=184 | ACTOS 30 mg+ SulfonylureaN=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 TrialAdverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with ACTOS 45 mg + Sulfonylurea than in Patients Treated with ACTOS 30 mg + Sulfonylurea | |||
% of Patients | |||
ACTOS 30 mg+ SulfonylureaN=351 | ACTOS 45 mg+ SulfonylureaN=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 ACTOS 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 ACTOS.
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 TrialAdverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with ACTOS + Metformin than in Patients Treated with Placebo + Metformin | ||
% of Patients | ||
Placebo+ MetforminN=160 | ACTOS 30 mg+ MetforminN=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 ACTOS 45 mg + Metformin than in Patients Treated withACTOS 30 mg + Metformin | ||
% of Patients | ||
ACTOS 30 mg+ MetforminN=411 | ACTOS 45 mg+ MetforminN=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 ACTOS 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 ACTOS.
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 TrialAdverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with ACTOS 30 mg + Insulin than in Patients Treated with Placebo + Insulin | ||||
% of Patients | ||||
Placebo+InsulinN=187 | ACTOS 15 mg+ InsulinN=191 | ACTOS 30 mg+ InsulinN=188 | ||
Hypoglycemia | 4.8 | 7.9 | 15.4 | |
Edema | 7.0 | 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 TrialAdverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with ACTOS 45 mg + Insulin than in Patients Treated with ACTOS 30 mg + Insulin | ||||
% of Patients | ||||
ACTOS 30 mg+ InsulinN=345 | ACTOS 45 mg+ InsulinN=345 | |||
Hypoglycemia | 43.5 | 47.8 | ||
Edema | 22.0 | 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 ACTOS than in patients who received placebo.
% of Patients | ||
---|---|---|
PlaceboN=2633 | ACTOSN=2605 | |
Mean duration of patient follow-up was 34.5 months. | ||
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 |
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.
Patients Treated with ACTOS or Placebo Added on to a Sulfonylurea | |||||
Number (%) of Patients | |||||
Placebo-Controlled Trial(16 weeks) | Non-Controlled Double Blind Trial(24 weeks) | ||||
Placebo+ SulfonylureaN=187 | ACTOS 15 mg+ SulfonylureaN=184 | ACTOS 30 mg + SulfonylureaN=189 | ACTOS 30 mg + SulfonylureaN=351 | ACTOS 45 mg+ SulfonylureaN=351 | |
At least one congestiveheart 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 ACTOS or Placebo Added on to Insulin | |||||
Number (%) of Patients | |||||
Placebo-Controlled Trial(16 weeks) | Non-ControlledDouble Blind Trial(24 weeks) | ||||
Placebo+ InsulinN=187 | ACTOS 15 mg+ InsulinN=191 | ACTOS 30 mg + InsulinN=188 | ACTOS 30 mg + InsulinN=345 | ACTOS 45 mg + InsulinN=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 ACTOS or Placebo Added on to Metformin | |||||
Number (%) of Patients | |||||
Placebo-Controlled Trial(16 weeks) | Non-ControlledDouble Blind Trial(24 weeks) | ||||
Placebo+ MetforminN=160 | ACTOS 30 mg+ MetforminN=168 | ACTOS 30 mg + MetforminN=411 | ACTOS 45 mg + MetforminN=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%) |
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 ACTOS 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.
Number (%) of Subjects | ||
---|---|---|
ACTOSN=262 | GlyburideN=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 CHFprogression 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.
Number (%) of Patients | ||
---|---|---|
PlaceboN=2633 | ACTOSN=2605 | |
At least one hospitalized congestive heart failure event | 108 (4.1%) | 149 (5.7%) |
Fatal | 22 (0.8%) | 25 (1.0%) |
Hospitalized, non-fatal | 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 ACTOS (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 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 a cardiovascular composite endpoint that included all-cause mortality, non-fatal 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 ACTOS and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).
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. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.
Cardiovascular Events | PlaceboN=2633 | ACTOSN=2605 | ||
---|---|---|---|---|
First Eventsn (%) | Total eventsn | First Eventsn (%) | Total eventsn | |
CABG = coronary artery bypass grafting; PCI = percutaneous intervention | ||||
Any event | 572 (21.7) | 900 | 514 (19.7) | 803 |
All-cause mortality | 122 (4.6) | 186 | 110 (4.2) | 177 |
Non-fatal 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 |
Weight Gain: Dose-related weight gain occurs when ACTOS is used alone or in combination with other anti-diabetic 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 ACTOS 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.
Control Group(Placebo) | ACTOS15 mg | ACTOS30 mg | ACTOS45 mg | ||
---|---|---|---|---|---|
Median(25th /75th percentile) | 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 | 2.6 (0.2/5.4)N=79 | |
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 | 4.1 (1.8/7.3)N=333 |
Metformin | -1.4 (-3.2/0.3)N=160 | N/A | 0.9 (-1.3/3.2)N=567 | 1.8 (-0.9/5.0)N=407 | |
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 | 4.1 (1.4/6.8)N=338 |
Placebo | ACTOS | |
---|---|---|
Median(25th /75th percentile) | Median(25th /75th percentile) | |
Note: median exposure for both ACTOS and Placebo was 2.7 years. | ||
Change from Baseline to Final Visit (kg) | -0.5 (-3.3, 2.0)N=2581 | +3.6 (0.0, 7.5)N=2560 |
Edema: Edema induced from taking ACTOS is reversible when ACTOS 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 ACTOS is provided in Table 12.
Number (%) of Patients | |||||
---|---|---|---|---|---|
Placebo | ACTOS15 mg | ACTOS30 mg | ACTOS45 mg | ||
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.” | |||||
Monotherapy (16 to 26 weeks) | 3 (1.2%)N=259 | 2(2.5%)N= 81 | 13 (4.7%)N= 275 | 11 (6.5%)N=169 | |
Combined Therapy(16 to 24 weeks) | Sulfonylurea | 4 (2.1%)N=187 | 3(1.6%)N=184 | 61 (11.3%)N=540 | 81 (23.1%)N=351 |
Metformin | 4 (2.5%)N=160 | N/A | 34 (5.9%)N=579 | 58 (13.9%)N=416 | |
Insulin | 13 (7.0%)N=187 | 24(12.6%)N=191 | 109(20.5%)N=533 | 90 (26.1%)N=345 |
Number (%) of Patients | |
---|---|
PlaceboN=2633 | ACTOSN=2605 |
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.” | |
419 (15.9%) | 712 (27.3%) |
Hepatic Effects: There has been no evidence of ACTOS-induced hepatotoxicity in the ACTOS controlled clinical trial database to date. One randomized, double-blind, 3-year trial comparing ACTOS to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than 3 times the upper limit of the reference range, measured every 8 weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with ACTOS and 9/1046 (0.9%) patients treated with glyburide developed ALT values >3 times the upper limit of the reference range. None of the patients treated with ACTOS in the ACTOS controlled clinical trial database to date have had a serum ALT > 3 times the upper limit of the reference range and a corresponding total bilirubin >2 times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.
Hypoglycemia: In the ACTOS 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 ACTOS 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 ACTOS 15 mg, 15.4% with ACTOS 30 mg, and 4.8% with placebo.
The incidence of reported hypoglycemia was higher with ACTOS 45 mg compared to ACTOS 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).
Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving ACTOS 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 ACTOS 45 mg in combination with sulfonylurea (n=2) or ACTOS 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 Nonclinical Toxicology (13.1)]. In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. 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 ACTOS and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.
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