Pioglitazone

Pronunciation

(pye oh GLI ta zone)

U.S. Brand Names

Actos®

Generic Available

Canadian Brand Names

Actos®

Use

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

Type 2 diabetes mellitus (noninsulin dependent, NIDDM), combination therapy with sulfonylurea, metformin, or insulin: When diet, exercise, and a single agent alone does not result in adequate glycemic control

Pregnancy Risk Factor

Pregnancy Implications

Treatment during mid-late gestation was associated with delayed parturition, embryotoxicity and postnatal growth retardation in animal models. Abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy. In anovulatory, premenopausal women, ovulation may occur, increasing the risk of pregnancy; adequate contraception is recommended.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to pioglitazone or any component of the formulation; active liver disease (transaminases >2.5 times the upper limit of normal at baseline); patients who have experienced jaundice during troglitazone therapy

Warnings/Precautions

Should not be used in diabetic ketoacidosis. Mechanism requires the presence of insulin, therefore use in type 1 diabetes (insulin dependent, IDDM) is not recommended. May potentiate hypoglycemia when used in combination with sulfonylureas or insulin. Use with caution in premenopausal, anovulatory women - may result in a resumption of ovulation, increasing the risk of pregnancy. Use with caution in patients with anemia (may reduce hemoglobin and hematocrit). May increase plasma volume and/or increase cardiac hypertrophy. Use with caution in patients with edema. Monitor closely for signs and symptoms of heart failure (including weight gain, edema, or dyspnea). Not recommended for use in patients with NYHA Class III or IV heart failure, unless serum glucose control outweighs the risk of excessive fluid retention. Discontinue if heart failure develops. Use with caution in patients with minor elevations in transaminases (AST or ALT). Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone) and postmarketing case reports of hepatitis (with rare hepatic failure) have been received for pioglitazone. Monitoring should include periodic determinations of liver function. Not for use in children <18 years of age.

Adverse Reactions

>10%:

Endocrine & metabolic: Serum triglycerides decreased, HDL-cholesterol increased

Gastrointestinal: Weight gain

Respiratory: Upper respiratory tract infection (13%)

1% to 10%:

Cardiovascular: Edema (5%) (in combination trials with sulfonylureas or insulin, the incidence of edema was as high as 15%)

Central nervous system: Headache (9%), fatigue (4%)

Endocrine & metabolic: Aggravation of diabetes mellitus (5%), hypoglycemia (range 2% to 15% when used in combination with sulfonylureas or insulin)

Hematologic: Anemia (1%)

Neuromuscular & skeletal: Myalgia (5%)

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

<1%: CPK increased, transaminases increased

Postmarketing and/or case reports: CHF, dyspnea (associated with weight gain and/or edema), hepatic failure (very rare), hepatitis

Overdosage/Toxicology

Experience in overdose is limited. Symptoms may include hypoglycemia. Treatment is supportive.

Drug Interactions

Substrate (major) of CYP2C8/9, 3A4; Inhibits CYP2C8/9 (strong), 2C19 (weak), 2D6 (moderate); Induces CYP3A4 (weak)

Bile acid sequestrants: May decrease pioglitazone levels.

CYP2C8/9 inducers: May decrease the levels/effects of pioglitazone. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of pioglitazone. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, and sulfonamides.

CYP2C8/9 substrates: Pioglitazone may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, rosiglitazone, sertraline, and warfarin.

CYP2D6 substrates: Pioglitazone may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Pioglitazone may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of pioglitazone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of pioglitazone. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Gemfibrozil: Gemfibrozil may increase pioglitazone levels.

Oral contraceptives (hormonal): Effects of oral contraceptives may be decreased, based on data from a related compound. This has not been specifically evaluated for pioglitazone.

Thioridazine: Pioglitazone may increase thioridazine levels; concomitant use is contraindicated.

Ethanol/Nutrition/Herb Interactions

Ethanol: Caution with ethanol (may cause hypoglycemia).

