Rosiglitazone Maleate / Glimepiride

Pronunciation: ROE-si-GLI-ta-zone MAL-ee-ate/glye-MEP-ir-ide
Class: Antidiabetic combination

Trade Names

Avandaryl
- Tablets, oral rosiglitazone 4 mg/glimepiride 1 mg
- Tablets, oral rosiglitazone 4 mg/glimepiride 2 mg
- Tablets, oral rosiglitazone 4 mg/glimepiride 4 mg
- Tablets, oral rosiglitazone 8 mg/glimepiride 2 mg
- Tablets, oral rosiglitazone 8 mg/glimepiride 4 mg

Pharmacology

Rosiglitazone, a thiazolidinedione, increases insulin sensitivity in the liver, skeletal muscle, and adipose tissues. Glimepiride, a sulfonylurea, stimulates insulin release from functioning pancreatic beta-cells.

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Indications and Usage

As an adjunct to diet and exercise to improve glycemic control when treatment with both rosiglitazone and glimepiride is appropriate in adults with type 2 diabetes mellitus who either are already taking rosiglitazone, or are not already taking rosiglitazone but are unable to achieve glycemic control taking 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

Initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure.

Dosage and Administration

Adults

PO Initial: Rosiglitazone 4 mg/glimepiride 1 mg once daily. For patients already treated with a sulfonylurea or thiazolidinedione, consider rosiglitazone 4 mg/glimepiride 2 mg. Titrate to clinical response (max, rosiglitazone 8 mg/glimepiride 4 mg).

Elderly, Debilitated, or Malnourished Patients, or Patients With Adrenal or Renal Function Impairment

PO Initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Consider an initial dosage of rosiglitazone 4 mg/glimepiride 1 mg once daily.

Hepatic Function Impairment

PO Treatment should not be initiated in patients exhibiting evidence of active liver disease or increased serum transaminase levels (ALT more than 2.5 × ULN at the start of therapy). In patients with mild liver impairment, consider an initial dosage of rosiglitazone 4 mg/glimepiride 1 mg once daily. Continue therapy with caution and monitor closely.

Sulfonylurea Monotherapy to Rosiglitazone/Glimepiride

PO Full effect of rosiglitazone component on glucose reduction may take 2 to 3 mo to develop. Titration of the rosiglitazone component is recommended if patients are not adequately controlled after 8 to 12 wk. Observe patients for 1 to 2 wk for hypoglycemia when being transferred from longer half-life sulfonylureas (eg, chlorpropamide) because of potential overlapping drug effect. After an increase in the dosage of the rosiglitazone component, dosage titration of the rosiglitazone component is recommended if the patient is not adequately controlled after 2 to 3 mo.

Rosiglitazone Monotherapy to Rosiglitazone/Glimepiride

PO Dose titration can occur at 1- to 2-wk intervals by increasing the glimepiride component by no more than 2 mg increments. After an increase in dosage of the glimepiride component, dose titration of rosiglitazone/glimepiride is recommended if patients are not adequately controlled after 1 to 2 wk.

Switching From Separate Doses of Rosiglitazone and Glimepiride to Combined Therapy

PO Usual starting dose is the dose of rosiglitazone and glimepiride already being taken.

General Advice

  • Administer once daily with the first meal of the day.
  • If hypoglycemia occurs during up-titration of dose or while on maintenance therapy, reduce dose of glimepiride component.
  • If at any time ALT levels increase to more than 3 times the ULN in patients on therapy with rosiglitazone/glimepiride, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain more than 3 times the ULN, or if jaundice is observed, therapy with rosiglitazone/glimepiride should be discontinued.

Storage/Stability

Store between 59° and 86°F. Protect from light.

Drug Interactions

Alcohol, ethanol

Hypoglycemia and hyperglycemia, as well as a disulfiram-type reaction, have been reported with this combination. Patients should avoid combination in excess of an occasional single drink.

