Pioglitazone and Metformin Hydrocholride (Page 4 of 10)

5.11 Hypoxic States

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving pioglitazone and metformin hydrochloride tablets therapy, the drug should be promptly discontinued.

5.12 Surgical Procedures

Use of pioglitazone and metformin hydrochloride tablets should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.

5.13 Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving pioglitazone and metformin hydrochloride tablets.

5.14 Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone and metformin hydrochloride tablets and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful.

5.15 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone and metformin hydrochloride tablets or any other oral antidiabetic 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)]
Lactic acidosis [see Boxed Warning and Warnings and Precautions (5.2)]
Edema [see Warnings and Precautions (5.3)]
Fractures [see Warnings and Precautions (5.5)]

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.

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 Pioglitazone and Metformin Hydrochloride Tablets Clinical Trial

Table 3 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of pioglitazone and metformin hydrochloride tablets dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600).

Table 3. Adverse Events (≥5% for Pioglitazone and Metformin Hydrochloride Tablets) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24-Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Tablets Administered Twice Daily

% of Patients

Pioglitazone and Metformin Hydrochloride Tablets 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 pioglitazone and metformin hydrochloride tablets 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: 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 pioglitazone and metformin hydrochloride tablets trial.

Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials

Control Group (Placebo)

Pioglitazone 15 mg

Pioglitazone 30 mg

Pioglitazone 45 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 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 Pioglitazone and Metformin Hydrochloride Tablets in Patients with Inadequate Glycemic Control on Diet and Exercise

Pioglitazone and Metformin Hydrochloride Tablets 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 pioglitazone and metformin hydrochloride tablets trial, edema was reported in 3.0% of patients in the pioglitazone and metformin hydrochloride tablets 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

Pioglitazone 45 mg

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

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 [see Nonclinical Toxicology (13.1)]. 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.

*
Reactions that were more common in metformin than placebo-treated patients.

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

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