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 The manufacturers had voluntarily withdrawn the drug in the UK.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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