Brand names: Actos, ActoPlus Met (combination), ActoPlus Met XR (combination), Duetact (combination)
Drug class: Thiazolidinediones
ATC class: A10BG03
VA class: HS502
Chemical name: (±)-5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione monohydrochloride
Molecular formula: C₁₉H₂₀N₂O₃S•ClH
CAS number: 112529-15-4

Medically reviewed by Drugs.com on Jun 12, 2023. Written by ASHP.

Introduction

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

Uses for Pioglitazone

Type 2 Diabetes Mellitus

Used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{1 2 14 28 83} Should be added to, not substituted for, other antidiabetic agents in patients whose type 2 diabetes mellitus is not adequately controlled by these agents.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}

In patients with metformin contraindications or intolerance (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}

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target).^{698 704} In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.^{698 704}

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.⁷⁰⁴

For patients with inadequate glycemic control on metformin monotherapy, consider 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 preferences when selecting additional antidiabetic agents for combination therapy.^{698 699 704 705 706}

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.^{698 704}

Not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.^{1 28 83}

Related/similar drugs

metformin, Trulicity, Lantus, Tresiba, Victoza, Levemir

Pioglitazone Dosage and Administration

Administration

Oral Administration

Administer pioglitazone once daily without regard to meals.¹

Administer fixed combination of pioglitazone and immediate-release metformin hydrochloride once or twice daily with meals to reduce the GI effects of metformin component.⁸³

Administer fixed combination of pioglitazone and glimepiride once daily with the first main meal.²⁸

Dosage

Available as pioglitazone hydrochloride; dosage expressed in terms of pioglitazone.¹

If hypoglycemia occurs during combination therapy with an insulin secretagogue (e.g., sulfonylurea), decrease dosage of the insulin secretagogue.^{1 28} If hypoglycemia occurs with concomitant pioglitazone and insulin therapy, reduce dosage of insulin by 10–25%; further adjustments to insulin dosage should be individualized according to glycemic response.^{1 28}

Initiation or discontinuance of a CYP2C8 inducer during pioglitazone therapy may necessitate changes in antidiabetic therapy.¹ (See Interactions.)

If a potent CYP2C8 inhibitor is used concomitantly, reduction of the maximum daily pioglitazone dosage is recommended.¹ (See Interactions.)

Adults

Type 2 Diabetes Mellitus

Monotherapy

Oral

Initially, 15 or 30 mg once daily in patients without congestive heart failure; use lower initial dosages in patients with NYHA class I or II heart failure.¹ (See Patients with Heart Failure under Dosage.) If response inadequate, increase dosage in increments of 15 mg based on glycemic response as determined by HbA_1c up to maximum of 45 mg daily.¹

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Base initial dosage of fixed combination on patient's existing dosage of pioglitazone and/or immediate-release metformin hydrochloride and on usual initial dosages of these drugs, effectiveness, and tolerability.⁸³

Initially, pioglitazone 15 mg/metformin hydrochloride 500 mg twice daily or pioglitazone 15 mg/metformin hydrochloride 850 mg once daily.⁸³

Patients receiving metformin hydrochloride monotherapy: Initially, 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 dosage.⁸³

Patients receiving pioglitazone monotherapy: Initially, pioglitazone 15 mg/metformin hydrochloride 500 mg twice daily or pioglitazone 15 mg/metformin hydrochloride 850 mg once daily.⁸³

Patients switching from combined therapy with separate pioglitazone and metformin preparations: Usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.⁸³

Gradually titrate dosage based on adequacy of therapeutic response and tolerability.⁸³

Pioglitazone/Glimepiride Fixed-combination Therapy

Oral

Base initial dosage of fixed combination on patient's existing dosage of pioglitazone and/or sulfonylurea (e.g., glimepiride).²⁸ (See Patients with Heart Failure under Dosage.)

