AVANDARYL (rosiglitazone maleate and glimepiride)

AVANDARYL (rosiglitazone maleate and glimepiride)

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AVANDARYL (rosiglitazone maleate and glimepiride)

AVANDARYL contains 2 oral antidiabetic drugs used in the management of type 2 diabetes: rosiglitazone maleate and glimepiride.

Rosiglitazone maleate is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The molecular formula is C18H19N3O3S•C4H4O4.

Rosiglitazone maleate is a white to off-white solid with a melting point range of 122° to 123°C. The pKa values of rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range.

Glimepiride is an oral antidiabetic drug of the sulfonylurea class. Chemically, glimepiride is 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans4-methylcyclohexyl)urea with a molecular weight of 490.62. The molecular formula for glimepiride is C24H34N4O5S. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water.

Indications and usage

AVANDARYL is a combination antidiabetic product containing a thiazolidinedione and a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Important Limitations of Use:

  • Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
  • Coadministration with insulin is not recommended

Mechanism of Action

AVANDARYL combines 2 antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Rosiglitazone maleate, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas act primarily by stimulating release of insulin from functioning pancreatic beta cells.

Rosiglitazone: Rosiglitazone improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferatoractivated receptor-gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism.

Glimepiride: Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

Dosage and administration

  • Individualize the starting dose based on the patient’s current regimen.
  • The recommended starting dose is 4 mg/1 mg administered once daily with the first meal of the day. For adults already treated with a sulfonylurea or rosiglitazone, a starting dose of 4 mg/2 mg may be considered.
  • Administer AVANDARYL at least 4 hours prior to colesevelam.
  • Dose increases should be accompanied by careful monitoring for adverse events related to fluid retention.
  • Do not exceed the maximum recommended daily dose of 8 mg rosiglitazone and 4 mg glimepiride.
  • Do not initiate if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels.

Contraindications

  • Initiation in patients with established NYHA Class III or IV heart failure.
  • Hypersensitivity to rosiglitazone, glimepiride, or any of the product’s ingredients.
  • Hypersensitivity to sulfonamide derivatives.

Warnings and precautions

  • Fluid retention, which may exacerbate or lead to heart failure, may occur. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk of other cardiovascular effects.
  • Meta-analysis of 52 mostly short-term trials suggested a potential risk of ischemic cardiovascular (CV) events relative to placebo, not confirmed in a long-term CV outcome trial versus metformin or sulfonylurea.
  • Hypoglycemia: AVANDARYL is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia.
  • Severe hypoglycemia may occur. Use particular care in elderly or debilitated patients and those with adrenal, pituitary, renal, or hepatic insufficiency.
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  • Dose-related edema, weight gain, and anemia may occur.
  • Macular edema has been reported.
  • Increased incidence of bone fracture.
  • Postmarketing reports for glimepiride include anaphylaxis, angioedema, and Stevens-Johnson syndrome. Promptly discontinue AVANDARYL, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
  • Hemolytic anemia can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative.
  • Potential increased risk of cardiovascular mortality with sulfonylureas: Inform patients of risks, benefits and treatment alternatives

Adverse reactions

Common adverse reactions (≥5%) reported in clinical trials for AVANDARYL without regard to causality were headache, hypoglycemia, and nasopharyngitis.

Drug interactions

Drugs Metabolized by Cytochrome P450: An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known.

There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of CYP 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control.

Miconazole: A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.

Concomitant: Administration of Colesevelam Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. Therefore, AVANDARYL should be administered at least 4 hours prior to colesevelam

Use in specific populations

Pregnancy: Pregnancy Category C. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure.

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.

Nursing Mothers: No trials have been conducted with AVANDARYL. It is not known whether rosiglitazone or glimepiride is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue AVANDARYL, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of AVANDARYL in pediatric patients have not been established. AVANDARYL and its components, rosiglitazone and glimepiride, are not indicated for use in pediatric patients.

Overdosage

Rosiglitazone: Limited data are available with regard to overdosage in humans. In clinical trials in volunteers, rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.

Glimepiride: An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery.

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.

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