ATC Class:A10BG03

VA Class:HS502

AHFS Class:

• Thiazolidinediones 68:20.28

Generic Name(s):

• Pioglitazone Hydrochloride

Chemical Name:

• (±)-5-[ p -[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione monohydrochloride

Molecular Formula:

• C₁₉H₂₀N₂O₃S•ClH

Pioglitazone is a thiazolidinedione (glitazone) antidiabetic agent that is structurally and pharmacologically related to troglitazone and rosiglitazone.1,8,9,1,12

Type 2 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.1,2,83 Pioglitazone also is used in fixed combination with glimepiride in patients with type 2 diabetes mellitus who are already receiving a thiazolidinedione and a sulfonylurea separately or who are inadequately controlled on a sulfonylurea or a thiazolidinedione alone.28 In patients whose hyperglycemia cannot be controlled with these other antidiabetic agents, pioglitazone should be added to, not substituted for, such antidiabetic therapy.13

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.698,704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

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.31,47,51 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).31 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.51 The incidence of serious heart failure was increased with pioglitazone therapy but without an associated increase in mortality.51 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 heart failure.1,19,31,41,47 Therefore, the potential risks and benefits of thiazolidinediones versus other second-line antidiabetic agents (sulfonylureas, insulin) should be carefully considered.43,47 (See Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that pioglitazone should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis because it will not be effective in treating these conditions.1,28,83

Pioglitazone Monotherapy

Efficacy as monotherapy for the management of type 2 diabetes mellitus was established in 3 controlled studies of 16-26 weeks' duration.1 Pioglitazone improved glycemic control as measured by fasting glucose and glycosylated hemoglobin (HbA_1c) concentrations.1

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).1,13 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.14 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.17 In a clinical trial in patients with type 2 diabetes mellitus poorly controlled (as determined by HbA_1c concentrations exceeding 7%) by metformin or sulfonylurea monotherapy, the combination of repaglinide and pioglitazone reduced fasting plasma glucose and HbA_1c concentrations compared with pioglitazone or repaglinide monotherapy. 17 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). 17

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.83 Efficacy and safety of pioglitazone in fixed combination with metformin were established in a 24-week, randomized clinical study in 600 patients with type 2 diabetes mellitus (mean baseline HbA_1c 8.7%) inadequately controlled with diet and exercise.83,89 Substantial improvements in fasting plasma glucose and HbA_1c were observed in patients receiving the fixed combination of pioglitazone and metformin compared with each individual component alone.83,89 Efficacy and safety of the fixed combination also have been established based on concurrent administration of the 2 agents given separately and extrapolations from clinical trials evaluating pioglitazone as add-on therapy to metformin.83 Bioequivalence has been demonstrated between the fixed combination of pioglitazone and metformin and each agent given concurrently.83

Pioglitazone also is used in fixed combination with glimepiride in patients with type 2 diabetes mellitus who are already receiving a thiazolidinedione and a sulfonylurea separately or who are inadequately controlled on a sulfonylurea or a thiazolidinedione alone.28 No clinical trials have been conducted evaluating the fixed combination of pioglitazone and glimepiride as second-line therapy in patients who are inadequately controlled on monotherapy with a sulfonylurea.28 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 have been extrapolated from clinical trials evaluating pioglitazone as add-on therapy to a sulfonylurea.28

General

Dosage should be carefully individualized based on patient response and tolerance.1,28,83 Hepatic function should be assessed before initiating pioglitazone therapy.1,28,83 (See Hepatic Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) Following initiation of pioglitazone therapy or dosage increases, patients should be carefully monitored for adverse effects related to fluid retention.1,83 (See Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Fasting plasma glucose (FPG) concentrations should be monitored periodically to determine the patient's response.1,28 Periodic glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) determinations also should be performed; HbA_1c is a better indicator of long-term glycemic control than fasting plasma glucose concentrations alone.1,28,83

Administration

Pioglitazone hydrochloride is administered orally once daily and can be taken without regard to meals.1 Pioglitazone in fixed combination with immediate-release metformin hydrochloride is administered once or twice daily with meals to reduce the GI effects of the metformin hydrochloride component.83 Pioglitazone in fixed combination with glimepiride is administered once daily with the first main meal.28

