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Uses

Diabetes Mellitus

Pioglitazone is used alone (monotherapy) or in combination with a sulfonylurea antidiabetic agent, metformin (either as a fixed-combination preparation or as individual drugs given concurrently), or insulin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pioglitazone also is used in fixed combination with glimepiride in patients with type 2 diabetes mellitus who are already receiving pioglitazone and a sulfonylurea separately or who are inadequately controlled on a sulfonylurea or pioglitazone alone. In patients whose hyperglycemia cannot be controlled with these other antidiabetic agents, pioglitazone should be added to, not substituted for, such antidiabetic therapy.

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus was previously described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on age of onset. Many patients' diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.

Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes mellitus generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes mellitus in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans). For additional details on the clinical classification, complications, and management of diabetes mellitus,

A thiazolidinedione (i.e., pioglitazone or rosiglitazone) generally is considered one of several second-line agents (e.g., including insulin and sulfonylureas) used for the management of hyperglycemia in patients with type 2 diabetes mellitus not responding adequately to oral monotherapy with metformin, the preferred initial oral antidiabetic therapy.

Some data suggest a possible protective effect of pioglitazone with regard to certain cardiovascular outcomes (e.g., death, myocardial infarction, stroke) in patients with type 2 diabetes mellitus. In a randomized, controlled study in over 5000 patients with type 2 diabetes mellitus who were at high risk for macrovascular complications, addition of pioglitazone to existing antidiabetic therapy was associated with a reduction in the secondary composite end point of all-cause mortality, nonfatal myocardial infarction, and stroke compared with placebo; no difference between the study groups was observed with respect to the primary composite study end point (all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention on the coronary or leg arteries, or above-the-ankle amputation). Results of a meta-analysis of data from randomized, placebo- or active-controlled trials in over 16,000 patients indicated an 18% lower risk of the primary composite end point of death, myocardial infarction, or stroke with pioglitazone therapy. The incidence of serious heart failure was increased with pioglitazone therapy but without an associated increase in mortality. While an increased risk of myocardial ischemic events has not been documented to date with pioglitazone therapy in patients with type 2 diabetes mellitus, both pioglitazone and rosiglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention and other cardiovascular effects that may lead to or exacerbate congestive heart failure (CHF). Therefore, the potential risks and benefits of thiazolidinediones versus other second-line antidiabetic agents (sulfonylureas, insulin) should be carefully considered.(See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.) For information on the effects of intensive glycemic control on microvascular and macrovascular complications in patients with diabetes mellitus,

Pioglitazone Monotherapy

Efficacy as monotherapy for the management of type 2 diabetes mellitus was established in 3 controlled studies of 16-26 weeks' duration. Pioglitazone improved glycemic control as measured by fasting glucose and glycosylated hemoglobin (HbA1c) concentrations.

Combination Therapy

Efficacy of pioglitazone in combination with a sulfonylurea antidiabetic agent, metformin, or insulin in patients whose type 2 diabetes mellitus was inadequately controlled by therapy with one or more of these agents was established in several controlled studies in which combined therapy improved glycemic control regardless of the dosage of the other antidiabetic agent(s). A thiazolidinedione such as pioglitazone also may be added to therapy with the fixed combination of glyburide and metformin in patients whose hyperglycemia is not adequately controlled with the fixed combination. A thiazolidinedione antidiabetic agent also may be used concomitantly with repaglinide in patients whose hyperglycemia is inadequately controlled with diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent. In a clinical trial in patients with type 2 diabetes mellitus poorly controlled (as determined by HbA1c concentrations exceeding 7%) by metformin or sulfonylurea monotherapy, the combination of repaglinide and pioglitazone reduced fasting plasma glucose and HbA1c concentrations compared with pioglitazone or repaglinide monotherapy. Greater glycemic control was achieved with the combination of pioglitazone (fixed dosage: 30 mg daily) and repaglinide at a lower daily dosage of repaglinide (final median dosage: 6 mg daily) than with repaglinide monotherapy (final median dosage: 10 mg daily).

Pioglitazone also is used in fixed combination with metformin in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components. No clinical trials have evaluated the fixed combination of metformin and pioglitazone; efficacy and safety of the fixed combination has been established based on concurrent administration of the 2 agents given separately. Safety and efficacy of the fixed combination of pioglitazone and metformin in patients with type 2 diabetes mellitus are extrapolated from clinical trials evaluating pioglitazone as add-on therapy to metformin. Bioequivalence has been demonstrated between the fixed combination of pioglitazone and metformin and each agent given concurrently.

