Rosiglitazone Maleate / Metformin Hydrochloride

Pronunciation: ROE-si-GLI-ta-zone MAL-ee-ate/met-FOR-min HYE-droe-KLOR-ide
Class: Antidiabetic combination

Trade Names

Avandamet
- Tablets, oral rosiglitazone 2 mg/metformin 500 mg
- Tablets, oral rosiglitazone 2 mg/metformin 1,000 mg
- Tablets, oral rosiglitazone 4 mg/metformin 500 mg
- Tablets, oral rosiglitazone 4 mg/metformin 1,000 mg

Pharmacology

Rosiglitazone

Increases insulin sensitivity.

Metformin

Decreases hepatic glucose production, increases peripheral glucose uptake and utilization, and decreases intestinal absorption of glucose.

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Pharmacokinetics

Special Populations

Renal Function Impairment

Plasma and blood half-life of metformin is prolonged and the renal Cl is decreased in proportion to the decrease in CrCl.

Hepatic Function Impairment

Cl of rosiglitzone was significantly lower in patients with moderate to severe liver disease and C _max and AUC _0-∞ were increased 2- and 3-fold, respectively.

Indications and Usage

As an adjunct to diet and exercise to improve glycemic control when treatment with combination rosiglitazone and metformin is appropriate in patients with type 2 diabetes mellitus who either are already taking rosiglitazone, or not already taking rosiglitazone and unable to achieve glycemic control on other diabetes medications and, in consultation with their health care provider, have decided not to take pioglitazone or pioglitazone-containing products for medical reasons.

Contraindications

Renal disease or renal impairment that may also result from conditions such as CV collapse, shock, acute MI, and septicemia; acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma; known hypersensitivity to any component of the product; established New York Heart Association (NYHA) class III or IV heart failure; patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.

Dosage and Administration

Drug-Naive Patients
Adults

PO Start with the lowest recommended dose. Perform gradual dose escalation and allow sufficient time to assess adequacy of therapeutic response. If additional glycemic control is needed, the daily dose may be increased by increments of rosiglitazone 4 mg and/or metformin 500 mg (max, 8 mg/2,000 mg/day).

Patients Inadequately Controlled on Metformin Monotherapy
Adults

PO Start with rosiglitazone 4 mg daily plus the metformin dose already being taken. If prior therapy consists of metformin 1,000 mg/day, start with 2 mg/500 mg and administer 1 tablet twice daily. If prior therapy consists of metformin 2,000 mg/day, start with 2 mg/1,000 mg and administer 1 tablet twice daily (max, 8 mg/2,000 mg/day).

Patients Inadequately Controlled on Rosiglitazone Monotherapy
Adults

PO Start with metformin 1,000 mg daily plus the rosiglitazone dose already being taken. If prior therapy consists of rosiglitazone 4 mg/day, start with 2 mg/500 mg and administer 1 tablet twice daily. If prior therapy consists of rosiglitazone 8 mg/day, start with 4 mg/500 mg and administer 1 tablet twice daily (max, 8 mg/2,000 mg/day).

Switching from Separate Doses of Rosiglitazone and Metformin to Combination Therapy
Adults

PO Start with the doses of rosiglitazone and metformin already being taken. Increase the dose in increments of rosiglitazone 4 mg and/or metformin 500 mg (max, 8 mg/2,000 mg/day).

Hepatic Function Impairment
Adults

PO Do not initiate treatment in patients exhibiting evidence of active liver disease or increased serum transaminase levels (ALT more than 2.5 × ULN at the start of therapy).

Renal Function Impairment
Adults

PO Dosage adjustments should be based on careful assessment of renal function.

General Advice

• Give in divided doses with meals.
• Generally, debilitated, elderly, and malnourished patients should not be titrated to the maximum dose.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alcohol

The effects of metformin on lactate metabolism may be potentiated. Caution patients against excessive alcohol intake, acute or chronic, while taking rosiglitazone/metformin.

Cationic drugs (eg, amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)

Use with caution; may interact with metformin by competing for common renal tubular transport systems.

Cimetidine

Increased metformin plasma levels. Closely monitor renal function. Rosiglitazone/metformin dosage reduction may be needed during coadministration of cimetidine.

