Avandia

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Avandia Information

Generic Name: Rosiglitazone Maleate

Brand Name: Avandia

Other Common Names: Rosiglitazona

Avandia (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. Avandia is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes). Avandia improves glycemic control while reducing circulating insulin levels.

Indications:

Avandia (rosiglitazone maleate) is indicated as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Avandia is also indicated for use in combination with metformin when diet, exercise, and Avandia alone or diet, exercise, and metformin alone do not result in adequate glycemic control in patients with type 2 diabetes. For patients inadequately controlled with a maximum dose of metformin, Avandia should be added to, rather than substituted for, metformin. 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. Prior to initiation of therapy with Avandia, secondary causes of p.o. glycemic control, e.g., infection, should be investigated and treated.

How Does Avandia Work?

Pharmacological studies in animal models indicate that Avandia (rosiglitazone) improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors.

The active ingredient in Avandia, 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 (PPARg). In humans, P.A. receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARg nuclear receptors regulates the transcription of insulinresponsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARg-responsive 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 Avandia (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. Rosiglitazone also prevents the development of overt diabetes in both the db/db mouse and Zucker fa/fa Diabetic Fatty rat models.

In animal models, Avandia's (rosiglitazone) antidiabetic activity was shown to be mediated by increased sensitivity to insulin's action in the liver, muscle, and adipose tissues. 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.

Avandia Ingredients and Composition

How To Take Avandia and Avandia Dosage and Administration

The management of antidiabetic therapy should be individualized.

Monotherapy

The usual starting dose of Avandia is 4 mg administered either as a single dose once daily or in divided doses twice daily. For patients who respond to Avandia inadequately following 12 weeks of treatment as determined by reduction in FPG, the dose may be increased to 8 mg administered as a single dose once daily or in divided doses twice daily. In clinical trials, the 4 mg twice daily regimen resulted in the greatest reduction in FPG and HbA1c.

Combination Therapy with Metformin

The usual starting dose of Avandia in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. The dose of Avandia may be increased to 8 mg/day following 12 weeks of therapy if there is insufficient reduction in FPG. Avandia may be administered as a single daily dose in the morning, or divided and administered in the morning and evening.

Avandia may be taken with or without food.

No dosage adjustments are required for the elderly.

No dosage adjustment is necessary when Avandia is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and Avandia is also contraindicated in patients with renal impairment.

Therapy with Avandia should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT 2.5 times the upper limit of normal at start of therapy. Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Avandia and periodically thereafter.

There are no data on the use of Avandia in patients under 18 years of age; therefore, use of Avandia in pediatric patients is not recommended.

If you suspect a Avandia Overdose

Limited data are available with regard to Avandia overdose in humans. In clinical studies 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.

Avandia Side Effects

Avandia Precautions and Contraindications

Due to its mechanism of action, Avandia is active only in the presence of insulin. Therefore, Avandia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

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 in maintaining the efficacy of drug therapy.

It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. Patients should be informed that blood will be drawn to check their liver function prior to the start of therapy and every two months for the first twelve months, and periodically thereafter. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.

Cardiac failure and other cardiac effects:

Avandia, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. Avandia should be discontinued if any deterioration in cardiac status occurs.

Patients with New York Heart Association (NYHA) Class 3 and 4 cardiac status were not studied during the clinical trials. Avandia is not recommended in patients with NYHA Class 3 and 4 cardiac status.

In two 26-week U.S. trials involving 611 patients with type 2 diabetes, Avandia plus insulin therapy was compared with insulin therapy alone. These trials included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions, including peripheral neuropathy (34%), retinopathy (19%), ischemic heart disease (14%), vascular disease (9%), and congestive heart failure (2.5%). In these clinical studies an increased incidence of cardiac failure and other cardiovascular adverse events were seen in patients on Avandia and insulin combination therapy compared to insulin and placebo. Patients who experienced heart failure were on average older, had a longer duration of diabetes, and were mostly on the higher 8 mg daily dose of Avandia. In this population, however, it was not possible to determine specific risk factors that could be used to identify all patients at risk of heart failure on combination therapy. Three of 10 who developed cardiac failure on combination therapy during the double blind part of the studies had no known prior evidence of congestive heart failure, or pre-existing cardiac condition. The use of Avandia in combination therapy with insulin is not currently indicated.

Hypoglycemia:

Patients receiving Avandia in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Edema:

Avandia should be used with caution in patients with edema. In a clinical study in healthy volunteers who received Avandia 8 mg once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.

Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandia should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure.

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Avandia, and may be dose related. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and Avandia.

Weight Gain:

Dose-related weight gain was seen with Avandia alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Hematologic:

Across all controlled clinical studies, decreases in hemoglobin and hematocrit (mean decreases in individual studies <1.0 gram/dL and <3.3%, respectively) were observed for Avandia alone and in combination with other hypoglycemic agents. The changes occurred primarily during the first 3 months following initiation of Avandia therapy or following an increase in Avandia dose. White blood cell counts also decreased slightly in patients treated with Avandia. The observed changes may be related to the increased plasma volume observed with treatment with Avandia and may be dose realated.

Ovulation:

Avandia, like other thiazolidinediones, may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance. As a consequence of their improved insulin sensitivity, these patients may be at risk for pregnancy if adequate contraception is not used.

Although hormonal imbalance has been seen in preclinical studies (see Carcinogenesis, Mutagenesis, Impairment of Fertility below), the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandia should be reviewed.

Edema:

Avandia should be used with caution in patients with edema. In a clinical study in healthy volunteers who received Avandia 8 mg once daily for 8 weeks, there was a statistically significant increase in median plasma volume (1.8 mL/kg) compared to placebo.

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Avandia.

Use in Patients with Heart Failure:

In preclinical studies, thiazolidinediones, including rosiglitazone, cause plasma volume expansion and pre-load-induced cardiac hypertrophy. Two ongoing echocardiography studies in patients with type 2 diabetes (a 52-week study with Avandia 4 mg twice daily [n= 86] and a 26-week study with 8 mg once daily [n= 90]), have shown no deleterious alteration in cardiac structure or function. These studies were designed to detect a change in left ventricular mass of 10% or more.

Patients with New York Heart Association (NYHA) Class 3 and 4 cardiac status were not studied during the clinical trials. Avandia is not indicated in patients with NYHA Class 3 and 4 cardiac status unless the expected benefit is judged to outweigh the potential risk.

Hepatic Effects:

Another drug of the thiazolidinedione class, troglitazone, has been associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death have been reported during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT 3X upper limit of normal) compared to placebo, and very rare cases of reversible jaundice were reported.

In clinical studies in 4598 patients treated with Avandia, encompassing approximately 3600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevation of ALT levels.

In controlled trials, 0.2% of patients treated with Avandia had elevations in ALT 3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with Avandia were reversible and were not clearly causally related to therapy with Avandia.

Although available clinical data show no evidence of Avandia induced hepatotoxicity or ALT elevations, rosiglitazone is structurally very similar to troglitazone, which has been associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death. Pending the availability of the results of additional large, long-term controlled clinical trials and postmarketing safety data following wide clinical use of Avandia to more fully define its hepatic safety profile, it is recommended that patients treated with Avandia undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Avandia in all patients. Therapy with Avandia should not be initiated in patients with increased baseline liver enzyme levels (ALT 2.5X upper limit of normal). In patients with normal baseline liver enzymes, following initiation of therapy with Avandia, it is recommended that liver enzymes be monitored every two months for the first twelve months, and periodically thereafter. Patients with mildly elevated liver enzymes (ALT levels one to 2.5X upper limit of normal) at baseline or during therapy with Avandia should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Avandia in patients with mild liver enzyme elevations should proceed with caution and include appropriate close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to 3X upper limit of normal in patients on therapy with Avandia, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain 3X the upper limit of normal, therapy with Avandia should be discontinued.

There are no data available to evaluate the safety of Avandia in patients who experience liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. Avandia should not be used in patients who experienced jaundice while taking troglitazone. For patients with normal hepatic enzymes who are switched from troglitazone to Avandia, a one week washout is recommended before starting therapy with Avandia.

If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Avandia should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Avandia and Alcohol Interaction

A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with Avandia.

Avandia and Women

Use of Avandia may cause resumption of ovulation in premenopausal, anovulatory women with insulin resistance. Therefore, contraceptive measures may need to be considered when Avandia is being used.

Drug related material was detected in milk from lactating rats. It is not known whether Avandia is excreted in human milk. Because many drugs are excreted in human milk, Avandia should not be administered to a nursing woman.

Avandia Clinical Trials and Studies

Storing Avandia

Store at 25° C (77° F); excursions 15° - 30° C (59° - 86° F).

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