Rosiglitazone

Pronunciation

(roh si GLI ta zone)

U.S. Brand Names

Avandia®

Generic Available

Canadian Brand Names

Avandia®

Use

Type 2 diabetes mellitus (noninsulin dependent, NIDDM):

Monotherapy: Improve glycemic control as an adjunct to diet and exercise

Combination therapy: In combination with a sulfonylurea, metformin, or insulin when diet, exercise, and a single agent do not result in adequate glycemic control

Pregnancy Risk Factor

Pregnancy Implications

Treatment during mid to late gestation was associated with fetal death and 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 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 previously 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. 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). May increase plasma volume and/or increase cardiac hypertrophy. Assess for fluid accumulation in patients with unusually rapid weight gain. Use with caution in patients with edema. Monitor closely for signs and symptoms of heart failure. 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 elevated transaminases (AST or ALT). Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone) and (rarely) with rosiglitazone; discontinue if jaundice occurs. Monitoring should include periodic determinations of liver function. Safety and efficacy in pediatric patients have not been established.

Adverse Reactions

Rare 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. Patients were also receiving other potentially hepatotoxic medications ( Ann Intern Med , 2000, 132:121-4; 132:164-6).

>10%: Endocrine & metabolic: Weight gain, increase in total cholesterol, increased LDL-cholesterol, increased HDL-cholesterol

1% to 10%:

Cardiovascular: Edema (5%)

Central nervous system: Headache (6%), fatigue (4%)

Endocrine & metabolic: Hyperglycemia (4%), hypoglycemia (1% to 2%; increased with insulin to 12% to 14%)

Gastrointestinal: Diarrhea (2%)

Hematologic: Anemia (2%)

Neuromuscular & skeletal: Back pain (4%)

Respiratory: Upper respiratory tract infection (10%), sinusitis (3%)

Miscellaneous: Injury (8%)

<1%, postmarketing, and/or case reports: Angioedema, CHF or exacerbation of CHF (increased with insulin to 2% to 3%), transaminases increased, hepatic failure, hepatitis, bilirubin increased, pleural effusion, pulmonary edema, urticaria, weight gain (rapid, excessive; usually due to fluid accumulation)

Overdosage/Toxicology

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

Drug Interactions

Substrate of CYP2C8/9 (major); Inhibits CYP2C8/9 (moderate), 2C19 (weak), 2D6 (weak)

Bile acid sequestrants: May decrease rosiglitazone levels.

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

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

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

Gemfibrozil: Gemfibrozil may increase rosiglitazone levels; a decreased rosiglitazone dose may be warranted

Rifampin: May decrease rosiglitazone levels/effects.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may cause hypoglycemia).

Food: Peak concentrations are lower by 28% and delayed when administered with food, but these effects are not believed to be clinically significant.

Herb/Nutraceutical: Avoid garlic, gymnema (may cause hypoglycemia).

Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); protect from light

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.

Pharmacodynamics/Kinetics

Onset of action: Delayed; Maximum effect: Up to 12 weeks

Distribution: Vdss (apparent): 17.6 L

Protein binding: 99.8%

Metabolism: Hepatic (99%) via CYP2C8; minor metabolism via CYP2C9

Bioavailability: 99%

Half-life elimination: 3-4 hours

Time to peak, plasma: 1 hour; delayed with food

Excretion: Urine (64%) and feces (23%) as metabolites

Dosage

Oral:

Adults:

Monotherapy: 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 Hb A1c.

Combination therapy:

With sulfonylureas: Initial: 4 mg daily as a single daily dose or in divided doses twice daily; dose of sulfonylurea should be reduced if the patient reports hypoglycemia. Doses of rosiglitazone >4 mg/day are not indicated in combination with sulfonylureas.

With metformin: 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. It is unlikely that the dose of metformin will need to be reduced due to hypoglycemia

With insulin: Initial: 4 mg daily as a single daily dose or in divided doses twice 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 of rosiglitazone >4 mg/day are not indicated in combination with insulin.

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.

Monitoring Parameters

Hemoglobin A1c, serum glucose; signs and symptoms of heart failure; liver enzymes (prior to initiation 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.

Dietary Considerations

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

Patient Education

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. Report unusually rapid weight gain; swelling of ankles, legs, or abdomen; or weakness or shortness of breath. Pregnancy/breast-feeding precautions: In anovulatory, premenopausal women, ovulation may occur, increasing the risk of pregnancy. Adequate contraception is recommended. Use alternate means of contraception if using oral contraceptives. Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment

Rosiglitazone-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 headache and fatigue

Mental Health: Effects on Psychiatric Treatment

Weight gain is common; caution with atypical antipsychotics

Dosage Forms

Tablet: 2 mg, 4 mg, 8 mg

References

Al-Salman J, Arjomand H, Kemp DG, et al, "Hepatocellular Injury in a Patient Receiving Rosiglitazone. A Case Report," Ann Intern Med , 2000, 132(2):121-4.

Freid J, Everitt D, and Boscia J, "Rosiglitazone and Hepatic Failure," Ann Intern Med , 2000, 132(2):164-6.

International Brand Names

Avandia® (AR, AT, AU, BE, BR, CA, CH, CO, CR, CZ, DE, DK, DO, EC, ES, FI, FR, GB, GT, HN, HR, IE, IL, IT, NO, NZ, PA, PL, PT, RO, SE, SG, SI, SV, TH, TR); Glimide® (AR); Rezult® (IN)

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