Pioglitazone also is used in fixed combination with glimepiride in patients with type 2 diabetes mellitus who are already receiving pioglitazone and a sulfonylurea separately or who are inadequately controlled on a sulfonylurea or pioglitazone alone. No clinical trials have been conducted evaluating the fixed combination of pioglitazone and glimepiride as second-line therapy in patients who are inadequately controlled with monotherapy with a sulfonylurea. Safety and efficacy of the fixed combination of pioglitazone and glimepiride in patients with type 2 diabetes mellitus who are inadequately controlled on a sulfonylurea alone are extrapolated from clinical trials evaluating pioglitazone as add-on therapy to a sulfonylurea.

Because pioglitazone requires insulin for activity, it would not be effective and should not be used in patients with type 1 diabetes mellitus or ketoacidosis.

Dosage and Administration

General

Dosage should be carefully individualized based on patient response and tolerance. Following initiation of pioglitazone therapy or dosage increase, patients should be monitored for adverse effects related to fluid retention.(See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.) Fasting plasma glucose (FPG) concentrations should be monitored periodically to determine the patient's response. Periodic glycosylated hemoglobin (hemoglobin A1c [HbA1c]) determinations also should be performed; HbA1c is a better indicator of long-term glycemic control than fasting plasma glucose concentrations alone. Following initiation of pioglitazone-containing therapy, determination of HbA1c concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy.

Administration

Pioglitazone hydrochloride is administered orally once daily and can be taken without regard to meals. Pioglitazone in fixed combination with immediate-release metformin hydrochloride (ActoPlus Met) is administered once or twice daily with meals to reduce the GI effects of the metformin hydrochloride component. Pioglitazone in fixed combination with extended-release metformin hydrochloride (ActoPlus Met XR) is administered once daily with meals to reduce the GI effects of the metformin hydrochloride component.

Dosage

Dosage of pioglitazone hydrochloride is expressed in terms of the base. Bioequivalence has been demonstrated between the fixed combination of immediate-release pioglitazone and immediate-release metformin hydrochloride (ActoPlus Met) and each agent given concurrently as separate tablets at the currently approved dosage strengths (500 or 850 mg of metformin hydrochloride and 15 mg of pioglitazone), and between the fixed combination of immediate-release pioglitazone and extended-release metformin hydrochloride (ActoPlus Met XR) and each agent given concurrently as separate tablets at the currently approved dosage strengths (1 g of metformin hydrochloride and 15 or 30 mg of pioglitazone). Bioequivalence also has been demonstrated between the fixed combination of pioglitazone and glimepiride (Duetact) and each agent given concurrently as separate tablets at the currently approved dosage strengths (2 or 4 mg of glimepiride and 30 mg of pioglitazone).

Pioglitazone Monotherapy

The initial dosage of pioglitazone as monotherapy is 15 or 30 mg once daily. If the response is inadequate, dosage may be increased gradually up to a maximum recommended dosage of 45 mg daily.

Combination Therapy with Other Oral Antidiabetic Agents

The usual initial dosage of pioglitazone in combination with a sulfonylurea antidiabetic agent, metformin hydrochloride, or insulin (as separate components) is 15 or 30 mg once daily. Pioglitazone dosage should not exceed 45 mg daily.

Should hypoglycemia occur during combination therapy with an insulin secretagogue (e.g., sulfonylurea), the dosage of the insulin secretagogue should be decreased. If hypoglycemia occurs with concomitant pioglitazone and insulin therapy, the dosage of insulin should be reduced by 10-25%; further adjustments to insulin dosage should be individualized according to glycemic response.(See Hypoglycemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) The manufacturer of pioglitazone states that it is unlikely that the metformin hydrochloride dosage will require adjustment because of hypoglycemia during combination therapy with pioglitazone.

When the commercially available fixed-combination preparations containing immediate-release pioglitazone and immediate-release metformin hydrochloride (ActoPlus Met) or immediate-release pioglitazone and extended-release metformin hydrochloride (ActoPlus Met XR) are used, dosage of the fixed combinations is based on the patient's current dosages of pioglitazone and/or metformin hydrochloride and on usual initial dosages of these drugs, effectiveness, and tolerability. The usual initial dosage of the fixed combination containing immediate-release metformin hydrochloride is pioglitazone 15 mg/metformin hydrochloride 500 mg or pioglitazone 15 mg/metformin hydrochloride 850 mg once or twice daily with food. The usual initial dosage of the fixed combination containing extended-release metformin hydrochloride is pioglitazone 15 mg/metformin hydrochloride 1 g or pioglitazone 30 mg/metformin hydrochloride 1 g once daily with the evening meal. Dosage should be titrated gradually after assessing therapeutic response, up to a maximum daily dosage of 45 mg of pioglitazone and 2.55 g of immediate-release metformin hydrochloride or 45 mg of pioglitazone and 2 g of extended-release metformin hydrochloride.