Patients receiving glimepiride monotherapy: Initially, 30 mg of pioglitazone and 2 or 4 mg of glimepiride once daily.²⁸

Patients receiving pioglitazone monotherapy: Initially, 30 mg of pioglitazone and 2 mg of glimepiride once daily.²⁸

Patients switching from combined therapy with separate pioglitazone and glimepiride preparations: Usual initial dosage of the fixed combination is as close as possible to the patient's existing dosage of the individual drugs.²⁸ When switching to the fixed combination, carefully monitor patients with inadequate glycemic control on pioglitazone 15 mg daily in combination with glimepiride.²⁸

Patients switching from monotherapy with a sulfonylurea other than glimepiride (e.g., glyburide, glipizide, tolbutamide) or from combined therapy with pioglitazone plus a sulfonylurea other than glimepiride: Initially, 30 mg of pioglitazone and 2 mg of glimepiride once daily.²⁸ Observe patients for hypoglycemia for 1–2 weeks following transition from a sulfonylurea with a prolonged half-life (e.g., chlorpropamide [no longer commercially available in the US]) due to potential overlapping hypoglycemic effect.²⁸

Gradually titrate dosage based on adequacy of therapeutic response and tolerability.²⁸

Prescribing Limits

Adults

Type 2 Diabetes Mellitus

Oral

Maximum 45 mg daily (as monotherapy or in combination with a sulfonylurea, metformin, or insulin).^{1 28 83}

Special Populations

Hepatic Impairment

Monotherapy

No dosage adjustment necessary; initiate with caution in hepatic impairment.^{1 28 83} (See Hepatic Effects under Cautions.)¹

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Not recommended in patients with hepatic impairment.⁸³

Pioglitazone/Glimepiride Fixed-combination Therapy

Use caution when initiating and increasing dosage of pioglitazone in fixed combination with glimepiride; individuals with hepatic impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.²⁸

Renal Impairment

Monotherapy

No dosage adjustment necessary.¹

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

eGFR 30–45 mL/minute per 1.73 m²: Do not initiate; assess benefits and risks of continued treatment in patients already receiving pioglitazone in fixed combination with immediate-release metformin hydrochloride.⁸³

eGFR <30 mL/minute per 1.73 m²: Use contraindicated; discontinue in patients already receiving pioglitazone in fixed combination with immediate-release metformin.⁸³

Pioglitazone/Glimepiride Fixed-combination Therapy

Use caution when initiating and increasing dosage of pioglitazone in fixed combination with glimepiride; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.²⁸

Geriatric Patients

Monotherapy

No dosage adjustment necessary.¹

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Conservative initial and maintenance dosages recommended; geriatric individuals are particularly sensitive to hypoglycemic effects.⁸³

Pioglitazone/Glimepiride Fixed-combination Therapy

Conservative initial and maintenance dosages recommended; geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.²⁸

Patients with Heart Failure

NYHA class III or IV heart failure: Use contraindicated.^{1 28 83}

Monotherapy

NYHA class I or II heart failure: Initially, 15 mg once daily.¹ Increase dosage, if needed, up to maximum of 45 mg daily based on HbA_1c concentrations.¹ Monitor carefully for weight gain, edema, or other manifestations of heart failure exacerbation following initiation and dosage increase.¹

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

NYHA class I or II heart failure: Initially, pioglitazone 15 mg/immediate-release metformin hydrochloride 500 mg or pioglitazone 15 mg/immediate-release metformin hydrochloride 850 mg once daily.⁸³ Monitor carefully for weight gain, edema, or other manifestations of heart failure exacerbation following initiation and dosage increase.⁸³

Pioglitazone/Glimepiride Fixed-combination Therapy

Systolic dysfunction: Initially, pioglitazone 15 mg once daily as monotherapy; safely titrate dosage to 30 mg once daily as monotherapy before initiating the fixed combination of glimepiride 2 mg and pioglitazone 30 mg.²⁸ If subsequent dosage adjustment is necessary with the fixed-combination preparation, monitor closely for weight gain, edema, or other manifestations of heart failure exacerbation.²⁸

Debilitated or Malnourished Patients

Pioglitazone/Glimepiride Fixed-combination Therapy

Use caution when initiating or increasing dosage; these individuals are particularly susceptible to hypoglycemic effects.^{28 83}

Patients with Adrenal or Pituitary Insufficiency

Pioglitazone/Glimepiride Fixed-combination Therapy

Use caution when initiating or increasing dosage; these individuals are particularly susceptible to hypoglycemic effects.²⁸

Cautions for Pioglitazone

Contraindications

• Initiation of therapy in patients with NYHA class III or IV heart failure.^{1 28 83} (See Boxed Warning.)

