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:

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.

Table 1: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of ACTOS Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in Patients Treated with ACTOS than in Patients Treated with Placebo
% 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.

Table 2: 16 to 24 Week Clinical Trials of ACTOS 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 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.

Table 3: 16 to 24 Week Clinical Trials of ACTOS 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 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.

Table 4: 16 to 24 Week Clinical Trials of ACTOS 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 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.

Table 5: PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients Treated with ACTOS and More Commonly than 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.

Table 6: Treatment –Emergent Adverse Events of Congestive Heart Failure (CHF)
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.

Table 7: Treatment –Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with ACTOS or Glyburide
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.

Table 8: Treatment –Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial
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.

Table 9: PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint
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.

Table 10: Weight Changes (kg) from Baseline during Randomized, Double-Blind Clinical Trials
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
Table 11: Median Change in Body Weight in Patients Treated with ACTOS Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial
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.

Table 12: Adverse Events of Edema in Patients Treated with ACTOS
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
Table 13: Adverse Events of Edema in Patients in the PROactive Trial
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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