The safety and efficacy of transferring from therapy with other oral antidiabetic agents to the fixed combination of pioglitazone and metformin hydrochloride have not been established in clinical studies. Any change in the therapy of type 2 diabetic patients should be undertaken with caution and appropriate monitoring, as changes in glycemic control can occur. Sufficient time should be allowed to assess therapeutic response. Ideally, long-term glycemic control should be evaluated at 8-12 weeks following transfer of therapy using Hb A1c, unless there is evidence of deterioration in glycemic control as measured by FPG concentrations.

The initial dosage of pioglitazone in fixed combination with glimepiride should be based on the patient's previous regimen with pioglitazone and/or a sulfonylurea. When the commercially available preparation containing pioglitazone in fixed combination with glimepiride is used in patients previously receiving glimepiride monotherapy, the usual initial dosage is 30 mg of pioglitazone and 2 or 4 mg of glimepiride once daily with the first main meal. The usual initial dosage in patients previously receiving pioglitazone monotherapy is 30 mg of pioglitazone and 2 mg of glimepiride once daily. When the fixed combination is used to replace concurrent therapy as separate tablets, the dosage of the fixed combination is based on the patient's previous dosage of glimepiride and pioglitazone. Therapy may be initiated with 2 or 4 mg of glimepiride and 30 mg of pioglitazone once daily. Patients who were not controlled with 15 mg of pioglitazone once daily in combination with glimepiride as separate tablets should be carefully monitored during transfer to the fixed combination. Following initiation of therapy in patients previously receiving monotherapy with pioglitazone or a sulfonylurea or combination therapy with each component given separately, subsequent dosage should be adjusted according to the patient's therapeutic response. For patients transferring from monotherapy with a sulfonylurea other than glimepiride or combination therapy with pioglitazone and a sulfonylurea other than glimepiride, the usual initial dosage of the fixed combination is 30 mg of pioglitazone and 2 mg of glimepiride once daily. Because an exaggerated hypoglycemic response may occur in some patients during the transition from a sulfonylurea antidiabetic agent with a prolonged half-life (e.g., chlorpropamide) to glimepiride in fixed combination with pioglitazone, patients being transferred from such agents should be monitored closely for the occurrence of hypoglycemia during the initial 1-2 weeks of the transition period.

Sufficient time should be allowed to assess the full therapeutic response to the fixed combination of pioglitazone and glimepiride (approximately 8-12 weeks) unless glycemic control (as measured by FPG concentrations) deteriorates. If additional glycemic control is needed, dosage may be increased to a maximum total daily dosage of 8 mg of glimepiride and 45 mg of pioglitazone.

Concomitant Therapy with Potent CYP2C8 Inhibitors or Inducers

Because concomitant use of pioglitazone and potent inhibitors of cytochrome P-450 (CYP) isoenzyme 2C8 (e.g., gemfibrozil) increases exposure to pioglitazone, the maximum recommended dosage of pioglitazone in patients taking strong CYP2C8 inhibitors is 15 mg once daily.

If treatment with a CYP2C8 inducer (e.g., rifampin) is initiated or discontinued during pioglitazone therapy, changes in antidiabetic therapy may be required based on clinical response; however, the dosage of pioglitazone should not exceed the maximum recommended dosage of 45 mg daily.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Special Populations

Hepatic Impairment

Pioglitazone dosage adjustment is not necessary in patients with hepatic impairment when the drug is given as monotherapy. If the fixed combination of glimepiride and pioglitazone is considered for use in patients with hepatic impairment, therapy with 1 mg of glimepiride daily as monotherapy should be initiated before using the fixed combination, followed by conservative initial and maintenance dosages of the fixed combination. Patients with hepatic impairment should be closely monitored for hypoglycemia during initiation and subsequent dosage adjustment of such combination therapy.

