Antidiabetic Drugs

Posts Tagged ‘Rezulin’

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Adverse Effects and Precautions

Troglitazone has been associated with severe hepatic reactions, sometimes fatal, which has led to its withdrawal in most countries. Regular monitoring of liver function during therapy, and withdrawal of the drug in any patient who develops j aundice or signs of liver dysfunction, is required. It should not be given to patients with pre-existing moderate or severe elevations of liver enzyme values, or active liver disease. Increased plasma volume has been reported in healthy subjects given troglitazone: it should be used with caution in patients with heart failure. Other adverse effects reported in patients receiving troglitazone include dizziness, headache, fatigue, musculoskeletal pain, and nausea and vomiting. There is no evidence of hypoglycaemia associated with the use of troglitazone alone.

Effects on the liver. The UK CSM was aware of over 130 cases of hepatic reactions to troglitazone worldwide as of December 1997, although only 1 had been in the UK. There had been 6 deaths. The average time to the onset of the reaction was 3 months, but the frequency of these reactions, and the existence of risk factors predisposing to them, were unclear. The manufacturers had voluntarily withdrawn the drug in the UK. The US manufacturer and the FDA recommended a schedule for routine monitoring of liver function in November 1997 and revised this again in December 1997. It was estimated that 2% of patients treated with troglitazone would have elevated liver enzyme values necessitating discontinuation of the drug. The FDAhad received 560 reports of troglitazone-associated hepatotoxic-ity by June 1998. There were 24 cases of hepatic failure which were likely to have been caused by the drug 21 patients died and 3 patients received transplants. More intensive liver function monitoring recommendations were made by the US manufacturer again in July 1998 and in June 1999. Subsequently the manufacturer withdrew the drug in Australiaia, Japan, and the USA in March 2000. The clinical details of 94 cases of liver failure associated with troglitazone, which were reported to the FDA, have been reviewed.

Interactions

Troglitazone may enhance the hypoglycaemic effects of sulfonylureas dosage adjustment may be necessary. There is a possibility that troglitazone may enhance the metabolism of drugs metabolised by cytochrome P450 isoenzyme CYP3A4, including some oral contraceptives and terfenadine.

Ciclosporin. For the effect of troglitazone on blood concentrations of ciclosporin see Hypoglycaemic Drugs.

Colestyramine. Colestyramine markedly impaired the absorption of troglitazone.

Pharmacokinetics

Troglitazone is rapidly absorbed after oral doses, with peak plasma concentrations 1 to 3 hours after a dose. Bioavailability is about 53% absorption is markedly increased in the presence of food. In the body, troglitazone is more than 99% bound to plasma albumin. It is extensively metabolised in the liver and excreted largely in faeces as metabolites small amounts of metabolites are excreted in urine. Plasma elimination half-life ranges from 10 to 39 hours.

Uses and Administration

Troglitazone is a thiazolidinedione oral antidiabetic (see Rosiglitazone Maleate). It has been given orally for the treatment of type 2 diabetes mellitus although as mentioned above it has been withdrawn in most countries owing to hepato-toxicity.

Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Rezulin¤; Japan: Noscal¤; Mexico: Rezulin; United Kingdom: Romozin¤; United States: Rezulin¤

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A report describes promising results from trials of a combination of the drug troglitazone (Rezulin) and insulin in Type II diabetics. Researchers at St. Michael’s Hospital, Toronto, Canada, administered 200 or 400 mg/day of troglitazone, in addition to insulin, to 539 diabetics to collect data. It was found that the combination therapy was effective in reducing levels of both HbA1c (hemoglobin) and fasting plasma glucose and that use of troglitazone allowed patients to reduce their daily insulin requirements. It was further found that those participants whose baseline HbA1c was 140 percent above the normal range experienced the greatest benefit from the combination therapy, with hemoglobin levels falling by an average of 1.35 percent. Results of the study were presented by Dr. Lawrence Leiter, director of the lipid disorders clinic at St. Michael’s Hospital, Toronto, at the American Diabetes Association’s 59th Annual Scientific Sessions in San Diego.

Thiazolidinediones were developed in Japan and have been available in the United States since March 1997. Today, more than 600,000 people in the United States are being treated with troglitazone. Until recently, troglitazone was the only available member of this group.

Troglitazone

Brand Name Drug: Rezulin, Resulin or Romozin

Troglitazone has been shown to improve peripheral insulin sensitivity (ie, increase peripheral glucose disposal) by an as yet undetermined mechanism. We do know that the drug binds to an intranuclear receptor (PPARgamma), and this complex has been found to function as a transcriptional activator. How PPARgamma activation by troglitazone results in improved insulin sensitivity is not clear.