CYP2C8 inducers (eg, rifampin)

May reduce rosiglitazone plasma levels, decreasing the pharmacologic effects. Monitor blood glucose and glycosylated hemoglobin (HbA 1c ) when starting or stopping rifampin. Adjust the rosiglitazone/glimepiride dose as needed.

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

May elevate rosiglitazone plasma levels, increasing pharmacologic effects and adverse reactions. Monitor blood glucose and observe the patient for rosiglitazone adverse reactions. Adjust rosiglitazone/glimepiride dose as needed when starting or stopping CYP2C8 inhibitors.

CYP2C9 inducers (eg, phenytoin, rifampin)

There is a potential that CYP2C9 inducers may decrease glimepiride plasma concentrations. Monitor blood glucose when starting, stopping, or changing the dose of a CYP2C9 inhibitor. If an interaction is suspected, adjust the rosiglitazone/glimepiride dose as needed

CYP2C9 inhibitors (eg, diclofenac, fluconazole)

There is a potential that CYP2C9 inhibitors may increase glimepiride and rosiglitazone plasma concentrations. Monitor blood glucose when starting, stopping, or changing the dose of a CYP2C9 inhibitor. If an interaction is suspected, adjust the rosiglitazone/glimepiride dose as needed.

Diazoxide

Diazoxide may impair the hypoglycemic effect of glimepiride. Rosiglitazone/glimepiride may reverse diazoxide-induced hyperglycemia. Monitor blood glucose and adjust the dose of 1 or both drugs accordingly.

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

May lead to loss of glycemic control of glimepiride by various mechanisms (eg, increased hepatic metabolism, decreased insulin release, increased renal excretion). Carefully monitor blood glucose when starting, stopping, or changing the dose of these agents.

Drugs that cause hypoglycemia (eg, ACE inhibitors, beta-adrenergic blockers, chloramphenicol, clofibrate, fenfluramine, fluconazole, fluvoxamine, gemfibrozil, H 2 antagonists [eg, cimetidine] , MAOIs, miconazole oral, NSAIDs (eg, ibuprofen), probenecid, quinolones [eg, ciprofloxacin, levofloxacin], salicylates, sulfonamides)

The hypoglycemic effect of glimepiride may be enhanced by various mechanisms (eg, decreased hepatic metabolism, inhibition of renal excretion, displacement from protein-binding sites, decreased blood glucose, alteration of carbohydrate metabolism). Carefully monitor blood glucose when starting, stopping, or changing the dose of these agents. Hypoglycemia may be more difficult to recognize in patients taking beta-blockers.

Glyburide

Repeat doses of rosiglitazone 8 mg once daily for 8 days caused a 30% decrease in glyburide AUC and C max .

Insulin

Risk of edema, CHF, and myocardial ischemia may be increased, even after several months of combined therapy. Coadministration is not recommended.

Mycophenolate

Pharmacologic effects of mycophenolate may be increased by rosiglitazone. Elevated plasma concentrations with toxicity characterized by suppression of erythropoiesis may occur. Dosage reduction of mycophenolate may be needed with coadministration.

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/glimepiride. Adjust the nevirapine dose as needed.

Warfarin

Anticoagulant effects may be increased or decreased. Monitor coagulation parameters and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Hypertension; major adverse cardiovascular event (a composite of MI, CV death, or stroke); CHF (postmarketing).

CNS

Headache (5% or more); asthenia, dizziness (2%).

Dermatologic

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

EENT

Changes in accommodation; decreased visual acuity, new-onset or worsening diabetic macular edema (postmarketing).

GI

Nausea (1%); diarrhea.

Hematologic

Agranulocytosis, aplastic anemia, decreased Hgb and Hct, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia.

Hepatic

Hepatic porphyria; hepatic enzyme elevations; hepatic failure with or without fatal outcome, hepatitis (postmarketing).

Hypersensitivity

Allergic vasculitis; photosensitivity reactions; porphyria cutanea tarda; anaphylactic reaction, angioedema (postmarketing).

Metabolic-Nutritional

Hypoglycemia (5% or more); hyponatremia, syndrome of inappropriate antidiuretic hormone secretion.

Musculoskeletal

Arthralgia; back pain.