Dosage

Type 2 Diabetes Mellitus

Dosage of pioglitazone hydrochloride is expressed in terms of pioglitazone.1,28,83 Bioequivalence has been demonstrated between the fixed combination of pioglitazone and immediate-release metformin hydrochloride 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).83 Bioequivalence also has been demonstrated between the fixed combination of pioglitazone and glimepiride 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).28

Pioglitazone Monotherapy

The recommended initial dosage of pioglitazone as monotherapy in patients without congestive heart failure is 15 or 30 mg once daily; lower initial dosages should be used in patients with NYHA class I or II heart failure.1 (See Dosage: Special Populations.) If the response is inadequate, dosage may be increased in increments of 15 mg based on glycemic response as determined by HbA_1c up to the maximum recommended dosage of 45 mg daily.1

Combination Therapy with Other Oral Antidiabetic Agents or Insulin

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.1,83 Pioglitazone dosage should not exceed 45 mg daily.1,83

Should hypoglycemia occur during combination therapy with an insulin secretagogue (e.g., sulfonylurea), the dosage of the insulin secretagogue should be decreased.1,28 If hypoglycemia occurs in patients receiving pioglitazone alone or concomitantly with metformin hydrochloride or glimepiride 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.1,28,83 (See Hypoglycemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

When the commercially available fixed-combination preparation containing pioglitazone and immediate-release metformin hydrochloride is used, dosage of the fixed combination is based on the patient's existing dosages of pioglitazone and/or metformin hydrochloride and on usual initial dosages of these drugs, effectiveness, and tolerability.83 Metformin hydrochloride doses exceeding 2 g may be better tolerated when administered three times daily.83

The usual initial dosage of the fixed combination containing pioglitazone and immediate-release metformin hydrochloride is pioglitazone 15 mg/metformin hydrochloride 500 mg twice daily or pioglitazone 15 mg/metformin hydrochloride 850 mg once daily.83

When the commercially available preparation containing pioglitazone in fixed combination with immediate-release metformin hydrochloride is used to replace metformin monotherapy, the usual initial dosage is pioglitazone 15 mg/metformin hydrochloride 500 mg twice daily or pioglitazone 15 mg/metformin hydrochloride 850 mg once or twice daily depending on the patient's existing metformin hydrochloride dosage.83 The usual initial dosage of the fixed combination in patients currently receiving pioglitazone monotherapy is pioglitazone 15 mg/metformin hydrochloride 500 mg twice daily or pioglitazone 15 mg/metformin hydrochloride 850 mg once daily.83 When the fixed combination is used to replace therapy with separate tablets given concurrently, the dosage of the fixed combination is based on the patient's existing dosage of metformin and pioglitazone.83 Dosage should be titrated gradually after assessing adequacy of therapeutic response and tolerability, up to a maximum daily dosage of 45 mg of pioglitazone and 2.55 g of immediate-release metformin hydrochloride.83

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.83 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.83

The initial dosage of pioglitazone in fixed combination with glimepiride should be based on the patient's existing regimen with pioglitazone and/or a sulfonylurea.28 (See also Dosage: Special Populations.) When the commercially available preparation containing pioglitazone in fixed combination with glimepiride is used in patients inadequately controlled on glimepiride monotherapy, the usual initial dosage of the fixed combination is 30 mg of pioglitazone and 2 or 4 mg of glimepiride once daily with the first main meal.28 The usual initial dosage of the fixed combination in patients inadequately controlled on pioglitazone monotherapy is 30 mg of pioglitazone and 2 mg of glimepiride once daily.28 When the fixed combination is used to replace concurrent therapy as separate tablets, the dosage of the fixed combination should be as close as possible to the patient's existing dosage of glimepiride and pioglitazone.28 Therapy may be initiated with 2 or 4 mg of glimepiride and 30 mg of pioglitazone once daily.28 Following initiation of therapy with the fixed combination 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 and tolerability.28 For patients transferring from monotherapy with a sulfonylurea other than glimepiride or from 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.28 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, no longer commercially available in the US) to glimepiride in fixed combination with pioglitazone, it has been recommended that patients being transferred from such agents be monitored closely for the occurrence of hypoglycemia during the initial 1-2 weeks of the transition period.28

