Introduction - Uppsala Monitoring Centre

SED 1963: agranulocytopenia, thrombocytopenias and pancytopenia. It is not
proven that it is more toxic than the others.
Withdrawn: an FDA warning that it could cause Stevens-Johnson syndrome
was given in 1968 after a report of a large number of cases (Carroll et al.,
1966). It was withdrawn in Canada in 1978, UK and Sweden in 1984; France,
UK and United Arab Emirates in 1986, Pakistan in 1988, also Argentina.
Commercial manufacture of the drug has been discontinued by at least one
major manufacturer but supplies can still be obtained on special request,
particularly for patients with dermatitis herpetiformis in which condition it has
been claimed to be beneficial (WHO, 2003).
Availability: not known
Drug Lifespan: 21 years
Delay in recognition: 4 years
Delay in regulatory action: 17 years
Time span of withdrawals: 10 years
Comment: aplastic anaemia, agranulocytosis and thrombocytopenia are
sulphonamide class effects (Albahary, 1953).
1957 Phenformin, Phenylethylbiguanide (Dibotin, Diphod)
Marketed in the UK in 1969.
Use: an antidiabetic drug (a biguanide)
ADR: lactic acidosis. A study in 1959 showed that an early diguanide
(phenethyldiguanide) caused lactic acidosis in 10% of patients and that it
could be fatal (Walker and Linton, 1959). The first paper was ‘phenformin
acidosis’ published in 1962 (Gottlieb, 1962). Several papers were published in
1963, one a report from a conference saying that ‘It is possible that
Phenformin may add to the excess lactic acid.’ (Danowski et al., 1963);
‘another reported the death of two patients.’ (Bernier et al., 1963). A study of
330 cases of lactic acidosis showed that 86% had had phenformin, 9%
buformin and 5% metformin (Ching et al., 2008; Luft, 1978). FDA office
estimated that 4 in 1000 users died from lactic acidosis (Citizen Action Group,
1985).
The frequency of lactic acidosis was estimated as 1 per 1110 patient-years
(Stang, 1998). In 1960 it was found that the blood lactate and plasma
hydrazine levels were raised at rest and this was exaggerated on exercise
(BMJ, 1960).
SED 1963: blood lactic acid raised.
A paper published in 1978 (Bergmanet al., 1978) showed more cases of lactic
acidosis with phenformin than with metformin. This paper led to the withdrawal
in Sweden. The sale of phenformin in the United States went up after there
was a threat that the drug would be withdrawn from the market (Lunde, 1980).