Respiratory

Nasopharyngitis, upper respiratory tract infection (5% or more); pleural effusions, pulmonary edema (postmarketing).

Miscellaneous

Fractures (9%); injury (5% or more); edema (5%); anemia (2%); decreased triglycerides and free fatty acids; disulfiram-like reactions; increased HDL, LDL, and total cholesterol.

Precautions

Warnings

Congestive heart failure and myocardial infarction

Thiazolidinediones, including rosiglitazone, cause or exacerbate CHF in some patients. After initiation of rosiglitazone/glimepiride and after dose 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 heart failure according to the current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone/glimepiride must be considered.

Rosiglitazone/glimepiride is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone/glimepiride in patients with established NYHA class III or IV heart failure is contraindicated.

A meta-analysis of 52 clinical studies (mean duration, 6 mo; 16,995 total patients), most of which compared rosiglitazone with placebo, showed rosiglitazone to be associated with an increased risk of MI.


Monitor

Obtain periodic fasting blood glucose and HbA 1c concentrations to monitor therapeutic response. Assess liver enzymes prior to initiation of therapy and periodically thereafter. Monitor all patients for signs and symptoms associated with heart failure, including excessive, rapid weight gain, dyspnea, and/or edema. Patients with diabetes should have regular eye exams by an ophthalmologist per the standards of care of the American Diabetes Association.


Pregnancy

Category C . Not recommended during pregnancy.

Lactation

Undetermined. Not recommend in breast-feeding women.

Children

Safety and efficacy not established.

Elderly

Particularly susceptible to hypoglycemic action. In general, do not titrate to the max dose because of age-related decreases in renal function. Rosiglitazone significantly increased the risk of all-cause mortality and hospitalized heart failure compared with pioglitazone.

Hepatic Function

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

Bone fractures

Increased incidence of bone fractures.

Coadministration with insulin

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

CV mortality

The administration of oral hypoglycemic drugs has been reported to be associated with increased CV mortality, compared with treatment with diet alone or diet plus insulin.

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.

Hemolytic anemia

May occur in patients with G-6-PD deficiency, and has also been reported in postmarketing data in patients without G-6-PD deficiency. Use with caution in patients with G-6-PD and consider using a nonsulfonylurea agent.

Hypoglycemia

May produce severe hypoglycemia. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible.

Macular edema

New-onset or worsening macular edema with decreased visual acuity has rarely been reported in patients receiving rosiglitazone.

Ovulation

Rosiglitazone therapy may result in resumption of ovulation in premenopausal anovulatory women with insulin resistance. Consider contraceptive measures in such patients.

Stress-related events

When a patient stabilized on any antidiabetic 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/glimepiride and temporarily administer insulin. Rosiglitazone/glimepiride may be reinstituted after the acute episode is resolved.

Type 1 diabetes

Do not use in these patients.

Weight gain

Dose-related weight gain has been reported. Assess patients who experience unusually rapid increases in weight for fluid accumulation and volume-related events (eg, edema, heart failure).

Overdosage

Symptoms

Hypoglycemic reactions with coma, seizures, or other neurological impairment.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Inform patients that rosiglitazone/glimepiride 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 for MI (heart attack), especially in patients taking insulin.
  • Inform patients that rosiglitazone/glimepiride 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 , liver function, and hematologic parameters.
  • Advise patients to immediately report unexplained symptoms of abdominal pain, anorexia, dark urine, fatigue, nausea, or vomiting to their health care provider.
  • Explain the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development.
  • Advise patients to immediately report an unusually rapid increase in weight, edema, shortness of breath, or other symptoms of heart failure to their health care provider.
  • Instruct patients to take rosiglitazone/glimepiride with the first meal of the day.
  • Inform patients that therapy with rosiglitazone/glimepiride 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/glimepiride. 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.
  • Advise patient to avoid unnecessary exposure to sunlight or tanning lamps, and to use sunscreen and wear protective clothing to avoid photosensitivity reactions.

Copyright © 2009 Wolters Kluwer Health.

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