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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

Vss (apparent): 0.63 L/kg

Metabolism

Hepatic (99%) via CYP2C8 and 3A4 to both active and inactive 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: 3-7 hours; Total: 16-24 hours

Protein Binding

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

Special Populations: Renal Function Impairment

The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate and severe renal impairment.

Special Populations: Hepatic Function Impairment

There is a 45% reduction in mean Cmax, but no change in AUC values.

Special Populations: Elderly

AUC value is slightly higher (approximately 21%); terminal half-life is slightly longer (approximately 10 h).

Special Populations: Gender

The mean Cmax and AUC are increased 20% to 60% in women.

Use: Labeled Indications

Type 2 diabetes mellitus (noninsulin dependent, NIDDM), monotherapy or combination therapy: Adjunct to diet and exercise, to improve glycemic control

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

Type 2 diabetes: Oral:

Initial:

U.S. labeling: Monotherapy or combination therapy: 15-30 mg once daily

Patients with heart failure (NYHA Class I or II): Monotherapy or combination therapy: 15 mg once daily

Note: Not recommended in patients with symptomatic heart failure

Canadian labeling: Monotherapy or combination therapy (with a sulfonylurea or metformin): 15-30 mg once daily

Dosage titration: If response is inadequate based on HbA1c, the dosage may be increased in 15 mg increments with careful monitoring of adverse effects (eg, weight gain, edema, signs/symptoms of heart failure); maximum recommended dose: 45 mg once daily

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%

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

No dosage adjustment necessary (mean AUC values are unaffected in Child-Pugh grade B/C compared to healthy subjects); however, liver injury has been associated with use.

U.S. labeling:

Prior to initiation: Evaluate liver tests (ALT, AST, alkaline phosphatase, total bilirubin) and if abnormal, initiate with caution.

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

If ALT >3 x ULN and without alternative etiologies: Do not reinitiate therapy.

If ALT >3 x ULN and total bilirubin >2 x ULN and without alternative etiologies: Do not reinitiate therapy (these patients are at increased risk for severe drug-induced hepatotoxicity).

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

Canadian labeling:

Severe hepatic impairment: Use is contraindicated.

Prior to initiation:

If ALT > 2.5 x ULN or clinical evidence of active liver disease: Do not initiate therapy.

If ALT 1-2.5 x ULN: Initiate therapy with caution and investigate etiology of liver enzyme elevation.

During therapy:

If ALT levels >3 x ULN: Recheck levels immediately and if ALT elevation >3 x ULN persists, discontinue therapy.

If ALT 1-2.5 x ULN: Continue therapy with caution and investigate etiology of liver enzyme elevation.

Administration

May be administered without regard to meals

Dietary Considerations

Dietary modification based on ADA recommendations is a part of therapy.

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

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

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

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 suggest an increased risk of bladder cancer in patients exposed to pioglitazone; risk may be increased with duration of use. 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. In Canada, use is contraindicated in patients with active or 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: Increased incidence of bone fractures in females treated with pioglitazone; 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. In Canada, use is contraindicated in patients with any stage of heart failure (NYHA I, II, III, IV).

• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume. Use with caution in patients with anemia.

• 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 (Canadian labeling recommends avoiding use in patients with baseline ALT >3 x ULN). 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. Depending on the results of the liver tests and whether an alternative etiology is identified, discontinuation of therapy may be recommended. U.S. labeling states that routine periodic monitoring of serum liver tests during therapy is not necessary unless patient has liver disease or signs/symptoms of liver injury arise during use (Canadian labeling recommends periodic monitoring of liver enzymes in all patients per clinical judgment). Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.

Concurrent drug therapy issues:

• CYP2C8 inhibitors: Concomitant administration of pioglitazone with a strong CYP2C8 inhibitor increases pioglitazone exposure threefold; dosage adjustments are recommended if pioglitazone is coadministered with a strong CYP2C8 inhibitor (eg, gemfibrozil).

• Insulin (Canadian labeling; not in U.S. labeling): Concomitant use with insulin is not indicated.

• Metformin/sulfonylureas (Canadian labeling; not in U.S. labeling): Pioglitazone may be added to metformin or a sulfonylurea if glycemic control is inadequate. The use of triple therapy (pioglitazone in combination with metformin and a sulfonylurea) is not indicated due to increased risks of congestive heart failure and fluid retention.

Special populations:

• Pediatric: Use in pediatrics is not recommended; risks and adverse effects have not been evaluated in this population and there is a lack of long-term safety data.

• Premenopausal/anovulatory females: Use with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy.

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; signs and symptoms of heart failure; 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 (Canadian labeling recommends continued periodic monitoring per clinician judgment in all patients). Routine ophthalmic exams are recommended; patients reporting visual deterioration should have a prompt referral to an ophthalmologist and consideration should be given to discontinuing pioglitazone. Signs/symptoms of bladder cancer (dysuria, macroscopic hematuria, dysuria, urinary urgency).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. The use of pioglitazone in pregnant women is limited to very few case reports in which pregnancy occurred during treatment for polycystic ovarian syndrome (PCOS); details concerning fetal outcomes are limited (Glueck 2003; Ortega-Gonzalez 2005; Ota 2008).

Thiazolidinediones may cause ovulation in anovulatory premenopausal women, increasing the risk of pregnancy. Adequate contraception in premenopausal women is recommended. Due to long-term safety concerns associated with their use, thiazolidinediones should be avoided in women of reproductive age (Fauser 2012).

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 2015; 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 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008).

Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013); pioglitazone should not be used for the treatment of PCOS (Legro 2013).

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, rhinitis, cough, 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), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), bone pain, loss of strength and energy, angina, vision changes, pain with urination, blood in urine, polyuria, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes) (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 healthcare 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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