Food: Peak concentrations are delayed when administered with food, but the extent of absorption is not affected. Pioglitazone may be taken without regard to meals.

Herb/Nutraceutical: St John's wort may decrease levels. Caution with chromium, garlic, gymnema (may cause hypoglycemia).

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Onset of action: Delayed

Peak effect: Glucose control: Several weeks

Distribution: Vss (apparent): 0.63 L/kg

Protein binding: 99.8%

Metabolism: Hepatic (99%) via CYP2C8/9 and 3A4 to both active and inactive metabolites

Half-life elimination: Parent drug: 3-7 hours; Total: 16-24 hours

Time to peak: ~2 hours

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

Dosage

Oral:

Adults:

Monotherapy: Initial: 15-30 mg once daily; if response is inadequate, the dosage may be increased in increments up to 45 mg once daily; maximum recommended dose: 45 mg once daily

Combination therapy: Maximum recommended dose: 45 mg/day

With sulfonylureas: Initial: 15-30 mg once daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia

With metformin: Initial: 15-30 mg once daily; it is unlikely that the dose of metformin will need to be reduced due to hypoglycemia

With insulin: Initial: 15-30 mg once daily; dose of insulin should be reduced by 10% to 25% if the patient reports hypoglycemia or if the plasma glucose falls to <100 mg/dL.

Dosage adjustment in patients with CHF (NYHA Class II) in mono- or combination therapy: Initial: 15 mg once daily; may be increased after several months of treatment, with close attention to heart failure symptoms

Elderly: No dosage adjustment is recommended in elderly patients.

Dosage adjustment in renal impairment: No dosage adjustment is required.

Dosage adjustment in hepatic impairment: Clearance is significantly lower in hepatic impairment. Therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (>2.5 times the upper limit of normal) at baseline.

Administration

May be administered without regard to meals

Monitoring Parameters

Hemoglobin A1c, serum glucose; signs and symptoms of heart failure; liver enzymes prior to initiation and periodically during treatment (per clinician judgment). If the ALT is increased to >2.5 times the upper limit of normal, liver function testing should be performed more frequently until the levels return to normal or pretreatment values. Patients with an elevation in ALT >3 times the upper limit of normal should be rechecked as soon as possible. If the ALT levels remain >3 times the upper limit of normal, therapy with pioglitazone should be discontinued.

Dietary Considerations

Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) should include diet control. May be taken without regard to meals.

Patient Education

Use exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. May be taken without regard to meals. Avoid or use caution with alcohol while taking this medication. If dose is missed, take as soon as possible. If dose is missed completely one day, do not double dose the next day. Follow dietary, exercise, and glucose monitoring instructions of prescriber (more frequent monitoring may be advised in periods of stress, trauma, surgery, increased exercise etc). Report respiratory infection, unusual weight gain, aggravation of hyper-/hypoglycemic condition, unusual swelling of extremities, shortness of breath, fatigue, yellowing of skin or eyes, dark urine, pale stool, nausea/vomiting, or muscle pain. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Use alternate means of contraception if using oral contraceptives. You may be at increased risk of pregnancy while taking this medication. Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment

Pioglitazone-dependent diabetics should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause fatigue

Mental Health: Effects on Psychiatric Treatment

Weight gain is common; caution with atypical antipsychotics; nefazodone and other CYP3A4 inhibitors may decrease the metabolism of pioglitazone; glucose may need to be checked more frequently

Dosage Forms

Tablet: 15 mg, 30 mg, 45 mg

International Brand Names

Actos® (AR, AT, BE, BR, CA, CH, CO, CR, CZ, DE, DK, ES, FI, FR, GB, GT, HN, IT, JP, NO, NZ, PA, RO, SE, SI, SV, TH); Cereluc® (AR); Glizone® (IN); G-Tase® (IN); Opam® (IN)

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