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Uses

Treatment of Diabetes Mellitus

Used alone or in combination with a sulfonylurea, metformin, or a sulfonylurea and metformin as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM). Should be added to, not substituted for, sulfonylurea or metformin therapy.

May be added to glyburide/metformin hydrochloride fixed-combination therapy if hyperglycemia is not adequately controlled with the fixed combination. Used in combination with a sulfonylurea and metformin (given separately) in patients who have inadequate glycemic control with a sulfonylurea and metformin. May be used in combination with repaglinide if hyperglycemia is not adequately controlled with diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione.

Use fixed combination of rosiglitazone/metformin hydrochloride (Avandamet^®) when treatment with rosiglitazone and metformin is appropriate.

Use fixed combination of rosiglitazone/glimepiride (Avandaryl^®) when treatment with rosiglitazone and glimepiride is appropriate. Safety and efficacy of switching to the fixed combination of rosiglitazone/glimepiride in patients previously receiving other oral antidiabetic agents not established.

Metformin is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus. Thiazolidinediones are one of several second-line agents used with other oral antidiabetic agents (e.g., metformin) in patients who are inadequately controlled on their current oral therapy. Because of potential for serious adverse effects (see Boxed Warning), American Diabetes Association (ADA) recommends that clinicians carefully weigh the potential risks and benefits of thiazolidinediones versus other second-line agents (i.e., insulin, sulfonylureas).

Use in combination with insulin not recommended. (See Heart Failure and Other Cardiac Effects under Cautions and also Specific Drugs under Interactions.)

Use with nitrates not recommended. (See Specific Drugs under Interactions.)

Not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is necessary.

Prevention of Diabetes Mellitus

Has been used to reduce the progression to frank diabetes mellitus† in patients at high risk for type 2 diabetes mellitus (i.e., those with impaired glucose tolerance or impaired fasting glucose concentrations). Use of rosiglitazone was associated with a lower incidence of diabetes mellitus than use of placebo in one large trial. However, CHF occurred more frequently in patients receiving rosiglitazone than in those receiving placebo. (See Heart Failure and Other Cardiac Effects under Cautions.)

Dosage and Administration

General

• Carefully individualize dosage based on patient's response and tolerance.
• Monitor regularly (e.g., fasting blood glucose concentrations, hemoglobin A_1c [HbA_1c]) to determine therapeutic response and minimum effective dosage.
• Allow sufficient time to assess therapeutic response (8–12 weeks) to rosiglitazone.
• When initiating therapy, consider the benefit-to-risk ratio of monotherapy versus combination therapy.

Administration

Oral Administration

Administer rosiglitazone once or twice daily without regard to meals.

Administer rosiglitazone/metformin hydrochloride fixed-combination preparation in divided doses with meals.

Administer rosiglitazone/glimepiride fixed-combination preparation once daily with the first main meal of the day.

If a dose is missed, take the missed dose as soon as it is remembered. If the missed dose is remembered at the time of the next dose, skip missed dose and resume the regular schedule. Do not double dose to replace missed dose.

Dosage

Available as rosiglitazone maleate; dosage expressed in terms of rosiglitazone.

Adults

Treatment of Diabetes Mellitus

Monotherapy

Oral

Usual initial dosage is 4 mg daily in 1 or 2 divided doses. If response is inadequate after 8–12 weeks, increase dosage to a maximum of 8 mg daily.

Combination Therapy with Other Antidiabetic Agents

Oral

May continue current dosage of the sulfonylurea, metformin hydrochloride, or a sulfonylurea and metformin hydrochloride upon initiation of rosiglitazone.

Combination therapy with a sulfonylurea: Initially, 4 mg of rosiglitazone daily in 1 or 2 divided doses. If response is inadequate after 8–12 weeks, increase to a maximum of 8 mg of rosiglitazone daily. If hypoglycemia occurs, reduce sulfonylurea dosage.

Combination therapy with metformin hydrochloride: Initially, 4 mg of rosiglitazone daily in 1 or 2 divided doses. If response is inadequate after 8–12 weeks, increase to a maximum of 8 mg of rosiglitazone daily. Need for adjustment of metformin hydrochloride dosage because of hypoglycemia unlikely.

Combination therapy with a sulfonylurea and metformin hydrochloride: Initially, 4 mg of rosiglitazone daily in 1 or 2 divided doses. If response is inadequate after 8–12 weeks, increase to a maximum of 8 mg of rosiglitazone daily. If hypoglycemia occurs, reduce sulfonylurea dosage.

Combination therapy with glyburide/metformin hydrochloride fixed combination: Initially, 4 mg of rosiglitazone and existing daily dosage of fixed combination. If response inadequate, increase to a maximum of 8 mg of rosiglitazone daily. If hypoglycemia develops, reduce glyburide dosage; consider dosage adjustments of other agents as clinically indicated.