Renal Impairment

Pioglitazone dosage adjustment is not necessary in patients with renal impairment. If the fixed combination of glimepiride and pioglitazone is considered for use in patients with renal impairment, therapy with 1 mg of glimepiride daily as monotherapy should be initiated before using the fixed combination, followed by conservative initial and maintenance dosages of the fixed combination. Patients with renal impairment should be closely monitored for hypoglycemia during initiation and subsequent dosage adjustment of such combination therapy.

Geriatric Patients

Pioglitazone dosage adjustment is not necessary for geriatric patients solely because of age. Pioglitazone in fixed combination with metformin hydrochloride should be used with caution in geriatric patients since aging is associated with reduced renal function. Initial and maintenance dosages of the fixed combination should be conservative and should be titrated carefully; dosage generally should not be titrated to the maximum level recommended for younger adults.

As geriatric patients are particularly susceptible to hypoglycemia, such patients should receive initial therapy with glimepiride at a dosage of 1 mg once daily prior to receiving the fixed-combination preparation, followed by conservative initial and maintenance dosages of the fixed combination. Blood glucose concentrations of such patients should be closely monitored prior to and after initiation of therapy to avoid hypoglycemia.

Debilitated or Malnourished Patients

Maintenance dosage of pioglitazone in fixed combination with metformin hydrochloride should be conservative in debilitated or malnourished geriatric patients and those with pituitary, adrenal, or hepatic insufficiency, and dosages should not be titrated to the maximum recommended dosage. Such patients are particularly susceptible to hypoglycemia and should receive initial therapy with glimepiride at a dosage of 1 mg once daily prior to receiving the fixed-combination preparation, followed by conservative initial and maintenance dosages of the fixed combination. Blood glucose concentrations of such patients should be closely monitored prior to and after initiation of therapy to avoid hypoglycemia.

Congestive Heart Failure

The recommended initial dosage of pioglitazone in patients with congestive heart failure (CHF) (e.g., New York Heart Association [NYHA] class I or II) is 15 mg once daily. If subsequent dosage escalation is necessary, the dosage should be increased gradually in increments of 15 mg up to a maximum dosage of 45 mg daily according to glycemic response based on HbA1c. Following initiation of pioglitazone and any increase in dosage, patients should be monitored carefully for weight gain, edema, and manifestations of CHF. Initiation of pioglitazone therapy in patients with more severe heart failure (NYHA class III or IV) is contraindicated. (See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions and see Cautions: Contraindications.)

Before receiving therapy with the fixed-combination preparation containing glimepiride 2 mg and pioglitazone 30 mg, patients with diabetes mellitus and systolic dysfunction should receive pioglitazone 15 mg once daily as monotherapy and should safely tolerate dosage titration to 30 mg once daily as monotherapy. If subsequent dosage adjustment is necessary with the fixed-combination preparation, patients should be closely monitored for weight gain, edema, or other signs or symptoms of exacerbation of CHF.

Cautions

Contraindications

Known serious hypersensitivity reaction to pioglitazone or any ingredient in the formulation.

Initiation of therapy with pioglitazone is contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure.(See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Warnings/Precautions

Warnings

Congestive Heart Failure

Thiazolidinediones, including pioglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention, which may lead to or exacerbate congestive heart failure (CHF). Use of thiazolidinediones is associated with an approximately twofold increased risk of CHF.(See Edema under Warnings/Precautions: Warnings, in Cautions.) Use of pioglitazone in combination with insulin or in patients with NYHA class I or II heart failure may increase the risk. Patients should be observed 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. If signs and symptoms of CHF develop, the disorder should be managed according to current standards of care. In addition, a decrease in the dosage or discontinuance of pioglitazone must be considered in such patients.

Patients with NYHA class III or IV cardiac status with or without CHF or with an acute coronary event were not studied in clinical trials of pioglitazone; initiation of therapy with the drug is contraindicated in patients with NYHA class III or IV heart failure. Use of pioglitazone is not recommended in patients with symptomatic heart failure. Caution should be exercised in patients with edema and in those who are at risk for CHF. Thiazolidinedione therapy should not be initiated in hospitalized patients with diabetes mellitus because of the delayed onset of action and because possible drug-related increases in vascular volume and CHF may complicate care of patients with hemodynamic changes induced by coexisting conditions or in-hospital interventions.

