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Pioglitazone

Pronunciation

Pronunciation

(pye oh GLI ta zone)

Index Terms

  • Pioglitazone HCl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Actos: 15 mg, 30 mg, 45 mg

Generic: 15 mg, 30 mg, 45 mg

Brand Names: U.S.

  • Actos

Pharmacologic Category

  • Antidiabetic Agent, Thiazolidinedione

Pharmacology

Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Distribution

Vd (apparent): 0.63 ± 0.41 L/kg

Metabolism

Hepatic (99%) via CYP2C8 and 3A4 to active and inactive metabolites; M-III and M-IV are major circulating active metabolites

Excretion

Urine (15% to 30%) and feces as metabolites

Onset of Action

Delayed; Peak effect: Glucose control: Several weeks

Time to Peak

~2 hours; delayed with food

Half-Life Elimination

Parent drug: 3 to 7 hours; M-III and M-IV metabolites: 16 to 24 hours

Protein Binding

Pioglitazone >99% and active metabolites >98%; primarily to albumin

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus

Contraindications

Hypersensitivity to pioglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy)

Canadian labeling: Additional contraindications (not is U.S. labeling): Any stage of heart failure (eg, NYHA Class I, II, III, IV); serious hepatic impairment; active bladder cancer; history of bladder cancer; uninvestigated macroscopic hematuria; pregnancy

Dosing: Adult

Diabetes mellitus, type 2: Oral:

Initial: 15 to 30 mg once daily; patients with heart failure (NYHA Class I or II) should initiate therapy with 15 mg once daily. Note: Not recommended in patients with symptomatic heart failure

Dosage titration: Based on HbA1c, the dosage may be increased in 15 mg increments up to a maximum of 45 mg once daily; monitor closely during titration for adverse effects (eg, weight gain, edema, signs/symptoms of heart failure)

Dosage adjustment for hypoglycemia with combination therapy:

With an insulin secretagogue (eg, sulfonylurea): Decrease the insulin secretagogue dose.

With insulin: Decrease insulin dose by 10% to 25%; individualize further adjustments per glycemic response

Dosage adjustment with strong CYP2C8 inhibitors (eg, gemfibrozil): Maximum recommended dose: 15 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Hepatic impairment prior to initiation: No dosage adjustment necessary; use with caution if baseline liver tests are abnormal

Hepatic impairment during therapy: If liver injury is suspected (eg, fatigue, jaundice, dark urine): Interrupt therapy, measure serum liver tests, and investigate possible etiologies:

If an alternative etiology is not identified and ALT >3 x ULN: Do not reinitiate therapy.

If an alternative etiology is identified and ALT elevated (but <3 x ULN) or total bilirubin elevated (but <2 x ULN): May reinitiate with caution.

Administration

Oral: May be administered without regard to meals

Dietary Considerations

Individualized medical nutrition therapy (MNT) is an integral part of therapy

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light, moisture, and humidity.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Clopidogrel: May increase the serum concentration of Pioglitazone. Monitor therapy

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Pioglitazone. Management: Limit pioglitazone adult maximum dose to 15 mg/day when used in combination with any strong CYP2C8 inhibitor. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Limit pioglitazone maximum adult dose to 15 mg/day, and consider dose reduction of rosiglitazone, when used in combination with gemfibrozil. Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: Pioglitazone may enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Lumacaftor: May increase the serum concentration of CYP2C8 Substrates. Lumacaftor may decrease the serum concentration of CYP2C8 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RifAMPin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Consider alternatives to the concomitant use of rifampin with thiazolidinedione antidiabetic agents. Monitor patients receiving these combinations for decreased effects of the thiazolidinedione derivative. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Selexipag. Management: If initiating selexipag in a patient on a moderate CYP2C8 inhibitor, consider a less frequent dosing regimen (ie, once daily). If initiating a moderate CYP2C8 inhibitor in a patient on selexipag, consider a selexipag dose reduction. Consider therapy modification

Sulfonylureas: Antidiabetic Agents (Thiazolidinedione) may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Trimethoprim: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

Adverse Reactions

Adverse reactions and incidences reported are associated with monotherapy unless otherwise stated.