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.28

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 potent CYP2C8 inhibitors is 15 mg once daily.1 Patients receiving pioglitazone in fixed combination with glimepiride and a potent CYP2C8 inhibitor should be switched to therapy with the individual drug components administered separately because the minimum dose of pioglitazone in the fixed-combination preparation exceeds 15 mg.28 The maximum recommended dosage of pioglitazone in fixed combination with immediate-release metformin hydrochloride is pioglitazone 15 mg/metformin hydrochloride 850 mg once daily when used in combination with a potent CYP2C8 inhibitor.83

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.1,83 (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.1 Pioglitazone should be initiated with caution in patients with hepatic impairment.1 (See Hepatic Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) If the fixed combination of glimepiride and pioglitazone is considered for use in patients with hepatic impairment, the drug should be initiated and dosage increased with caution.28 Patients with hepatic impairment should be closely monitored for hypoglycemia during initiation and subsequent dosage adjustment of such combination therapy.28 The use of the fixed combination of metformin hydrochloride and pioglitazone is not recommended in patients with hepatic impairment.83

Renal Impairment

Pioglitazone dosage adjustment is not necessary in patients with renal impairment.1 Due to the risk of lactic acidosis with metformin hydrochloride therapy, the manufacturers state that the initiation of pioglitazone in fixed combination with metformin hydrochloride is not recommended in patients with an estimated glomerular filtration rate (eGFR) of 30-45 mL/minute per 1.73 m²; the benefits and risks of continuing the drug should be assessed in those with an eGFR in this range who are already receiving the drug.83 The manufacturers state that pioglitazone in fixed combination with metformin hydrochloride should not be used in patients with an eGFR of less than 30 mL/minute per 1.73 m².83 If the fixed combination of glimepiride and pioglitazone is considered for use in patients with renal impairment, the initial dosage, dose increments, and maintenance dosage of the drug should be conservative.28 Patients with renal impairment should be closely monitored for hypoglycemia during initiation and subsequent dosage adjustment of such combination therapy.28

Geriatric Patients

Pioglitazone dosage adjustment is not necessary for geriatric patients solely because of age.1 Pioglitazone in fixed combination with metformin hydrochloride should be used with caution in geriatric patients since aging is associated with reduced renal function.83 Initial and maintenance dosages of the fixed combination should be conservative and should be titrated carefully.83

As geriatric patients are particularly susceptible to hypoglycemia, the initial and maintenance dosages of pioglitazone in fixed combination with glimepiride should be conservative.28 Blood glucose concentrations of such patients should be closely monitored prior to and after initiation of therapy to avoid hypoglycemia.28

Debilitated or Malnourished Patients

Caution should be used when initiating and increasing the dosage of pioglitazone in fixed combination with glimepiride in patients who are debilitated or malnourished and in those with adrenal, pituitary, or hepatic impairment.28 Such patients are particularly susceptible to the hypoglycemic effect of glucose-lowering drugs.28,83

Patients with Heart Failure

The recommended initial dosage of pioglitazone in patients with New York Heart Association (NYHA) class I or II heart failure is 15 mg once daily.1 If subsequent dosage escalation is necessary, the dosage should be increased in increments of 15 mg up to a maximum dosage of 45 mg daily according to glycemic response based on HbA_1c.1 For patients with NYHA class I or II heart failure, the recommended initial dosage of the fixed combination containing pioglitazone and immediate-release metformin hydrochloride is pioglitazone 15 mg/metformin hydrochloride 500 mg or pioglitazone 15 mg/metformin hydrochloride 850 mg once daily.83 Following initiation of pioglitazone and any increase in dosage, patients should be monitored carefully for weight gain, edema, and other manifestations of congestive heart failure (CHF).1 Initiation of pioglitazone therapy in patients with more severe heart failure (NYHA class III or IV) is contraindicated.1,28,37,83 (See 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.28 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.28

Contraindications

Known serious hypersensitivity reaction to pioglitazone or any ingredient in the formulation.1

Initiation of therapy with pioglitazone is contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure.1,28,37,83 (See Heart Failure under Warnings/Precautions: Warnings, in Cautions.)

