Pioglitazone Hydrochloride

The following serious adverse reactions are discussed elsewhere in the labeling:

• Congestive heart failure [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Edema [see WARNINGS AND PRECAUTIONS]
• Fractures [see WARNINGS AND PRECAUTIONS]

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.

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 six 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 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 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.

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

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

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

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

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

Mean duration of patient follow-up was 34.5 months.

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

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

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

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, 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 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 threeyear 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

Dose-related weight gain occurs when ACTOS 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 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

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

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

Table 13: Adverse Events of Edema in Patients in the PROactive Trial

There has been no evidence of induced hepatotoxicity with ACTOS in the ACTOS controlled clinical trial database to date. One randomized, double-blind 3-year trial comparing ACTOS to glyburide as addon 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 ACTOS 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 ACTOS in the ACTOS 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.

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).

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology]. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to ACTOS and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on ACTOS and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to ACTOS. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to ACTOS or placebo (HR =1.00; 95% CI: 0.59-1.72) [see WARNINGS AND PRECAUTIONS].

Laboratory Abnormalities

ACTOS may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and are not likely to be associated with any clinically significant hematologic effects.

During protocol-specified measurement of serum creatine phosphokinase (CPK) in ACTOS 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 ACTOS (values of 2150 to 11400 IU/L) and in no comparatortreated patients. Six of these nine patients continued to receive ACTOS, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued ACTOS due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ACTOS. 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 [see WARNINGS AND PRECAUTIONS].
• Fatal and nonfatal hepatic failure [see WARNINGS AND PRECAUTIONS].

Postmarketing reports of congestive heart failure have been reported in patients treated with ACTOS, 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

You should not use this medication if you are allergic to pioglitazone, if you have severe heart failure, if you have active bladder cancer, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Do not take pioglitazone for longer than recommended. Taking this medication for longer than 1 year (12 months) may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Before taking pioglitazone, tell your doctor if you have congestive heart failure or heart disease, fluid retention, a history of bladder cancer, a history of heart attack or stroke, or liver disease.

Take care not to let your blood sugar get too low. Low blood sugar (hypoglycemia) can occur if you skip a meal, exercise too long, drink alcohol, or are under stress. Symptoms include headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating. Carry hard candy or glucose tablets with you in case you have low blood sugar. Other sugar sources include orange juice and milk. Be sure your family and close friends know how to help you in an emergency.

Some women using pioglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

Women may also be more likely than men to have bone fractures in the upper arm, hand, or foot while taking pioglitazone. Talk with your doctor if you are concerned about this possibility.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with pioglitazone.

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

Your pharmacist can provide more information about pioglitazone.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Antidiabetic agent; thiazolidinedione (glitazone).1 8 9 12

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Initiation of therapy in patients with NYHA class III or IV heart failure.1 27 28 (See Boxed Warning.)

• Known serious1 hypersensitivity to pioglitazone or any ingredient in the formulation.1 27 28

Warnings/Precautions

Warnings

Fluid retention associated with use of pioglitazone, alone or in combination with other antidiabetic agents, may lead to or exacerbate CHF.1 19 27 28 30 31 37 38 40 41 (See Boxed Warning.) Use in combination with insulin or in patients with NYHA class I or II heart failure may increase the risk.1

Monitor for signs and symptoms of CHF (e.g., dyspnea, rapid weight gain, edema, unexplained cough or fatigue), especially during initiation of therapy and dosage titration.1 19 27 28 37 40

If CHF develops, manage according to current standards of care.1 19 27 28 37 40 Consider dosage reduction or discontinuance of pioglitazone.1 19 27 28 37 40

Do not initiate thiazolidinedione therapy in hospitalized patients with diabetes mellitus because of delayed onset of action and potential for increased vascular volume and CHF.34

Fluid retention reported; may lead to or exacerbate CHF.1 13

Use with caution in patients with edema and in those at risk for CHF.1 27 Observe for manifestations of CHF (e.g., dyspnea, rapid weight gain, edema).1 (See CHF under Cautions.)

Reported; may involve fluid retention and fat accumulation.1 (See Boxed Warning.)