Findings from a meta-analysis of randomized controlled studies that assessed the risk of development of CHF and death from cardiovascular causes in patients receiving thiazolidinediones indicate that the risk of CHF is higher in patients receiving thiazolidinediones (relative risk of 1.72; 95% confidence interval: 1.21-2.42) than in controls (individuals receiving other antidiabetic agents or placebo). The relative risk for CHF was increased across a wide background of cardiovascular risk (i.e., patients with prediabetes, with type 2 diabetes mellitus without cardiovascular disease, with type 2 diabetes mellitus and cardiovascular disease other than CHF, or with type 2 diabetes mellitus and CHF [NYHA class I and II] and ejection fraction less than 40%). In contrast to the increased risk for CHF observed in thiazolidinedione-treated patients, the risk of cardiovascular death was not increased in patients receiving these agents.

In a 16-week, controlled study in patients with type 2 diabetes mellitus, CHF was reported in 1.1% of patients receiving combined therapy with pioglitazone and insulin and in none of the patients receiving insulin therapy alone; all patients who experienced CHF had a history of cardiac disease (e.g., coronary artery disease, previous coronary artery bypass graft procedures, myocardial infarction).

CHF has been reported during postmarketing experience in pioglitazone-treated patients who did or did not have previously known heart disease and who did or did not receive concomitant insulin therapy. In a 24-week postmarketing safety study in patients with NYHA class II and III heart failure and poorly controlled diabetes despite use of pioglitazone or glyburide, a higher incidence of CHF requiring hospitalization was observed in those receiving pioglitazone (9.9% of patients) than in those receiving glyburide (4.7% of patients). Patients who were older than 64 years of age or receiving insulin at study entry were particularly susceptible to this adverse event. No differences in cardiovascular mortality were noted between pioglitazone and glyburide therapy.

Data from a long-term (34.5 months) cardiovascular outcomes study (PROspective pioglitAzone Clinical Trial In macroVascular Events [PROACTIVE]) in patients with a history of macrovascular disease (those with NYHA class II-IV heart failure were excluded) receiving pioglitazone or placebo in addition to existing antidiabetic therapy (e.g., insulin, metformin, sulfonylureas) and cardiovascular agents indicated a higher incidence of serious heart failure (e.g., requiring hospitalization or prolonging hospital stay, fatal or life-threatening, resulting in substantial disability) in patients receiving pioglitazone than in those receiving placebo. Serious heart failure occurred in 5.7 or 4.1% of patients receiving pioglitazone or placebo, respectively; mortality rates from heart failure did not differ between pioglitazone or placebo recipients.

Edema

Fluid retention can occur and may lead to or exacerbate CHF in patients receiving a thiazolidinedione, including pioglitazone, alone or in combination with other antidiabetic agents, including insulin. Diuretic therapy may be necessary for management of fluid retention. Caution should be exercised in patients with edema and those at risk for CHF.(See Congestive Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

All patients receiving thiazolidinedione therapy (e.g., rosiglitazone, pioglitazone) should be advised to monitor for weight gain and edema. Other potential causes of edema should be excluded. Pioglitazone-induced edema is reversible when the drug is discontinued. Hospitalization for edema usually is not required unless there is coexisting CHF.

Weight Gain

Dose-related weight gain, probably involving a combination of fluid retention and fat accumulation, has been observed during therapy with pioglitazone alone or in combination with other antidiabetic agents (e.g., metformin, sulfonylureas, insulin). Unusually rapid increases in weight and increases in excess of that usually observed in clinical trials have been reported during postmarketing experience. Patients who experience rapid or excessive weight gain should be assessed for fluid accumulation and volume-related events such as excessive edema and CHF.

Other Warnings/Precautions

Hepatic Effects

No evidence of hepatotoxicity has been noted with pioglitazone in clinical studies to date. However, hepatitis, liver function test abnormalities (i.e., elevations in hepatic enzymes to at least 3 times the upper limit of normal), mixed hepatocellular-cholestatic liver injury, and liver failure with or without fatalities have been reported during postmarketing experience with the drug. Patients with type 2 diabetes mellitus may have fatty liver disease or cardiac disease with episodic CHF, both of which may cause liver test abnormalities; such patients also may have other forms of liver disease, many of which can be treated or managed. Liver function tests (serum ALT and AST, alkaline phosphatase, total bilirubin) should be obtained prior to initiation of pioglitazone therapy. If results of such tests are abnormal, the probable cause should be investigated, treated (if possible), and monitored appropriately. Pioglitazone should be initiated with caution in patients with abnormal liver function test results. The manufacturer states that routine periodic monitoring of liver function tests during pioglitazone treatment is not recommended in patients without liver disease.