Warnings/Precautions

Warnings

Heart Failure

Thiazolidinediones, including pioglitazone, alone or in combination with other antidiabetic agents, can cause dose-related fluid retention, which may lead to or exacerbate heart failure.1,19,28,30,31,37,38,40,41,83 Use of thiazolidinediones is associated with an approximately twofold increased risk of heart failure.41,42,43,47,77 (See Edema under Warnings/Precautions: Warnings, in Cautions.) Fluid retention is most common when pioglitazone is used in combination with insulin.1,83 Patients should be observed for signs and symptoms of heart failure (e.g., dyspnea, rapid weight gain, edema, unexplained cough or fatigue), especially during initiation of therapy and dosage titration.1,19,28,37,40,83 If signs and symptoms of heart failure develop, the disorder should be managed according to current standards of care.1,19,28,37,40,83 In addition, a decrease in the dosage or discontinuance of pioglitazone must be considered in such patients.1,19,28,37,40,83

Patients with NYHA class III or IV cardiac status with or without congestive heart failure (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.1,28,30,32,33,37,83 Use of pioglitazone is not recommended in patients with symptomatic heart failure.1,28,30,32,33,44,83 Caution should be exercised in patients with edema and in those who are at risk for heart failure.1,19,28,83 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.34

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).41 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%).41 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.41

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).1,28,83

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.1 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).1,28,83 Patients who were older than 64 years of age or receiving insulin at study entry were particularly susceptible to this adverse event.1,28 No differences in cardiovascular mortality were noted between pioglitazone and glyburide therapy.1,28,83

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.1,28,31,37,38,83 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.1,28,31,37,38,83

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.1,13,19,28,83 Diuretic therapy may be necessary for management of fluid retention.19 Caution should be exercised in patients with edema and those at risk for CHF.1,28,83 (See 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.1,19,83 Other potential causes of edema should be excluded.19 Pioglitazone-induced edema is reversible when the drug is discontinued.1 Hospitalization for edema usually is not required unless there is coexisting CHF.1,28,83

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).1,19,83 Unusually rapid increases in weight and increases in excess of that usually observed in clinical trials have been reported during postmarketing experience.1,83 Patients who experience rapid or excessive weight gain should be assessed for fluid accumulation and volume-related events such as excessive edema and CHF.1,83

Other Warnings/Precautions

Hepatic Effects

No evidence of drug-induced hepatotoxicity has been noted with pioglitazone in the controlled clinical trial database to date.1,12,13,28,83 However, hepatic failure with or without fatalities has been reported during postmarketing experience with the drug, although insufficient information is available to establish a cause.1,15,28,83 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.1,28,83 Liver function tests (serum ALT and AST, alkaline phosphatase, total bilirubin) should be obtained prior to initiation of pioglitazone therapy.1,28,83 If results of such tests are abnormal, pioglitazone therapy should be initiated with caution.1,28,83

Development of manifestations suggestive of hepatic dysfunction (e.g., right upper abdominal discomfort, fatigue, anorexia, dark urine, jaundice) should lead to prompt rechecking of liver function.1,28,83 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; the drug should not be restarted in such patients without another explanation for the liver test abnormalities.1,12,28,83 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.1,28,83 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.1,28,83

Musculoskeletal Effects

Thiazolidinedione use is associated with bone loss and fractures in women and possibly in men with type 2 diabetes mellitus.1,29,35,36,39,47,50 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),1,31,37,38 5.1 or 2.5% of women receiving pioglitazone or placebo, respectively, experienced a fracture.1,28,83 Such effects were noted after the first year of treatment and persisted throughout the study.1,28,30,32,33,83 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).1,28,29,83 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.50 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.50

Risk of fracture should be considered when initiating or continuing thiazolidinedione therapy, particularly in female patients.1,29,35 Bone health should be assessed and maintained according to current standards of care.1,28,30,32,33,35,83

Risk of Bladder Cancer

Although the results of various clinical studies evaluating the association of pioglitazone use and bladder cancer have varied, overall findings from studies in animals and humans suggest that pioglitazone therapy may be associated with an increased risk of bladder cancer.1,28,78,79,80,82,83,87 There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.1,28,83