Rosiglitazone/Metformin Hydrochloride Fixed-combination Therapy (Avandamet^®)

Oral

Previously untreated patients: Usual initial dosage is 2 mg of rosiglitazone and 500 mg of metformin hydrochloride once or twice daily. For more severe hyperglycemia (i.e., HbA_1c >11% or fasting plasma glucose [FPG] concentrations >270 mg/dL), consider 2 mg of rosiglitazone and 500 mg of metformin hydrochloride twice daily. If additional glycemic control needed after 4 weeks, titrate dosage upward in increments of 2 mg of rosiglitazone and 500 mg of metformin hydrochloride per day until adequate glycemic control is achieved or a maximum daily dosage of 8 mg of rosiglitazone and 2 g of metformin hydrochloride is reached.

Patients inadequately controlled on metformin or rosiglitazone monotherapy: Dosage of the fixed combination is based on the patient’s current dosage of metformin hydrochloride or rosiglitazone. (See Table.)

Patients inadequately controlled on metformin monotherapy: Usual initial dosage of rosiglitazone is 4 mg daily given with patient's existing dosage of metformin hydrochloride.

Patients inadequately controlled on rosiglitazone monotherapy: Usual initial dosage of metformin hydrochloride is 1 g daily given with patient's existing dosage of rosiglitazone.

Tablet strength of fixed-combination preparation that is selected should be the one that most closely provides patient’s existing dosage of rosiglitazone or metformin hydrochloride, respectively. (See Table.)

If additional glycemic control is needed following transfer, titrate dosage upward in increments of 4 mg of rosiglitazone and/or 500 mg of metformin hydrochloride per day until adequate glycemic control is achieved or a maximum daily dosage of 8 mg of rosiglitazone and 2 g of metformin hydrochloride is reached. Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks. Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.

For replacement of concurrent therapy with the drugs given as separate tablets, dosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone.

Rosiglitazone/Glimepiride Fixed-combination Therapy (Avandaryl^®)

Oral

Previously untreated patients: Usual initial dosage is 4 mg of rosiglitazone and 1 mg of glimepiride once daily.

Patients inadequately controlled on sulfonylurea or rosiglitazone monotherapy: Initially, 4 mg of rosiglitazone and 1 or 2 mg of glimepiride once daily.

In patients previously receiving thiazolidinedione monotherapy, allow approximately 1–2 weeks to assess therapeutic response to newly initiated glimepiride component before adjusting dosage. If additional glycemic control is needed after 1–2 weeks, increase dosage of the glimepiride component in increments of ≤2 mg. Assess response to increase in glimepiride component after 1–2 weeks to determine need for further dosage adjustment. If additional glycemic control is needed, increase dosage of glimepiride and rosiglitazone until adequate glycemic control is achieved or maximum daily dosage of 8 mg of rosiglitazone and 4 mg of glimepiride is reached.

In patients previously receiving sulfonylurea monotherapy, allow 2 weeks to observe reduction in blood glucose concentrations and 2–3 months to observe full therapeutic response to newly initiated rosiglitazone component. If additional glycemic control is needed after 8–12 weeks, increase dosage of the rosiglitazone component. If additional glycemic control is needed 2–3 months after an increase in rosiglitazone component, increase dosage of glimepiride and rosiglitazone. During transfer from chlorpropamide (a sulfonylurea with a long elimination half-life), closely monitor for hypoglycemia during the initial 1–2 weeks of the transition period.

For replacement of concurrent therapy with the drugs given as separate tablets, dosage of the fixed combination is based on the patient’s current dosages of glimepiride and/or rosiglitazone.

If hypoglycemia occurs, reduce dosage of the glimepiride component.

Prescribing Limits

Adults

Treatment of Diabetes Mellitus

Oral

Rosiglitazone monotherapy: Maximum 8 mg daily; no additional benefit observed with dosage of 12 mg daily.

Combination with a sulfonylurea, metformin hydrochloride, or sulfonylurea and metformin hydrochloride, given separately: Maximum 8 mg of rosiglitazone daily.

Fixed-combination preparation with metformin hydrochloride: Maximum 8 mg of rosiglitazone and 2 g of metformin hydrochloride daily.

Fixed-combination preparation with glimepiride: Maximum 8 mg of rosiglitazone and 4 mg of glimepiride daily.

Special Populations

Dosage in Hepatic Impairment

Rosiglitazone monotherapy: Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily. Conservative initial and maintenance dosages recommended in patients with mild hepatic impairment; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride. Do not initiate therapy with fixed combination in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).

Fixed-combination preparation with metformin hydrochloride: Do not initiate therapy with fixed combination in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).

Dosage in Renal Impairment

Rosiglitazone monotherapy: No dosage adjustment necessary.

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily. Conservative initial and maintenance dosages recommended; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.

Geriatric Patients

Rosiglitazone monotherapy: No dosage adjustment necessary.

Fixed-combination preparation with metformin hydrochloride: Conservative initial and maintenance dosages recommended. Generally, do not titrate to maximum recommended dosage.

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily. Conservative initial and maintenance dosages recommended; geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.

Other Populations

Fixed-combination preparation with metformin hydrochloride: Do not titrate to maximum recommended dosage in debilitated or malnourished patients.

Fixed-combination preparation with glimepiride: Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily in debilitated or malnourished patients or patients with adrenal insufficiency. Conservative initial and maintenance dosages recommended; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.