AVANDIA (rosiglitazone maleate tablets)

AVANDIA (rosiglitazone maleate tablets)

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AVANDIA (rosiglitazone maleate tablets)

AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. AVANDIA improves glycemic control while reducing circulating insulin levels.

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.

Each pentagonal film-coated TILTAB tablet contains rosiglitazone maleate equivalent to rosiglitazone 2 mg or 4 mg for oral administration. Inactive ingredients are: hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: synthetic red and yellow iron oxides and talc

Indications and usage

AVANDIA is a thiazolidinedione antidiabetic agent indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use:

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

Mechanism of Action

Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated 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, PPARγresponsive genes also participate in the regulation of fatty acid metabolism.

Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.

In animal models, the antidiabetic activity of rosiglitazone was shown to be mediated by increased sensitivity to insulin’s action in the liver, muscle, and adipose tissues. Pharmacological studies in animal models indicate that rosiglitazone inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance.

Pharmacokinetics

Absorption: The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, AVANDIA may be administered with or without food.

Distribution: The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Metabolism: Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.

In vitro data demonstrate that rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.

Excretion: Following oral or intravenous administration of [14

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C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma halflife of [14 C]related material ranged from 103 to 158 hours.

Dosage and administration

  • Start at 4 mg daily in single or divided doses; do not exceed 8 mg daily.
  • Dose increases should be accompanied by careful monitoring for adverse events related to fluid retention.
  • Do not initiate AVANDIA 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 or any of the product’s ingredients

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.
  • Dose-related edema and weight gain may occur.
  • Measure liver enzymes prior to initiation and periodically thereafter. Do not initiate therapy in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Discontinue therapy if ALT levels remain >3X the upper limit of normal or if jaundice is observed.
  • Macular edema has been reported.
  • Increased incidence of bone fracture was observed in long-term trials.
  • Dose-related decreases in hemoglobin and hematocrit have occurred.
  • When used in combination with other hypoglycemic agents, a dose reduction of the concomitant agent may be necessary to reduce the risk of hypoglycemia

Adverse reactions

Common adverse reactions (>5%) reported in clinical trials without regard to causality were upper respiratory tract infection, injury, and headache.

Drug interactions

CYP2C8 Inhibitors and Inducers: 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.

Use in specific populations

Pregnancy: Limited data with AVANDIA in pregnant women are not sufficient to determine a drugassociated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Lactation: There are no data on the presence of rosiglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Rosiglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVANDIA and any potential adverse effects on the breastfed infant from AVANDIA or the underlying maternal condition.

Females and Males of Reproductive Potential: Discuss the potential for unintended pregnancy with premenopausal women as therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some anovulatory women.

Overdosage

Limited data are available with regard to overdosage in humans. In clinical trials in volunteers, AVANDIA 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.

Storage

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

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