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.1,28,78,83 In addition, results from two 3-year controlled clinical studies of pioglitazone1,28,83 (the PROACTIVE study31 and a liver safety study) demonstrated a higher percentage of bladder cancer cases in patients receiving pioglitazone versus comparator drugs.1,28,78,83 However, an increased risk of bladder cancer was not observed when patients who completed the PROACTIVE study were observed for an additional 10 years, with minimal exposure to pioglitazone.1,28,82,83,85

A 10-year epidemiologic study conducted by the manufacturer concluded that there was no statistically significant association overall between pioglitazone exposure and bladder cancer.1,28,82,83,86 However, there was a slight trend towards higher risk of bladder cancer with increasing duration of pioglitazone use.82 The median duration of therapy among pioglitazone-treated patients in this study was 2.8 years (range 0.2-13.2 years).86 In addition, results of a 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.80 This cohort study 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.80 Similarly, another retrospective cohort study involving more than 145,000 patients found a 63% increase in the rate of bladder cancer with pioglitazone therapy and no increased risk with rosiglitazone therapy.1,28,82,83,87 A duration-response and dose-response relationship also was evident in this study; substantial increases in the risk of bladder cancer were observed with increasing cumulative duration of use and cumulative dose of pioglitazone.82,87

The manufacturer and FDA 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.1,28,80,82,83 Patients who are concerned about the possible risks associated with using pioglitazone should be advised to consult their healthcare professional.1,80

Hypoglycemia

Concomitant therapy with pioglitazone and insulin or other antidiabetic drugs (particularly insulin secretagogues such as sulfonylureas) increases the risk for hypoglycemia.1,28,83 A reduced dosage of the concomitant antidiabetic agent may be needed to decrease the risk of hypoglycemia.1,28,83 (See Combination Therapy with Other Oral Antidiabetic Agents or Insulin under Dosage and Administration: Dosage.) Hypoglycemia can also occur when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplement.83 Hypoglycemia may be difficult to recognize in geriatric patients and in individuals taking β-adrenergic blocking drugs.83

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; most patients had concurrent peripheral edema.1,28,32,33,83 Some patients with macular edema presented with symptoms of blurred vision or decreased visual acuity, but other cases were detected by routine ophthalmologic examination.1,28,32,33,83 Symptoms improved in some patients following discontinuance of pioglitazone.1,28,32,33,83 Patients with diabetes mellitus should have regular eye examinations by an ophthalmologist according to current standards of care.1,28,32,33,34,83 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.1,28,32,33,83

Ovulatory Effects

Like other thiazolidinediones, pioglitazone may promote ovulation in some premenopausal anovulatory women.1,83 Premenopausal women receiving pioglitazone should be advised of the potential for an unintended pregnancy.1,28,83

Macrovascular Outcomes

Evidence of macrovascular risk reduction with pioglitazone has not been conclusively demonstrated in controlled clinical trials.1

Laboratory Abnormalities

Dose-related decreases in hemoglobin and hematocrit usually becomes evident 4-12 weeks after initiation of therapy and values remain stable thereafter.1,13,28,83 These effects may be related to plasma volume expansion and have rarely been associated with clinically important hematologic manifestations.1,28,83

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.1 Such elevations resolved in most patients without apparent sequelae despite continued therapy; any relationship to pioglitazone therapy is unknown.1

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.28,83

Specific Populations

Pregnancy

Data are lacking on the use of pioglitazone in pregnant women.1,28,83 Blood glucose abnormalities during pregnancy are associated with an increased incidence of congenital anomalies and neonatal morbidity and mortality.1,28,83 In reproduction studies in rats and rabbits, pioglitazone administered during organogenesis at exposures up to 5 and 35 times the maximum recommended human dose, respectively, was not associated with adverse developmental effects.1,28,83 However, delayed parturition and reduced embryofetal viability were observed with pioglitazone dosages at least 9 times the maximum recommended human dose.1,28,83 Offspring of pregnant rats who were administered pioglitazone at dosages at least 2 times the maximum recommended human dose during late gestation and lactation had delayed postnatal development attributed to decreased body weight.1,28,83