Other Warnings/Precautions

No evidence of hepatotoxicity in clinical studies to date.1 12 13 However, hepatitis, elevations in hepatic enzymes, mixed hepatocellular-cholestatic liver injury,15 and, very rarely, hepatic failure associated with fatalities reported during postmarketing experience.1

Monitor liver function tests prior to initiation of therapy, then periodically thereafter according to clinician judgment.1 12 Monitor more frequently if used in patients with mild hepatic impairment (ALT 1–2.5 times the upper limit of normal [ULN]).1 (See Hepatic Impairment under Cautions.)

Recheck liver function if ALT increases to >3 times the ULN or if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.1 Discontinue therapy if ALT remains elevated at >3 times the ULN or if jaundice develops.1

Risk of bone loss and fractures in women, and possibly in men, receiving thiazolidinedione therapy.1 29 35 36 39 47 50

Fractures reported more frequently in women receiving pioglitazone (5.1%) than in women receiving placebo (2.5%) in long-term study (mean 34.5 months follow-up).1 27 28 30 32 33 Effects noted after first year of treatment and persisted throughout treatment.1 27 28 30 32 33 Most fractures were nonvertebral, occurring in a distal limb (forearm, hand, wrist, foot, ankle, fibula, tibia).1 27 28 29

In an observational study, use of pioglitazone or rosiglitazone for approximately 12–18 months associated with twofold to threefold increase in fractures, particularly of hip and wrist.50 Overall risk of fracture similar among men and women.50

Consider risk of fracture, particularly in female patients.1 29 35 Assess and maintain bone health according to current standards of care.1 28 29 30 32 33 35

Increased risk of bladder cancer.1 27 28 Do not use in patients with active bladder cancer; use with caution in patients with history of bladder cancer, weighing benefits of glycemic control against unknown risks of cancer recurrence.1 27 28 80

Concomitant use of insulin or other antidiabetic drugs (e.g., insulin secretagogues) increases risk for hypoglycemia.1 27 28 May need to reduce dosage of concomitant antidiabetic agent to decrease risk of hypoglycemia.1 27 28 (See Dosage under Dosage and Administration.)

New-onset or worsening (diabetic) macular edema with decreased visual acuity reported rarely; concurrent peripheral edema reported frequently.1 27 28 32 33 Symptoms improved in some patients following discontinuance of pioglitazone.1 27 28 32 33

Regular eye examinations by ophthalmologist advised.1 27 28 32 33 34 Promptly refer patients reporting visual symptoms to ophthalmologist, regardless of other concurrent therapy or physical findings.1 27 28 32 33

May cause ovulation in premenopausal anovulatory women; risk of pregnancy unless adequate contraceptive measures initiated.1

Evidence of macrovascular risk reduction with pioglitazone or any other antidiabetic agent has not been conclusively demonstrated in controlled clinical trials.1

Possible dose-related decreases in hemoglobin and hematocrit; usually evident within 4–12 weeks of therapy.1 May be related to plasma volume expansion.1 Rarely associated with clinically important hematologic manifestations.1

Isolated elevations in serum CK >10 times ULN noted rarely during clinical trials.1 Resolved in most patients without apparent sequelae despite continued therapy with the drug; any relationship to pioglitazone therapy unknown.1

When used in fixed combination with metformin hydrochloride or glimepiride, consider the cautions, precautions, and contraindications associated with the concomitant agent.27 28

Specific Populations

Category C.1 Most clinicians recommend that insulin be used during pregnancy in women with diabetes mellitus.1

Distributed into milk in rats; not known whether distributed into human milk.1 Use not recommended.1

Safety and efficacy not established in pediatric patients <18 years of age; use not recommended.1 13

No substantial differences in safety and efficacy relative to younger adults.1

Use with caution in patients with mild hepatic impairment (ALT 1–2.5 times the ULN).1 12 Use not recommended in patients with active hepatic disease, ALT >2.5 times the ULN, or troglitazone-associated jaundice (troglitazone no longer commercially available in US).1 12

Common Adverse Effects

Upper respiratory tract infection, headache, sinusitis, myalgia, pharyngitis, edema.1

Storage

Oral

Tight containers at 25°C (may be exposed to 15–30°C).1 Protect from moisture and humidity.1