Antidiabetic Agent (Thiazolidinedione)

Type 2 diabetes, monotherapy: Adjunct to diet and exercise, to improve glycemic control

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

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Treatment during mid-late gestation was associated with delayed parturition, embryotoxicity and postnatal growth retardation in animal models. In animal studies, pioglitazone has been found to be excreted in milk. It is not known whether pioglitazone is excreted in human milk. Should not be administered to a nursing woman.

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

Should not be used in diabetic ketoacidosis. Mechanism requires the presence of insulin, therefore use in type 1 diabetes 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). Use with caution in patients with heart failure or edema - may increase plasma volume and/or increase cardiac hypertrophy. In general, use should be avoided in patients with NYHA class III or IV heart failure. Use with caution in patients with elevated transaminases (AST or ALT) - see Contraindications and Monitoring Parameters. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone) - monitoring should include periodic determinations of liver function.

>10%:

Endocrine & metabolic: Decreased serum triglycerides, increased HDL cholesterol

Gastrointestinal: Weight gain

Respiratory: Upper respiratory tract infection (13.2%)

1% to 10%:

Cardiovascular: Edema (4.8%)

Central nervous system: Headache (9.1%), fatigue (3.6%)

Endocrine & metabolic: Aggravation of diabetes mellitus (5.1%), hypoglycemia (range 2% to 15% when used in combination with sulfonylureas or insulin)

Hematologic; Anemia (1%)

Neuromuscular & skeletal: Myalgia (5.4%)

Respiratory: Sinusitis (6.3%), pharyngitis (5.1%)

<1%: Elevated transaminases, elevated CPK

In combination trials with sulfonylureas or insulin, the incidence of edema was as high as 15%.

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

Substrate for cytochrome P-450 isoenzyme 2C8 (CYP2C8) and 3A4 (CYP3A4)

Increased effect/toxicity: Ketoconazole ( in vitro) inhibits metabolism of pioglitazone. Other inhibitors of CYP3A4, including itraconazole, are likely to decrease pioglitazone metabolism. Patients receiving inhibitors of CYP3A4 should have their glycemic control evaluated more frequently.

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.

Onset: Delayed, may require several weeks to maximal effect

Absorption: Time to peak: Within 2 hours

Distribution: Protein binding: 99.8% Vss (apparent): 0.63 L/kg

Metabolism: Hepatic (99%), including metabolism by cytochrome P-450 isoenzyme 2C8 (CYP2C8) and isoenzyme 3A4 (CYP3A4) to both active and inactive metabolites

Half-life: 3-7 hours (parent); 16-24 hours (total)

Elimination: As metabolites, in urine (15% to 30%) and feces

Adults: Oral:

Combination therapy:

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. Doses >30 mg/day have not been evaluated in combination regimens.

A 1-week washout period is recommended in patients with normal liver enzymes who are changed from troglitazone to pioglitazone therapy.

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.

Elderly patients: No dosage adjustment is recommended in elderly patients.

Management of type 2 diabetes should include diet control.

Oral: May be taken without regard to meals

Hemoglobin A_1c, liver enzymes (prior to initiation and every 2 months for the first year of treatment, then periodically). 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 rosiglitazone should be discontinued.

No information available to require special precautions

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

Use exactly as directed (do not increase dose or frequency or discontinue without consulting prescriber). May be taken without regard to meals; avoid 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- or hypoglycemic condition, unusual swelling of extremities, 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 be pregnant. Use alternate means of contraception if using oral contraceptives. Breast-feeding is not recommended.

Tablet: 15 mg, 30 mg, 45 mg