Lactation

Pioglitazone is distributed into milk in rats; it is unknown whether pioglitazone is distributed into human milk.1,28,83 The benefits of breast-feeding should be weighed against the potential risk of adverse effects on the breast-fed infant from pioglitazone.1,28,83

Pediatric Use

Safety and efficacy of pioglitazone have not been established in children1 or adolescents younger than 18 years of a 13 use in this age group currently is not recommended by the manufacturer because of adverse effects observed in adults (e.g., fluid retention and heart failure, fractures, urinary bladder tumors).1,28,83 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.16

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.1,28,83 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.1,83

Hepatic Impairment

Pioglitazone therapy should be initiated with caution in patients with abnormal liver function test results.1 Pioglitazone therapy should be interrupted if ALT exceeds 3 times the upper limit of normal and the cause of liver test abnormalities should be investigated.1 (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,1 headache,1 sinusitis,1 myalgia,1 pharyngitis,1 and edema.1 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.1 Pioglitazone-induced reductions in hyperglycemia are associated with mild weight gain.13,83

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or Inducers of CYP3A4

Potential pharmacokinetic interaction with inhibitors or inducers of cytochrome P-450 (CYP) isoenzyme 3A4.1

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.1,13,28,83

Concomitant use of ranitidine (150 mg twice daily for 4 days), a relatively weak CYP3A4 inhibitor,1,25,83 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.1,28,83

CYP3A4 Substrates

Pioglitazone is a weak inducer of CYP3A4.1,22 Potential pharmacokinetic interaction (reduction in peak plasma concentration and AUC) with CYP3A4 substrates (e.g., atorvastatin, midazolam, ethinyl estradiol, nifedipine).1,21,22,23,28,83

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.1,28,83

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%.1,28,83

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).1,28,83

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.1,28,83 The clinical importance of these changes is unknown.1

Inhibitors or Inducers of CYP2C8

Pioglitazone is a CYP2C8 substrate; potential pharmacokinetic interaction with inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampin) of CYP2C8.1,28,83 Adjustments in pioglitazone dosage may be needed during initiation or discontinuance of an inhibitor or inducer of CYP2C8.1 (See Concomitant Therapy with Potent CYP2C8 Inhibitors or Inducers under Dosage and Administration: Dosage.)

Concomitant use of pioglitazone (single 15-mg dose) and gemfibrozil (600 mg twice daily for 2 days) resulted in a 3.2-fold increase in AUC of pioglitazone and a 6% increase in pioglitazone peak plasma concentration; half-life of pioglitazone also increased from 8.3 to 22.7 hours.1,28,83

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.1,28,83

CYP2C9 or CYP1A2 Substrates

Pharmacokinetic interaction is unlikely with CYP2C9 substrates (e.g., warfarin).20,21,24 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.1,28,83

Pharmacokinetic interaction is unlikely with theophylline, a CYP1A2 substrate.1,25 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.1,28,83

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.1,28,83

Pharmacokinetic interaction with metformin or glipizide is unlikely.1 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.1,28,83 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.1,28,83

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.1,83

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;1 fexofenadine had no appreciable effect on pioglitazone pharmacokinetics.1,28,83

Topiramate

Concomitant administration of pioglitazone (30 mg daily for 7 days) and topiramate (96 mg twice daily for 7 days) resulted in a 15% decrease in the AUC of pioglitazone; in addition, AUC of its M-III (keto derivative) and M-IV (hydroxyl derivative) active metabolites was decreased by 60 and 16%, respectively.1,28,83 Although the clinical relevance of this decrease is unknown, patients receiving pioglitazone and topiramate concomitantly should be monitored for adequate glycemic control.1,28,83

Description

Pioglitazone is a thiazolidinedione (glitazone) antidiabetic agent that is structurally and pharmacologically related to troglitazone and rosiglitazone1,8,9,12 but unrelated to other antidiabetic agents, including sulfonylureas, biguanides, and α-glucosidase inhibitors.12

