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|Rosiglitazone/Glimepiride

Rosiglitazone/Glimepiride

Trade Names:
Avandaryl
- Tablets rosiglitazone 4 mg and glimepiride 1 mg
- Tablets rosiglitazone 4 mg and glimepiride 2 mg
- Tablets rosiglitazone 4 mg and glimepiride 4 mg

Mechanism of Action

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.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with rosiglitazone plus a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who initially responded to rosiglitazone alone and require additional glycemic control.

Contraindications

Diabetic ketoacidosis with or without coma; known hypersensitivity to any component of the product.

Dosage and Administration

PO Initial: Rosiglitazone 4 mg and glimepiride 1 mg or rosiglitazone 4 mg and glimepiride 2 mg once daily. Titrate to clinical response (max, rosiglitazone 8 mg and glimepiride 4 mg).

Initial dosing, dose increments, and maintenance dosage should be conservative based on blood glucose levels prior to and after initiation of therapy.

General Advice

• Administer once daily with first meal of the day.
• When switching from combination therapy of rosiglitazone plus glimepiride as separate tablets, usual starting rosiglitazone/glimepiride combination tablet is the dose of rosiglitazone and glimepiride previously being taken.
• For patients previously treated with thiazolidinedione monotherapy and switched to rosiglitazone/glimepiride combination tablet, dose titration can occur at 1- to 2-wk intervals by increasing the glimepiride component in no more than 2 mg increments.
• For patients previously treated with sulfonylurea monotherapy and switched to rosiglitazone/glimepiride combination tablet, full effect of rosiglitazone component on glucose reduction may take 2 to 3 mo to develop. If additional glycemic control is needed, dose of glimepiride component may be increased.
• If hypoglycemia occurs during up-titration of dose or while on maintenance therapy, reduce dose of glimepiride component.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Drug Interactions

Disulfiram-like reactions (eg, breathlessness, facial flushing, headache) may occur.

May reduce rosiglitazone plasma levels, decreasing the pharmacologic effects.

May elevate rosiglitazone plasma levels, increasing pharmacologic and adverse effects.

May lead to loss of glycemic control.

May lead to loss of glycemic control.

Risk of edema may be increased, even after several months of combined therapy.

Adverse Reactions

Cardiovascular

CHF (postmarketing).

CNS

Headache (at least 5%).

Asthenia, dizziness, headache (2%).

Dermatologic

Urticaria (postmarketing).

EENT

Worsening or new onset of diabetic macular edema with decreased visual acuity (postmarketing).

GI

Nausea (1%).

Hematologic-Lymphatic

Anemia (2%).

Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia.

Metabolic-Nutritional

Hypoglycemia (2%), hyponatremia, SIADH.

Respiratory

Upper respiratory tract infection (at least 5%); pulmonary edema, pleural effusions (postmarketing).

Miscellaneous

Injury (at least 5%); edema (5%); angioedema (postmarketing).

Hepatic porphyria, disulfiram-like reactions (5%).

Precautions

Pregnancy

Category C . Not recommended during pregnancy.

Lactation

Undetermined. Not recommended for use during breast-feeding.

Children

Safety and efficacy not established.

Elderly

Particularly susceptible to hypoglycemic action.

Hepatic Function

Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × the upper limit of normal (ULN). Initiation or continuation of therapy in patients with mildly elevated liver enzymes (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.

Cardiac effects

Rosiglitazone may cause fluid retention that may exacerbate heart failure. Discontinue therapy if any deterioration in cardiac status occurs. Rosiglitazone is not recommended in patients with NYHA class 3 or 4 cardiac status.

CV mortality

Has occurred in patients treated with oral hypoglycemic drugs.

Concomitant treatment with insulin

Safety and efficacy of rosiglitazone/glimepiride in combination with insulin not established; therefore, concomitant use is not recommended.

Edema

Rosiglitazone may cause fluid retention. Use with caution in patients with edema or at risk of heart failure.

Hematologic

Decreases in hemoglobin (1 g/dL or less), hematocrit (3.3% or less), and WBC have been reported in patients receiving rosiglitazone.

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 been reported rarely 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.

Type I 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

Coma, hypoglycemia, seizure, or other neurological impairment.

Patient Information

• Explain name, dose, action, potential benefits, and potential side effects of drug.
• Advise patient to review the Patient Information leaflet carefully before starting therapy and to read and check for new information each time the medication is refilled.
• Advise patient to take prescribed dose with the first meal of the day.
• Advise patient that a reduction in blood glucose may be noted within days of starting therapy but that it may take 2 to 3 mo before the full effect is seen.
• Instruct patient that this drug is not a substitute for diet and exercise, and to follow prescribed regimens.
• Educate patient regarding type 2 diabetes and its management.
• Emphasize the importance of regular daily blood glucose monitoring and periodic glycosylated hemoglobin (A _1c ) tests. Ensure that patient knows their target values for both.
• Educate patient regarding potential long-term complications of diabetes and need for regular general physical and eye examinations.
• Advise patient to carry medical identification that indicates diabetes (eg, Medi-Alert ).
• Advise patient to report any of the following to health care provider immediately: abdominal pain, anorexia, dark urine, edema or swelling, fatigue, unexplained nausea and/or vomiting, unexplained shortness of breath, unusually rapid increase in weight, vision changes, or yellowing of the skin or eyes.
• Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake if either occur.
• Advise patient to discuss with health care provider a plan for managing each of the following situations: accidental administration of too little or too much medication, change in physical activity, dosing during intercurrent conditions (eg, infection, sick days, stress, trauma, vomiting), inadequate food intake or a skipped meal, missed doses, travel across time zones.
• Instruct patient to notify health care provider if experiencing hypoglycemic or hyperglycemic episodes.
• Advise patient that blood will be drawn to check liver function prior to starting therapy and then periodically thereafter.
• Advise patient to avoid unnecessary exposure to sunlight or tanning lamps and to use sunscreen and wear protective clothing to avoid photosensitivity reactions.
• Caution women that drug can cause resumption of ovulation in premenopausal, anovulatory women with insulin resistance. Advise such women to discuss adequate contraceptive measures with health care provider.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breast-feeding.
• Instruct patient not to take any other prescription or OTC drugs, dietary supplements, or herbal preparations unless advised by health care provider.
• Advise patient that follow-up visits and laboratory tests will be required to monitor therapy and to keep appointments.