CYP2C8 inducers (eg, rifampin)

Rosiglitazone plasma concentrations may be reduced, decreasing the efficacy. Changes in rosiglitazone/metformin treatment may be needed when a CYP2C8 inducer is started or stopped.

CYP2C8 inhibitors (eg, azole antifungal agents [ketoconazole], fluvoxamine, gemfibrozil, trimethoprim)

May elevate rosiglitazone plasma levels, increasing the pharmacologic effects and adverse reactions. Changes in rosiglitazone/metformin treatment may be needed when a CYP2C8 inhibitor is started or stopped.

Drugs that cause hyperglycemia (eg, calcium channel blockers, corticosteroids, diuretics, estrogens, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazines, phenytoin, sympathomimetics, thiazide diuretics, thyroid products)

May lead to loss of glycemic control. Monitor blood glucose carefully when starting, stopping, or changing the dose of these agents.

Furosemide

Metformin plasma levels may be elevated, while furosemide levels may be decreased. Use with caution.

Insulin

Risk of edema may be increased, even after several months of therapy. Coadministration of rosiglitazone with insulin is not recommended.

Iodinated contrast material

May cause acute renal failure and has been associated with lactic acidosis in patients receiving metformin. Withhold rosiglitazone/metformin for at least 48 h prior and subsequent to the procedure and reinstitute only after renal function has been reevaluated and found to be normal.

Mycophenolate

Pharmacologic effects of mycophenolate may be increased by rosiglitazone. Elevated plasma concentrations with toxicity characterized by suppression of erythropoiesis may occur. Mycophenolate dosage reduction may be needed during coadministration of rosiglitazone/metformin.

Nevirapine

Nevirapine plasma concentrations may be reduced, decreasing efficacy. Monitor nevirapine concentrations and observe the clinical response of the patient when starting or stopping rosiglitazone/metformin. Adjust the nevirapine dose as needed.

Nifedipine

Metformin plasma levels may be increased.

Adverse Reactions

Cardiovascular

CHF (postmarketing).

CNS

Headache (7%); fatigue (6%).

Dermatologic

Pruritus, rash, Stevens-Johnson syndrome, urticaria (postmarketing).

EENT

Decreased visual acuity, diabetic macular edema (postmarketing).

Hematologic-Lymphatic

Anemia (7%).

Hepatic

Hepatic failure, hepatitis, and hepatic enzyme elevations (postmarketing).

Metabolic-Nutritional

Edema (4%); hypoglycemia (3%).

Musculoskeletal

Arthralgia, back pain (5%).

Respiratory

Upper respiratory tract infection (16%); sinusitis (6%); pulmonary edema, pulmonary effusions (postmarketing).

Miscellaneous

Diarrhea (13%); injury (8%); viral infection (5%); anaphylactic reaction, angioedema (postmarketing).

Precautions

Warnings Congestive heart failure and myocardial infarction Thiazolidinediones, including rosiglitazone, cause or exacerbate CHF in some patients. After initiation of rosiglitazone/metformin and after dosage increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, manage the patient's heart failure according to the current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone/metformin must be considered. Rosiglitazone/metformin is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone/metformin in patients with established NYHA class III or IV heart failure is contraindicated. A meta-analysis of 52 clinical trials showed rosiglitazone to be associated with an increased risk of MI. Lactic acidosis Lactic acidosis is a rare but serious metabolic complication that can occur because of metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal function impairment, and acute CHF. If acidosis is suspected, discontinue rosiglitazone/metformin and hospitalize the patient immediately.

Monitor Monitor all patients for signs and symptoms relating to fluid retention, including heart failure, and for CV adverse reactions. Measure fasting blood glucose and HbA 1c periodically to monitor therapeutic response. Initial and periodic monitoring of liver enzymes, hematologic parameters, and renal function is recommended. Ensure that patients with diabetes have regular eye exams by an ophthalmologist per the standards of care of the American Diabetes Association.

Pregnancy

Category C . Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to healthy as possible. Rosiglitazone/metformin should not be used during pregnancy.

Lactation

Undetermined. Do not administer to a breast-feeding woman.

Children

Safety and efficacy not established.

Elderly

In general, elderly patients should not be titrated to the maximum dose because of age-related decreases in renal function.