Development of manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) should lead to prompt rechecking of liver function. If such symptoms are accompanied by serum ALT increases exceeding 3 times the upper limit of normal, pioglitazone therapy should be interrupted and investigation done to establish the probable cause of the abnormal test results. Patients receiving pioglitazone who have serum ALT concentrations exceeding 3 times the reference range and serum total bilirubin concentrations exceeding twice the reference range without alternative explanations are at risk for severe drug-induced liver injury; the drug should not be restarted in such patients. The manufacturer states that pioglitazone may be used with caution in patients with lesser elevations of serum ALT or bilirubin who have an alternative probable cause for such elevations.

Musculoskeletal Effects

Thiazolidinedione use is associated with bone loss and fractures in women and possibly in men with type 2 diabetes mellitus. In a long-term (34.5 months of follow-up) cardiovascular outcomes study (PROACTIVE) in patients with type 2 diabetes mellitus (mean duration of diabetes: 9.5 years), 5.1 or 2.5% of women receiving pioglitazone or placebo, respectively, experienced a fracture. Such effects were noted after the first year of treatment and persisted throughout the study. The majority of fractures observed in female patients receiving pioglitazone were nonvertebral, occurring in a distal upper limb (i.e., forearm, hand, wrist) or distal lower limb (i.e., foot, ankle, fibula, tibia). In an observational study in the United Kingdom in men and women (mean age: 60.7 years) with diabetes mellitus, use of pioglitazone or rosiglitazone for approximately 12-18 months (as estimated from prescription records) was associated with a twofold to threefold increase in fractures, particularly of the hip and wrist. The overall risk of fracture was similar among men and women and was independent of body mass index, comorbid conditions, diabetic complications, duration of diabetes mellitus, and use of other oral antidiabetic drugs.

Risk of fracture should be considered when initiating or continuing thiazolidinedione therapy, particularly in female patients. Bone health should be assessed and maintained according to current standards of care.

Risk of Bladder Cancer

Findings from studies in animals and humans suggest that pioglitazone therapy may be associated with an increased risk of bladder cancer. In preclinical carcinogenicity studies of pioglitazone, bladder tumors were observed in male rats receiving doses of pioglitazone that produced blood concentrations of pioglitazone approximately equivalent to those resulting from the maximum recommended clinical dose in humans. In addition, results from two 3-year controlled clinical studies of pioglitazone (the PROACTIVE study and a liver safety study) demonstrated a higher percentage of bladder cancer cases in patients receiving pioglitazone versus comparator drugs.

In a planned 5-year interim analysis of the epidemiologic study conducted by the manufacturer, there was no statistically significant association overall between pioglitazone exposure and bladder cancer. However, the risk of bladder cancer was increased among patients with the longest exposure to pioglitazone and those receiving the highest cumulative dosage of the drug. The median duration of therapy among pioglitazone-treated patients in this study was 2 years (range 0.2-8.5 years). In addition, results of a recent retrospective cohort (nested case-control design) study involving more than 115,000 patients in a United Kingdom general practice database found a statistically significant 83% increase in the rate of bladder cancer with ever use of pioglitazone, but no increased risk with rosiglitazone therapy. Similar to the interim findings of the 10-year epidemiologic study, this cohort study also found a dose-response relationship for cumulative duration of pioglitazone use, with the highest risk observed in patients who received the drug for more than 24 months.

The manufacturer and FDA currently state that pioglitazone should not be used in patients with active bladder cancer; in addition, the drug should be used with caution in patients who have a history of bladder cancer, weighing the benefits of glycemic control against the unknown risks of cancer recurrence with pioglitazone therapy. Patients who are concerned about the possible risks associated with using pioglitazone should be advised to consult their healthcare professional.

Hypoglycemia

Concomitant therapy with pioglitazone and insulin or other antidiabetic drugs (particularly insulin secretagogues such as sulfonylureas) increases the risk for hypoglycemia. A reduced dosage of the concomitant antidiabetic agent may be needed to decrease the risk of hypoglycemia.(See Combination Therapy with Other Oral Antidiabetic Agents under Dosage and Administration: Dosage.)

Ocular Effects

During postmarketing experience, rare cases of new-onset or worsening (diabetic) macular edema with decreased visual acuity have been reported with pioglitazone or another thiazolidinedione; such patients frequently reported concurrent peripheral edema. Some patients with macular edema presented with symptoms of blurred vision or decreased visual acuity, but other cases were detected by routine ophthalmologic examination. Symptoms improved in some patients following discontinuance of pioglitazone. Patients with diabetes mellitus should have regular eye examinations by an ophthalmologist. Patients receiving pioglitazone who report any visual symptoms should be referred promptly to an ophthalmologist, regardless of the presence of other concurrent therapy or physical findings.