• Known serious¹ hypersensitivity to pioglitazone or any ingredient in the formulation.^{1 28 83}

Warnings/Precautions

Warnings

Heart Failure

Dose-related fluid retention associated with use of pioglitazone, alone or in combination with other antidiabetic agents, may lead to or exacerbate heart failure.^{1 19 28 30 31 37 38 40 41 83} (See Boxed Warning.) Fluid retention most common when used in combination with insulin.¹

Monitor 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 heart failure develops, manage according to current standards of care.^{1 19 28 37 40 83} Consider dosage reduction or discontinuance of pioglitazone.^{1 19 28 37 40 83}

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

Edema

Fluid retention reported; may lead to or exacerbate heart failure.^{1 13}

Use with caution in patients with edema and in those at risk for heart failure.^{1 28 83} Observe for manifestations of heart failure (e.g., dyspnea, rapid weight gain, edema).¹ (See Heart Failure under Cautions.)

Weight Gain

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

Other Warnings/Precautions

Hepatic Effects

No evidence of drug-induced hepatotoxicity in controlled clinical trial database to date.^{1 12 13 28 83} However, hepatic failure with or without fatalities reported during postmarketing experience.^{1 28 83}

Obtain liver function tests (serum ALT and AST, alkaline phosphatase, total bilirubin) and assess patient prior to initiation of therapy; if tests abnormal, initiate pioglitazone with caution.^{1 28 83} (See Hepatic Impairment under Cautions.)

Recheck liver function promptly if manifestations suggestive of hepatic dysfunction (e.g., right upper abdominal discomfort, fatigue, anorexia, dark urine, jaundice) occur.¹ Interrupt therapy if ALT is >3 times the upper limit of normal (ULN) in patients with symptoms of liver injury; do not restart drug in patients without another explanation for liver test abnormalities.¹ Patients with serum ALT >3 times the reference range and serum total bilirubin >2 times the reference range without alternative etiologies are at risk for severe drug-induced liver injury; do not restart drug in such patients.^{1 28 83} May use pioglitazone 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

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

Fractures reported more frequently in women receiving pioglitazone (5.1%) than in women receiving placebo (2.5%) in long-term study (mean 34.5 months follow-up).^{1 28 30 32 33 83} Effects noted after first year of treatment and persisted throughout treatment.^{1 28 30 32 33 83} Most fractures were nonvertebral, occurring in a distal limb (forearm, hand, wrist, foot, ankle, fibula, tibia).^{1 28 29 83}

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

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

Risk of Bladder Cancer

Increased risk of bladder cancer.^{1 28 78 79 80 82 83 87} Do not use in patients with active bladder cancer; use with caution in patients with history of bladder cancer, weighing benefits of glycemic control against unknown risks of cancer recurrence.^{1 28 80 82 83}

Hypoglycemia

Concomitant use of insulin or other antidiabetic drugs (e.g., insulin secretagogues) increases risk for hypoglycemia.^{1 28 83} May need to reduce dosage of concomitant antidiabetic agent to decrease risk of hypoglycemia.^{1 28 83} (See Dosage under Dosage and Administration.)

Ocular Effects

New-onset or worsening (diabetic) macular edema with decreased visual acuity reported rarely; concurrent peripheral edema reported frequently.^{1 28 32 33 83} Symptoms improved in some patients following discontinuance of pioglitazone.^{1 28 32 33 83}

Regular eye examinations by ophthalmologist advised.^{1 28 32 33 34 83} Promptly refer patients reporting visual symptoms to ophthalmologist, regardless of other concurrent therapy or physical findings.^{1 28 32 33 83}

Ovulatory Effects

May cause ovulation in premenopausal anovulatory women; advise women 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

Possible dose-related decreases in hemoglobin and hematocrit; usually evident within 4–12 weeks of therapy.^{1 13 28 83} May be related to plasma volume expansion.^{1 28 83} Rarely associated with clinically important hematologic manifestations.^{1 28 83}