Renal Function

Decreased renal function results in decreased renal Cl and prolongation of the metformin half-life. Concomitant medications that affect renal function may result in hemodynamic changes or interfere with disposition of metformin (eg, cationic drugs); use with caution. Avoid metformin in patients whose serum creatinine levels exceed the ULN for their age.

Hepatic Function

Avoid metformin in patients with clinical or laboratory evidence of hepatic disease.

Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × ULN. Initiation or continuation of therapy in patients with ALT less than 2.5 × ULN should proceed with caution; discontinue therapy in these patients if ALT increases to more than 3 × ULN and persists.

Bone fractures

Increased incidence of bone fractures has been noted in women taking rosiglitazone.

Coadministration with insulin

The addition of rosiglitazone to insulin therapy increased the risk of CHF and myocardial ischemia. Coadministration is not recommended.

Edema

Rosiglitazone may cause fluid retention; use with caution in patients with edema or who are at risk of heart failure.

Hematologic effects

Dose-related decreases in Hgb and Hct have been reported in patients taking rosiglitazone.

Hypoglycemia

Risk may be increased when used in combination with other hypoglycemic agents, necessitating dose reduction of concomitant therapy.

Hypoxic states

Immediately discontinue therapy in any condition characterized by hypoxemia (eg, acute CHF, MI).

Iodinated contrast materials

Withhold metformin therapy at the time of or prior to parenteral contrast studies with iodinated materials. Reinstitute therapy 48 h after the study and after renal function has been determined to be healthy.

Macular edema

Has been reported in postmarketing experience in patients taking rosiglitazone.

Ovulation

Rosiglitazone therapy may result in ovulation in some premenopausal anovulatory women, increasing the risk of pregnancy.

Stress-related states

When a patient stabilized on any diabetic regimen is exposed to stress, such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold rosiglitazone/metformin and temporarily administer insulin. Rosiglitazone/metformin may be reinstituted after the acute episode is resolved.

Surgical procedures

Treatment should be temporarily suspended for any surgical procedure, except minor procedures not associated with restricted intake of food and fluids, and should not be restarted until oral intake has resumed and renal function has been evaluated as normal.

Type 1 diabetes

Not indicated for use in patients with type 1 diabetes.

Vitamin B ₁₂ levels

Metformin may decrease vitamin B ₁₂ levels.

Weight gain

Dose-related weight gain was seen with rosiglitazone.

Overdosage

Symptoms

Lactic acidosis.

Patient Information

• Advise patients to read the Medication Guide before starting therapy and with each refill.
• Explain to patients the risks of lactic acidosis, its symptoms, and the conditions that predispose to its development. Advise patients to discontinue rosiglitazone/metformin immediately and promptly notify their health care provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Inform patients that once stabilized on any dose level of rosiglitazone/metformin, GI symptoms, which are common during initiation of metformin therapy, are unlikely to be drug-related. Inform patients that later occurrence of GI symptoms could be caused by lactic acidosis or other serious disease.
• Advise patients to avoid excessive alcohol intake, either acute or chronic, while receiving rosiglitazone/metformin.
• Inform patients that rosiglitazone/metformin is not recommended for patients with symptoms of heart failure.
• Advise patients that results of a set of clinical studies suggest that treatment with rosiglitazone is associated with an increased risk of MI (heart attack), especially in patients taking insulin.
• Inform patients that rosiglitazone/metformin is not recommended for patients who are taking insulin.
• Advise patients that management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy.
• Emphasize the importance of regular testing of blood glucose, HbA _1c , renal function, and hematologic parameters.
• Inform patients that blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgement of their health care provider. Advise patients to immediately report unexplained symptoms of abdominal pain, anorexia, dark urine, fatigue, nausea, or vomiting to their health care provider.
• Advise patients to immediately report an unusually rapid increase in weight, edema, development of shortness of breath, or other symptoms of heart failure while on rosiglitazone/metformin to their health care provider.
• Inform patients that therapy with rosiglitazone/metformin may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone/metformin. Thus, recommend adequate contraception in premenopausal women. This possible effect has not been specifically investigated in clinical studies, so the frequency of this occurrence is not known.

Copyright © 2009 Wolters Kluwer Health.