>10%:

Cardiovascular: Edema (combination trials: ≤27%)

Endocrine and metabolic: Hypoglycemia (combination trials: ≤27%)

Respiratory: Upper respiratory tract infection (13%)

1% to 10%:

Cardiovascular: Cardiac failure (combination trials: ≤8%)

Central nervous system: Headache (9%)

Neuromuscular & skeletal: Bone fracture (females: ≤5%), myalgia (5%)

Respiratory: Sinusitis (6%), pharyngitis (5%)

Frequency not defined:

Endocrine & metabolic: Decreased serum triglycerides, increased HDL-cholesterol, weight gain, weight loss

Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin

<1% (Limited to important or life-threatening): Bladder carcinoma, blurred vision, decreased visual acuity, dyspnea (associated with weight gain and/or edema), hepatic failure (very rare), hepatitis, increased creatine phosphokinase, increased serum transaminases, macular edema (new-onset or worsening), pulmonary edema, rhabdomyolysis

ALERT: U.S. Boxed Warning

Congestive heart failure:

Thiazolidinediones, including pioglitazone, can cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of pioglitazone, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, manage the heart failure according to the current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered.

Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.

Warnings/Precautions

Concerns related to adverse effects:

• Bladder cancer: Clinical trial data is inconsistent regarding the risk of bladder cancer in patients exposed to pioglitazone. Given the uncertainty of the findings, the manufacturer recommends to avoid use in patients with active bladder cancer and consider risks vs. benefits prior to initiating therapy in patients with a history of bladder cancer.

• Edema: Dose-related edema, including new-onset or exacerbation of existing edema, has been reported; use with caution in patients with edema. Monitor for signs/symptoms of heart failure.

• Fractures: An increased incidence of bone fractures in females treated with pioglitazone has been observed; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if heart failure develops, treat accordingly and consider dose reduction or discontinuation of pioglitazone. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; if used in patients with NYHA class I or II (systolic) heart failure, initiate at lowest dosage and monitor closely.

• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume.

• Hepatic effects: Hepatic failure, including fatalities, has been reported. Monitor for signs/symptoms of liver injury closely during therapy; discontinuation of therapy may be necessary.

• Hypoglycemia: The risk of hypoglycemia is increased when pioglitazone is combined with insulin or other diabetic medications; dosage adjustment of concomitant hypoglycemic agents may be necessary.

• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Diabetes, type 1: Mechanism requires the presence of insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended.

• Hepatic impairment: Due to the possible risk of drug-induced liver injury, serum liver function tests (ALT, AST, alkaline phosphatase, and total bilirubin) should be obtained prior to initiation in all patients. In patients with abnormal hepatic tests, therapy should be initiated with caution. During therapy, if signs/symptoms of liver injury (eg, fatigue, anorexia, jaundice, dark urine, right upper abdominal discomfort) arise, interrupt pioglitazone therapy, obtain liver tests immediately and evaluate alternative etiologies. If an alternative etiology is not identified and serum ALT is >3 times ULN, do not resume therapy. Patients with serum ALT >3 times ULN and serum total bilirubin >2 times ULN are at risk for severe drug-induced liver injury.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016b]), serum glucose.

Liver enzymes (ALT, AST, alkaline phosphatase, and total bilirubin) prior to initiation in all patients (with or without liver disease); continue routine periodic monitoring during treatment only in patients with liver disease or suspected liver disease.

Signs and symptoms of fluid retention or heart failure; weight gain; signs/symptoms of bladder cancer (dysuria, macroscopic hematuria, dysuria, urinary urgency); ophthalmic exams

Pregnancy Considerations

Information related to the use of pioglitazone in pregnant women is limited (Glueck 2003; Ortega-Gonzalez 2005; Ota 2008). Thiazolidinediones may cause ovulation in anovulatory premenopausal women, increasing the risk of unintended pregnancy.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008).

Agents other than pioglitazone are currently recommended to treat diabetes in pregnant women (ADA 2017c).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, common cold symptoms, sinus pain, pharyngitis, muscle pain, or flatulence. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), bone pain, severe loss of strength and energy, angina, vision changes, painful urination, hematuria, polyuria, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), or signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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