Ovulatory Effects

Risk for pregnancy unless contraceptive measures initiated; anovulatory premenopausal women with insulin resistance may resume ovulation during therapy. The frequency of resumption of ovulation with pioglitazone therapy has not been evaluated in clinical studies, and, therefore, is unknown. If menstrual dysfunction occurs, weigh risks versus benefits of continued pioglitazone.

Macrovascular Outcomes

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

Laboratory Abnormalities

Dose-related decreases in hemoglobin and hematocrit usually becomes evident 4-12 weeks after initiation of therapy and values remain stable thereafter. These effects may be related to plasma volume expansion and have rarely been associated with clinically important hematologic manifestations.

Isolated elevations in serum creatine kinase (CK, creatine phosphokinase, CPK) exceeding 10 times the upper limit of normal were noted rarely during protocol-specified measurements in clinical trials. Such elevations resolved in most patients without apparent sequelae despite continued therapy; any relationship to pioglitazone therapy is unknown.

Use of Fixed Combinations

When pioglitazone is used in fixed combination with other drugs (e.g., metformin, glimepiride), the cautions, precautions, and contraindications associated with those drugs must be considered in addition to those associated with pioglitazone.

Specific Populations

Pregnancy

Category C. Because of strong suggestion that blood glucose abnormalities during pregnancy are associated with an increased incidence of congenital anomalies and neonatal morbidity and mortality, most clinicians recommend use of insulin for maintenance of optimum blood glucose control during pregnancy in women with diabetes mellitus. Pioglitazone should be used during pregnancy only if the anticipated benefit outweighs the potential risk to the fetus.

Lactation

Pioglitazone is distributed into milk in rats; a decision should be made whether to discontinue nursing or the drug because of the potential for serious adverse reactions in nursing infants. If pioglitazone in fixed combination with metformin or glimepiride is discontinued in a nursing mother and dietary therapy is inadequate for glycemic control, insulin therapy should be considered.

Pediatric Use

Safety and efficacy of pioglitazone have not been established in children or adolescents younger than 18 years of age; use in this age group currently is not recommended by the manufacturer because of a lack of long-term safety data, including that on the risk of fracture and other adverse effects. However, the American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance with therapy and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.

Geriatric Use

Pharmacokinetic, efficacy, and adverse effect profiles in geriatric patients are similar to those in younger adults, although small sample sizes in studies of patients 75 years or older limit conclusions. While pioglitazone area under the concentration-time curve (AUC) is about 21% higher in healthy geriatric individuals than in younger individuals and mean terminal half-life is also prolonged (10 hours versus 7 hours, respectively), these changes are not considered clinically relevant.

Hepatic Impairment

Use with caution in mild hepatic impairment; use is not recommended in moderate to severe hepatic impairment (ALT exceeding 2.5 times upper limit of normal, or active liver disease).(See Hepatic Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Common Adverse Effects

Adverse effects (not dose related) occurring in at least 5% of patients receiving pioglitazone and more frequently than with placebo include upper respiratory tract infection, headache, sinusitis, myalgia, pharyngitis, and edema. Adverse effects generally were similar with pioglitazone monotherapy versus combined therapy with sulfonylureas, metformin, or insulin; however, edema was more common during pioglitazone monotherapy and during all combined therapies than with placebo. Pioglitazone-induced reductions in hyperglycemia are associated with mild weight gain.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or Inducers of CYP3A4

Potential pharmacokinetic interaction with inhibitors or inducers of cytochrome P-450 (CYP) isoenzyme 3A4.

Concomitant use of pioglitazone (45 mg daily for 7 days) and ketoconazole (200 mg twice daily for 7 days), an inhibitor of CYP3A4, increased peak plasma concentration and area under the concentration-time curve (AUC) of pioglitazone by 14 and 34%, respectively.

Concomitant use of ranitidine (150 mg twice daily for 4 days), a relatively weak CYP3A4 inhibitor, and pioglitazone (45 mg daily for 7 days) reduced pioglitazone AUC and peak plasma concentration by 13 and 16%, respectively; pioglitazone had a negligible effect on ranitidine pharmacokinetics.