Troglitazone comes in 200-mg and 400-mg tablets, and patients are started at 200 mg in the morning with food to aid in rapid absorption. Thereafter, the dose can be increased to 400 mg/day and eventually to the maximum of 600 mg/day. The tablets should be given once in the morning, as there is no advantage to dividing the dose.

Troglitazone was initially proven effective in type 2 diabetic patients who already were being treated with insulin. In 1998, troglitazone was approved by the FDA for use as monotherapy in the treatment of type 2 diabetes. Studies in patients already receiving insulin therapy have shown a significant improvement in HgbA₁C and a reduction in insulin requirements. A 1.5% reduction in HgbA₁C has been reported when troglitazone is added to conventional insulin therapy. Monotherapy has been less effective, with an average decrease in HgbA₁C of .9%. Whether used as single or combination therapy, there is a lag time of several weeks for troglitazone to have a glucose-lowering effect and a delay of several months for maximum glucose lowering effect. The drug is not effective in those patients with relative insulinopenia. It is important to use clinical judgment in determining which patients with type 2 diabetes have significant insulin resistance with hyperinsulinemia and therefore are better candidates for troglitazone therapy. Significant reduction in HgbA₁C recently has been shown when troglitazone is used in combination therapy with glyburide or metformin.

Adverse effects range from mild peripheral edema and weight gain to recendy reported cases of florid hepatic failure. Weight gain can be seen in many patients, likely secondary to increased insulin sensitivity and improved glycemic control. The cases of hepatotoxicity are more concerning and recendy were detailed in Annals of Internal Medicine. In the initial clinical studies, troglitazone was associated with mild increases in liver function tests (1.9% compared with .6% for placebo) and reversible jaundice. However, there have been at least five cases of troglitazone-induced hepatotoxicity and death in the United States since the drug’s release in 1997.

Despite these events, the incidence of liver disease is rare, and troglitazone remains a useful weapon against type 2 diabetes, particularly in those with significant insulin resistance. The FDA now recommends that patients undergo monitoring of their liver function tests (LFTs) on a monthly basis for the first eight months of use. Over the next four months, LFTs can be monitored every other month and then periodically thereafter. Troglitazone should be stopped with any evidence of significant hepatic impairment or a threefold rise in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.

Recendy, two additional thiazolidinediones have become available. It is hoped that rosiglitazone and pioglitazone will have many of the same insulin-sensitizing effects as troglitazone without the risk of hepatic injury.

Approximately 40% of all type 2 diabetics take a drug from the sulfonylurea class (see TABLE 2) — usually glyburide, glipizide, or chlorpropamide. The sulfonylureas cause the beta-cells of the pancreas to increase insulin secretion. Weight gain is common with sulfonylurea use and ranges from 1.8 to 2.8 kg.

Metformin (Glucophage) is a biguanide antidiabetic agent that reduces basal hepatic glucose production by altering gluconeogenesis and/or glycogenolysis. Additionally, metformin decreases insulin resistance by promoting insulin-sensitive glucose uptake by muscle cells. Metformin can also reduce triglycerides and low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. Weight reductions of 0.6 to 0.8 kg have been noted in study subjects taking metformin.When metformin is combined with the sulfonylurea glyburide, however, average weight gains of 0.7 kg have been reported.

Acarbose (Precose) is an alpha-glucosidase inhibitor as well as an inhibitor of pancreatic alpha-amylase. These enzymes are responsible for the hydrolysis of oligosaccharides and related saccharides in the small intestine. Inhibition of these enzymes results in reductions in the rate and extent of carbohydrate digestion and absorption of glucose in the body. Patients treated with acarbose tend to experience no changes in weight or serum lipids.

Troglitazone (Rezulin) belongs to a new class of drugs called thiazolidinediones. It works by decreasing insulin resistance. Its primary actions involve increasing glucose disposal from the blood stream into muscle tissue and decreasing glucose production in the liver. No or very small weight changes in patients taking troglitazone are seen. Decreases in plasma triglyceride and free fatty acid levels have also been reported.

Approximately three-quarters of all the insulin used in the U.S. is taken by people with type 2 diabetes. Exogenous insulin reduces hepatic glucose production in type 2 diabetics. It also increases insulin-stimulated glucose utilization and endogenous insulin secretion. Weight gain is common in patients using insulin and may include gains up to 6.0 kg in a 12-month period.