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

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride or glimepiride, consider the cautions, precautions, and contraindications associated with the concomitant agent.^{28 83}

Specific Populations

Pregnancy

Data are lacking on use of pioglitazone in pregnant women.^{1 28 83} No adverse developmental effects observed in animal reproduction studies; however, delayed postnatal development (attributed to decreased body weight), delayed parturition, and reduced embryofetal viability were observed.^{1 28 83}

Blood glucose abnormalities during pregnancy are associated with increased incidence of congenital anomalies and neonatal morbidity and mortality.^{1 28 83}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 28 83} Weigh the benefits of breast-feeding against the potential risk of adverse effects on the breast-fed infant from pioglitazone.^{1 28 83}

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age; use not recommended.^{1 13 28 83}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.^{1 28 83}

Hepatic Impairment

Initiate with caution in patients with abnormal liver function test results.¹ Interrupt pioglitazone therapy if ALT >3 times the ULN and investigate the cause of liver test abnormalities.¹ (See Hepatic Effects under Cautions.)

Common Adverse Effects

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

Drug Interactions

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).¹ Weak inducer of CYP3A4.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2C8 inhibitors: Increased pioglitazone AUC and half-life; do not exceed maximum pioglitazone dosage of 15 mg once daily.¹

CYP2C8 inducers: Decreased pioglitazone AUC.¹ Initiation or discontinuance of a CYP2C8 inducer during pioglitazone therapy may necessitate changes in antidiabetic therapy; however, do not exceed maximum recommended pioglitazone dosage of 45 mg daily.¹

Specific Drugs

Pioglitazone Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations attained within 2 hours.^{1 28}

Absolute bioavailability is 83%.⁸¹

Food

Food delays time to peak serum concentration to 3–4 hours but does not affect extent of absorption.^{1 28}

Special Populations

In patients with hepatic impairment (Child-Pugh class B or C), peak pioglitazone concentration is decreased by 45%.¹

In geriatric patients, AUC of pioglitazone is increased; not clinically relevant.¹

In females, peak serum concentration and AUC are increased by 20–60%.¹

Distribution

Extent

Distributed into milk in rats.¹ Not known whether the drug distributes into human milk.¹

Plasma Protein Binding

>99% (mainly albumin).¹

Elimination

Metabolism

Extensively metabolized via hydroxylation and oxidation, principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).¹ Major circulating active metabolites are M-III (keto derivative) and M-IV (hydroxyl derivative).^{1 28 83}

Elimination Route

Excreted in urine (15–30%) and in feces, primarily as metabolites.¹

Half-life

3–7 hours (for pioglitazone) or 16–24 hours (for pioglitazone and metabolites).¹

Special Populations

In geriatric patients, terminal half-life is prolonged; not clinically relevant.¹

Stability

Storage

Oral

Tablets

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

Actions

• Structurally and pharmacologically related to rosiglitazone and troglitazone (no longer commercially available in the US);^{1 8 9 1 12} unrelated to other antidiabetic agents (e.g., sulfonylureas, biguanides, α-glucosidase inhibitors).^{1 12}

• A peroxisome proliferator-activated receptor_γ (PPAR_γ) agonist; increases transcription of insulin-responsive genes.^{1 88}

• Increases insulin sensitivity in target tissues and decreases hepatic gluconeogenesis.^{1 88} Ameliorates insulin resistance associated with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells.^{1 88} Does not lower glucose concentrations below euglycemia.¹

• Ineffective in absence of insulin.¹

• 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 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 immediately informing clinician if potential manifestations of heart failure (e.g., rapid weight gain, edema, unusual fatigue, trouble breathing, shortness of breath) occur.^{1 28 83}

• Advise patients to inform clinician if potential manifestations of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, yellowing of skin or whites of eyes) occur.^{1 28 83}

• Increased risk of bladder cancer.^{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 clinician; do not double the dose to make up for the missed dose.^{1 28 83} Importance of changing dosage with caution and 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 adhering to diet and exercise regimen.¹ Importance of regular monitoring (preferably self-monitoring) of blood glucose and of HbA_1c.¹

• 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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