CYP3A4 Substrates

Pioglitazone is a weak inducer of CYP3A4. Potential pharmacokinetic interaction (reduction in peak plasma concentration and AUC) with CYP3A4 substrates (e.g., atorvastatin, midazolam, ethinyl estradiol, nifedipine).

Concomitant use of pioglitazone (45 mg daily for 7 days) and atorvastatin (80 mg daily for 7 days) resulted in reductions of 14 and 23% in atorvastatin AUC and peak plasma concentration, respectively; pioglitazone AUC and peak plasma concentration were reduced by 24 and 31%, respectively.

Administration of pioglitazone (45 mg daily for 7 days) and midazolam (single dose of 7.5 mg on day 15) reduced midazolam AUC and peak plasma concentration each by 26%.

Administration of pioglitazone (45 mg daily for 4 days) with extended-release nifedipine (30 mg daily for 4 days) reduced nifedipine AUC and peak plasma concentration by 13 and 17%, respectively; pioglitazone AUC and peak plasma concentration were increased by 5 and 4%, respectively, with concomitant use of pioglitazone (45 mg daily for 7 days) and extended-release nifedipine (30 mg daily for 7 days).

Concomitant use of an estrogen-progestin contraceptive (ethinyl estradiol 0.035 mg with norethindrone 1 mg daily for 21 days) and pioglitazone (45 mg daily for 21 days) resulted in small decreases in peak plasma concentration (13%) and AUC (11%) of ethinyl estradiol. The clinical importance of these changes is unknown.

Inhibitors or Inducers of CYP2C8

Pioglitazone is a CYP2C8 substrate; potential pharmacokinetic interaction with inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampin) of CYP2C8. Adjustments in pioglitazone dosage may be needed during initiation or discontinuance of an inhibitor or inducer of CYP2C8.(See Concomitant Therapy with Potent CYP2C8 Inhibitors or Inducers under Dosage and Administration: Dosage.)

Concomitant use of pioglitazone (single 30-mg dose) and gemfibrozil (600 mg twice daily for 2 days) resulted in a 3.4-fold increase in AUC of pioglitazone and a 6% increase in pioglitazone peak plasma concentration; half-life of pioglitazone also increased from 6.5 to 15.1 hours.

Concomitant use of pioglitazone (single 30-mg dose) and rifampin (600 mg daily for 5 days) resulted in a 54% decrease in AUC and a 5% decrease in peak plasma concentration of pioglitazone.

CYP2C9 or CYP1A2 Substrates

Pharmacokinetic interaction is unlikely with CYP2C9 substrates (e.g., warfarin). Concomitant therapy with warfarin sodium (dosage adjusted to achieve therapeutic anticoagulation [Quick's prothrombin value of 35 +/- 5%]) and pioglitazone (45 mg daily for 7 days) resulted in changes of 3% or less in AUC and peak plasma concentration of R- or S-warfarin.

Pharmacokinetic interaction is unlikely with theophylline, a CYP1A2 substrate. Concomitant use of pioglitazone (45 mg daily for 7 days) and theophylline (400 mg twice daily for 7 days) did not appreciably alter (i.e., 5% or less change) AUC and peak plasma concentration of pioglitazone or theophylline.

Antidiabetic Agents

Potential pharmacodynamic interaction (risk of hypoglycemia) with insulin or oral hypoglycemic agents; reduction in the dose of the concomitant agent may be necessary.

Pharmacokinetic interaction with metformin or glipizide is unlikely. With concomitant use of pioglitazone (45 mg daily for 7 days) and glipizide (5 mg daily for 7 days), glipizide AUC and peak plasma concentration were reduced by 3 and 8%, respectively. Concomitant administration of pioglitazone (45 mg daily for 8 days) and metformin hydrochloride (single 1-g dose on day 8) resulted in reductions of 3 and 5% in metformin AUC and peak plasma concentration, respectively.

Digoxin

Concomitant therapy with digoxin (0.2 mg for 2 doses as a loading dose, then 0.25 mg daily for 7 days) and pioglitazone (45 mg daily for 7 days) resulted in increases of 15 and 17% in digoxin AUC and peak plasma concentration, respectively.

Fexofenadine

Concomitant administration of pioglitazone (45 mg daily for 7 days) and fexofenadine hydrochloride (60 mg twice daily for 7 days) resulted in an increase of 30 and 37% in fexofenadine AUC and peak plasma concentration, respectively; fexofenadine had no appreciable effect on pioglitazone pharmacokinetics.

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