Pioglitazone acts principally by increasing insulin sensitivity in target tissues, as well as decreasing hepatic gluconeogenesis.1,88 Pioglitazone is a peroxisome proliferator-activated receptor_γ (PPAR_γ) agonist that increases transcription of insulin-responsive genes and increases insulin sensitivity.1,88 Pioglitazone, like other thiazolidinediones, ameliorates insulin resistance associated with type 2 diabetes mellitus without stimulating insulin release from pancreatic β cells, thus avoiding the risk of hypoglycemia.1,88 Because pioglitazone does not lower glucose concentrations below euglycemia,1 the drug is appropriately referred to as an antidiabetic agent rather than a hypoglycemic agent. Some evidence suggests that the glucoregulatory effects of thiazolidinediones are mediated in part via enhanced hepatic and peripheral glucose uptake2,10 and reduced systemic and tissue lipid availability.1,3

Following oral administration of pioglitazone, peak plasma concentrations are achieved within 2 hours.1,28 Food delays time to peak concentrations to 3-4 hours but does not alter AUC.1,28 Pioglitazone is extensively metabolized via hydroxylation and oxidation,1 principally via the cytochrome P-450 (CYP) 2C8 and CYP3A4 isoenzymes,1,28,83 with involvement of several other isoforms, including CYP1A1 (mainly an extrahepatic isoenzyme).1,28,83 The major circulating active metabolites of pioglitazone are M-III (keto derivative) and M-IV (hydroxyl derivative).1,28,83

Advice to Patients

When pioglitazone is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).1,28,83

Importance of reading medication guide provided by the manufacturer before starting pioglitazone and each time prescription is refilled.1

Importance of informing patients of potential risks and advantages of therapy and of alternative therapies.28

Discuss potential for alterations in dosage requirements during periods of stress (e.g., fever, trauma, infection, surgery); importance of contacting a clinician promptly.1,28,83

Importance of informing patients that pioglitazone must not be used in patients with severe heart failure (NYHA class III or IV).1,28,83 Importance of identifying and reporting to clinicians potential symptoms of heart failure, such as unusually rapid increase in weight, edema (especially in ankles or legs), unusual fatigue, trouble breathing, or shortness of breath (especially when lying down).1,28,83

Importance of immediate reporting of potential manifestations of hepatotoxicity (e.g., unexplained nausea or vomiting, abdominal pain, fatigue, loss of appetite, or dark urine, yellowing of skin or whites of eyes).1,28,83

Increased risk of bladder cancer with pioglitazone therapy.1,28,82,83 Importance of patient not taking pioglitazone if receiving treatment for bladder cancer.1,28 Importance of patient reporting any sign of macroscopic hematuria or symptoms such as dysuria or urinary urgency that develop or increase during pioglitazone treatment.1,28,82,83

Importance of taking exactly as prescribed.1,28,83 If a dose is missed on one day, take the next dose as prescribed unless otherwise instructed by your clinician; do not double the dose to make up for the missed dose.1,28,83 Importance of changing dosage only under medical supervision.28,83 Importance of immediately contacting a clinician if accidental overdosage occurs.83

Risk of hypoglycemia in patients receiving concomitant insulin or other antidiabetic therapy.1,28,83 Provide instructions to patients and responsible family members regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.1,28,83

Risk of pregnancy in premenopausal anovulatory women.1,28,83

Importance of diet and exercise regimen adherence.1,83 Importance of regular monitoring (preferably self-monitoring) of blood glucose and of glycosylated hemoglobin (HbA_1c) concentrations.1,28,83

Risk of fractures (e.g., hand, upper arm, foot) in women.1,50

Importance of regular eye examinations.1 Importance of reporting changes in vision.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1,28,83

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1,28,83

Importance of informing patients of other important precautionary information.1,28,83 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Takeda Pharmaceuticals America. Actos^® (pioglitazone hydrochloride) tablets prescribing information. Deerfield, IL; 2020 Jun.

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3. Berger J, Bailey P, Biswas C et al. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-γ: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology . 1996; 137:4189-95. [PubMed 8828476]

8. Young PW, Buckle DR, Cantello BC et al. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisonal proliferator-activated receptor gamma. J Pharmacol Exp Ther . 1998; 284:751-9. [PubMed 9454824]

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13. Takeda Pharmaceuticals North America, Indianapolis, IN: Personal communication.

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