IN THIS ISSUE:

Serious hepatic reactions

Troglitazone (Romozin ) is the first of a new class of orally active anti-diabetic agents. It was launched in the United States and Japan in March, and in the UK in October this year.

By early November, 40 cases of serious hepatic reactions occuring during treatment with troglitazone had been reported worldwide. None had originated in the UK. Reactions included severe hepatocellular damage, hepatic necrosis and hepatic failure. One patient had died and another required liver transplantation. GlaxoWellcome and Sankyo Pharma, the companies marketing troglitazone in the UK, wrote to doctors and pharmacists warning about these reactions and providing advice about monitoring liver function tests.

We have now become aware of over 130 cases (6 fatal) worldwide of hepatic reactions to troglitazone. The average time to the onset of the reaction was 3 months (range 2 weeks to 8 months). In the UK, some 5,000 patients have been treated with one reported case of liver dysfunction. At present no clear risk factors for the development of hepatic reactions have been identified which might allow the drug to be used safely in some patients. The frequency of these reactions is currently unclear. Approximately 370,000 patients worldwide have been treated with the drug for at least 3 months.

Overall it is considered that, based on present information, the risks of troglitazone therapy outweigh the potential benefits. It has therefore been voluntarily withdrawn from the UK as from 1 December 1997 by the companies concerned, who have informed doctors and pharmacists by letter. Any patient who is taking troglitazone should be transfered to an alternative therapy for the treatment of their diabetes.

Further cases of valvular heart disease

In the last issue of Current Problems in Pharmacovigilance reported on the occurence of Valvualr heart disease associated with the combination of fenfluramine (Ponderax Pacaps) and phentermine (Ionamine and Duromine) .¹

Following publicaion of a paper in the New England Journal of Medicine² the number of cases reported in the USA increased to more than 100. Some of these were associated with dexfenfluramine (Adifax ) or fenfluramine treatment alone but none with phentermine alone. Patients developed mitral, aortic, tricuspid or mixed value disease. A survey in the USA also described asymptomatic cases where only physical examination and/or echocardiography revealed the abnormalities.

The manufacturers have voluntarily withdrawn fenfluramine and dexfenfluramine worldwide and effectively these drugs have not been available in the UK since 1 October 1997. Doctors and pharmacists were informed of this via an Epinet message and by a letter from the company.

We have received 3 retrospective UK reports of cardiac complications following fenfluramine and/or dexfenfluramine treatment. All cases were confirmed by echocardiography.

Doctors should be alert to the possibility of cardiac complications in patients treated with fenfluramines. If any symptoms and signs of valvular heart disease are discovered, doctors may wish to refer patients to a cardiologist.

References

1. CSM/MHRA Current Problems in Pharmacovigilance 1997: 23: 12.
2. Connolly HM, et al, New Eng. J. Med. 1997, 337: 581

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