Introduction - Uppsala Monitoring Centre

1952 Iproniazid (Marsilid)
Was introduced for TB, but it was first introduced for angina and depression in
1957.
Use: a monoamine oxidase inhibitor (MAOI)
ADR: four patients were reported with hepatitis (hepatocellular and sometimes
necrosis) in 1954 (Bosworth et al., 1955). In 1955 an interaction between
iproniazid and the tyramine in food, especially cheese, which caused
hypertensive crises, was recognised, (Ogilvie, 1955). Hepatocellular toxicity
and cirrhosis with 20% mortality (Kline, 1958), but the incidence was
estimated as under 0.05% (Benaim & Dixon, 1958).
SED 1960: particularly toxic for the liver. Fatalities 15%
SED 1963: hypertensive crises described. Robert Temple of the FDA said ‘it
took 3 years to discover any evidence that it was hepatotoxic and 6 years to
recognise that it should be off the market, after hundreds of deaths from liver
failure. Given its approximately 10% rate of liver injury, it is not easy to see
why discovery of its toxicity took so long.’ (Temple, 1996).
Withdrawn: in the USA in 1959, in Canada in 1964 and in Italy.
Availability: MAOIs retain a place in the treatment of serious depressive illness
although there is no international consensus on which compounds should be
preferred. Thus, iproniazid remains available in several countries (WHO,
2003).
Drug Lifespan: 7 years
Delay in recognition: 2 years
Delay in regulatory action: 6 years
Time span of withdrawals: 5 years
Comment: it had been known for 50 years that cheese contained tyramine,
which was capable of causing a rise in blood pressure. ‘there would seem to
be no reason why their effects should not have been predicted.’ (Doll, 1969).
The interaction with tyramine is a class effect, but autoimmune hepatitis is
specific to iproniazid. Further reading: KK Jain’s Drug-induced Neurological
Disorders. Hogrefe & Huber Publishers 2001, 406-414.
1953 Thenalidine (Sandostene)
Introduced in Europe and in 1955 in the USA.
Use: a piperadine anti-histamine
ADR: severe neutropenia and agranulocytosis (Adams & Perry, 1958)). It is to
the credit of Sandoz Pharmaceuticals that the drug was immediately
withdrawn on 9th July 1958 only four days after the first report (Zolov,1958).
SED 1958: no mention
SED 1960: agranulocytosis mentioned
Withdrawn: in the USA in 1958 after 3 cases of agranulocytosis, two of which