Antidiabetic Agent (Thiazolidinedione)

Type 2 diabetes, monotherapy: Improve glycemic control as an adjunct to diet and exercise

Type 2 diabetes, combination therapy: In combination with metformin or a sulfonylurea when:

- diet, exercise, and metformin or a sulfonylurea alone do not result in adequate glycemic control, or

- diet, exercise, and rosiglitazone alone do not result in adequate glycemic control

C

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

Hypersensitivity to rosiglitazone or any component of the formulation; active liver disease (transaminases >2.5 times the upper limit of normal at baseline); contraindicated in patients who experience 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. Use with caution in premenopausal, anovulatory women; may result in resumption of ovulation, increasing the risk of pregnancy. May result in hormonal imbalance; development of menstrual irregularities should prompt reconsideration of therapy. Use with caution in patients with anemia or depressed leukocyte counts (may reduce hemoglobin, hematocrit, and/or WBC). Use with caution in patients with heart failure or edema; may increase in plasma volume and/or increase cardiac hypertrophy. In general, use should be avoided in patients with NYHA class 3 or 4 heart failure. Use with caution in patients with elevated transaminases (AST or ALT); see Contraindications and Monitoring. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone). Monitoring should include periodic determinations of liver function.

Two cases of hepatocellular injury have been reported in men in their 60s within 2-3 weeks after initiation of rosiglitazone therapy. LFTs in these patients revealed severe hepatocellular injury which responded with rapid improvement of liver function and resolution of symptoms upon discontinuation of rosiglitazone. Both patients were also receiving other hepatotoxic medications ( Ann Int Med, 2000, 132:121-4; 132:164-6).

1% to 10%:

Cardiovascular: Edema (4.8%)

Central nervous system: Headache (5.9%), fatigue (3.6%)

Endocrine & metabolic: Hyperglycemia (3.9%), hypoglycemia (0.5% to 1.6%)

Gastrointestinal: Diarrhea (2.3%)

Hematologic: Anemia (1.9%)

Neuromuscular & skeletal: Back pain (4%)

Respiratory: Upper respiratory tract infection (9.9%), sinusitis (3.2%)

Miscellaneous: Injury (7.6%)

<1%: Elevated transaminases, increased bilirubin

Experience in overdose is limited; symptoms may include hypoglycemia; treatment is supportive

Substrate for cytochrome P-450 isoenzyme 2C8 (CYP2C8); minor metabolism by CYP2C9

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.

Onset: Delayed, may require up to 12 weeks to achieve maximal effect

Distribution: V_dss (apparent): 17.6 L

Protein binding: 99.8%

Metabolism: Hepatic (99%), metabolism by cytochrome P-450 isoenzyme 2C8 (CYP2C8), minor metabolism via CYP2C9

Bioavailability: 99%

Half-life: 3.15-3.59 hours

Time to peak: 1 hour

Elimination: As metabolites, in urine (64%) and feces (23%)

Adults: Oral: Initial: 4 mg daily as a single daily dose or in divided doses twice daily. If response is inadequate after 12 weeks of treatment, the dosage may be increased to 8 mg daily as a single daily dose or in divided doses twice daily. In clinical trials, the 4 mg twice-daily regimen resulted in the greatest reduction in fasting plasma glucose and HbA_1c. ( Note: Doses >4 mg in combination with sulfonylureas have not been evaluated in clinical trials.)

Changing patients from troglitazone to rosiglitazone: For patients with normal hepatic enzymes who are switched from troglitazone to rosiglitazone, a 1-week washout is recommended before initiating therapy with rosiglitazone.

Elderly: No dosage adjustment is recommended

Dosage adjustment in renal impairment: No dosage adjustment is required

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

Management of type 2 diabetes should include diet control. Peak concentrations are lower by 28% and delayed when administered with food, but these effects are not believed to be clinically significant. Rosiglitazone may be taken without regard to meals.

Hemoglobin A_1c liver enzymes (prior to initiation of therapy, every 2 months for the first year of therapy, then periodically thereafter). 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

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

May be taken without regard to meals. Follow directions of prescriber. If dose is missed at the usual meal, take it with next meal. Do not double dose if daily dose is missed completely. Monitor urine or serum glucose as recommended by prescriber. More frequent monitoring is required during periods of stress, trauma, surgery, pregnancy, increased activity or exercise. Avoid alcohol. Report chest pain, rapid heartbeat or palpitations, abdominal pain, fever, rash, hypoglycemia reactions, yellowing of skin or eyes, dark urine or light stool, or unusual fatigue or nausea/vomiting. Pregnancy/breast-feeding precautions: Use alternate means of contraception if using oral contraceptives. Breast-feeding is not recommended.

Tablet: 2 mg, 4 mg, 8 mg