Pioglitazone Hydrochloride

Pronunciation

Pronunciation: PYE-oh-GLI-ta-zone HYE-droe-KLOR-ide
Class: Thiazolidinedione

Trade Names

Actos
- Tablet, oral 15 mg
- Tablet, oral 30 mg
- Tablet, oral 45 mg

Pharmacology

Increases insulin sensitivity in muscle and adipose tissue, and inhibits hepatic gluconeogenesis.

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Pharmacokinetics

Absorption

Rapid. T max is 2 h. Food slightly delays T max 3 to 4 h. Steady state is reached in 7 days.

Distribution

Vd is 0.63 L/kg (single dose). Protein binding is extensive (more than 99%), mainly to albumin.

Metabolism

Extensively metabolized in the liver by hydroxylation and oxidation. Metabolites M-III (keto derivative) and M-IV (hydroxy derivative) are the major circulatory active metabolites in humans. The major isoforms involved include CYP2C8, CYP3A4, and CYP1A1.

Elimination

15% to 30% excreted primarily as metabolites in urine. Excreted into bile (unchanged as metabolites) and then eliminated in the feces. Serum half-life is 3 to 7 h (pioglitazone) and 16 to 24 h (metabolites M-III and M-IV). Apparent Cl is 5 to 7 L/h.

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.

Hepatic Function Impairment

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

Elderly

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

Children

Data are not available.

Gender

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

Race

Data are not available.

Indications and Usage

As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes in multiple clinical settings.

Unlabeled Uses

Polycystic ovary syndrome; prevention of in-stent restenosis.

Contraindications

Established New York Heart Association (NYHA) class III or IV heart failure; hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO Initially, 15 or 30 mg/day (start with 15 mg in patients with CHF [NYHA class I or II]); may titrate in increments of 15 mg daily (max, 45 mg daily).

Combination Therapy
Insulin secretagogues Adults

PO In combination with insulin secretagogues (eg, sulfonylurea); decrease insulin secretagogue dose if the patient reports hypoglycemia.

Insulin Adults

PO Decrease the insulin dose by 10% to 25% if the patient reports hypoglycemia. Individualize further adjustment based on glucose-lowering response.

Strong CYP2C8 inhibitors
Adults

PO Max recommended dose of pioglitazone is 15 mg when used with gemfibrozil or other strong CYP2C8 inhibitors.

General Advice

  • Should be taken once daily without regard to meals.

Storage/Stability

Store at 59° to 86°F. Protect from moisture and humidity.

Drug Interactions

Atorvastatin

Pioglitazone and atorvastatin serum concentrations may be decreased.

Contraceptives, hormonal

Oral contraceptives may decrease both hormone components about 30%, potentially reducing contraceptive effectiveness.

CYP2C8 enzyme inhibitors (eg, azole antifungal agents [eg, ketoconazole], fluvoxamine, gemfibrozil, trimethoprim)

Pioglitazone plasma levels may be elevated, increasing the pharmacologic effects and adverse reactions. A maximum dose of pioglitazone 15 mg daily is recommended when administered with gemfibrozil or other strong CYP2C8 inhibitors.

CYP2C8 inducers (eg, rifampin)

Pioglitazone plasma concentrations may be reduced, decreasing the efficacy. If a CYP2C8 inducer is started or stopped, changes in the pioglitazone dose may be needed. The maximum recommended daily dose of pioglitazone 45 mg should not be exceeded.

Digoxin

The digoxin AUC and C max may be increased. Because digoxin has a narrow therapeutic index, use with caution. Monitoring for clinical and laboratory evidence of digoxin toxicity is warranted.

Fexofenadine

Coadministration may increase the fexofenadine AUC and C max . The clinical importance is unknown.

Food

Food slightly delays the T max but does not alter the extent of absorption. Pioglitazone may be taken without regard to meals.

Gatifloxacin

Severe and persistent hypoglycemia may occur. If coadministration cannot be avoided, closely monitor blood glucose.

Insulin, sulfonylureas (eg, tolbutamide)

The risk of hypoglycemia may be increased. If hypoglycemia occurs, reduce the dose of insulin or sulfonylurea.

Midazolam

Plasma concentrations may be reduced by pioglitazone, decreasing the efficacy.

Nifedipine

Concurrent use of pioglitazone and nifedipine ER may decrease nifedipine concentrations. The clinical importance is unknown.

Warfarin

The anticoagulant effect of warfarin may be increased or decreased. Monitor anticoagulant activity.

Adverse Reactions

Cardiovascular

CHF.

CNS

Headache (9%).

EENT

Pharyngitis (5%); macular edema (postmarketing).

Hepatic

Hepatic failure (postmarketing).

Lab Tests

Decreased Hgb and Hct, elevated CPK levels.

Metabolic-Nutritional

Hypoglycemia, weight gain.

Musculoskeletal

Bone fractures, myalgia (5%).

Respiratory

Upper respiratory tract infection (13%); sinusitis (6%).

Miscellaneous

Edema (27%); urinary bladder tumors.

Precautions

Warnings

Pioglitazone can cause or exacerbate CHF in some patients. Consider discontinuing or reducing the dose if symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema) occur. Treatment of patients with symptomatic heart failure is not recommended. Initiation of pioglitazone in patients with established NYHA class III or IV heart failure is contraindicated.


Monitor

After starting treatment or increasing the dose, carefully observe patients for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). Monitor liver enzymes (serum ALT, AST, alkaline phosphatase, total bilirubin) prior to the start of therapy.

Perform fasting blood glucose and hemoglobin A 1c (HbA 1c ) measurements periodically; regular eye exams by an ophthalmologist are recommended.


Pregnancy

Category C . Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Lactation

Undetermined.

Children

Safety and efficacy not established; use is not recommended.

Hepatic Function

Use with caution.

Bone fractures

Increased incidence of bone fractures noted in women but not men.

Edema

Use caution; can cause fluid retention.

Hepatic effects

Fatal and nonfatal hepatic failure has been reported.

Hypoglycemia

May increase the risk of hypoglycemia when used in combination with insulin or oral hypoglycemic agents (particularly insulin secretagogues such as sulfonylureas); may need dose reduction of concomitant agents.

Macular edema

Has been reported.

Ovulation

May result in ovulation in premenopausal anovulatory women.

Urinary bladder tumors

Do not use in patients with active bladder cancer.

Overdosage

Symptoms

No symptoms were reported after ingestion of 120 to 180 mg daily for 11 days.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patients to take every day without regard to meals.
  • Educate patient, family, or caregiver regarding type 2 diabetes and its management.
  • Instruct patients that this drug is not a substitute for diet and exercise and to follow prescribed regimens.
  • Advise the patient that if a dose is missed on 1 day, the dose should not be doubled the next day.
  • Emphasize the importance of regular daily blood glucose monitoring and periodic HbA 1c tests.
  • Advise diabetic patients to carry medical identification (eg, card, bracelet).
  • Advise patients to report any of the following to health care provider immediately: abdominal pain, anorexia, dark urine, edema, fatigue, increase in weight, nausea, shortness of breath, vomiting, yellowing of the skin or eyes, other symptoms of CHF.
  • Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake in the event either occurs. Instruct patients to report hypoglycemic or hyperglycemic episodes to health care provider.
  • Caution women that drug can cause resumption of ovulation in premenopausal anovulatory women with insulin resistance. Address adequate contraceptive measures for these women.
  • Advise patients to promptly report any sign of macroscopic hematuria or other symptoms, such as dysuria or urinary urgency, that develop or increase during treatment, because these may be due to bladder cancer.

Copyright © 2009 Wolters Kluwer Health.

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