Introduction - Uppsala Monitoring Centre

een undertaken (Dykes, 1998), but a Lyon University thesis was published in
1954 entitled ‘Les Ictères au Cincophen’ [The jaundice caused by Cincophen]
(Cerf R, 1954). Cirrhosis was reported in 1957; toxic hepatitis was reported in
1957 (Ann Int Med, 1957) and in 1991 (Prieto, 1991). A case of
agranulocytosis was first reported in 1936 (Shapiro & Lehman, 1936).
Haemolytic anaemia was described in 1937 (Esbach & Bérard, 1937).
SED 1952: agranulocytosis, hepatitis and jaundice and yellow atrophy (Lenyer
et al., 1947; Cabot & Cabot, 1925)
SED 1957 acute yellow atrophy
SED 1960 agranulocytosis
Withdrawn: in Germany in 1991 and in Spain in 1992 for cytolytic hepatotoxicity
and cirrhosis, which had a 50% fatality rate (Alvarez-Del-Castillo et al., 1991).
Also withdrawn in Italy and South Africa.
Availability: still available in Spain (Prieto et al., 1991), Italy, US and the
Netherlands.
Drug Lifespan: 83 years
Delay in recognition: 15 years
Delay in regulatory action: 68 years
Time span of withdrawals: 1 year
Comment: perhaps the Prieto paper stimulated Germany and Spain to withdraw
cincophen, but there was ample evidence of the problem in the 1930s. It
would appear that there were two types of hepatitis: the first a benign
cholestatic hepatitis, which could come on after dechallenge and was mild,
and secondly an allergic hepatitis which sometimes occurred on rechallenge
and this might be accompanied by an allergic rash. This could cause a rapid
death. Only enormous doses could produce hepatic damage in rabbits
(Albahary, 1953).
1912 Phenobarbitone (Luminal)
Synthesised in 1911 by Hörlein and introduced the following year, but not in
England until 1923 and in France in 1927.
Use: sedative, hypnotic and antiepileptic
ADR: by 1928 forty-one papers had been published on cutaneous reactions with
phenobarbitone; the earliest dating back to 1912 (Menninger, 1928) Severe
cutaneous reactions (Lyell’s disease and Stevens-Johnson syndrome), fatal
poisoning (20 per year in the UK) and abuse. Known to cause habituation in
1928 (Lewin, 1928). ‘I have seen a large number of cases where a definite
craving for the drug has arisen after repeated daily administration, and the
daily use of the drug has been continued in spite of strong medical advice to
the contrary. Addiction to the barbituric acid group is different from morphine
and heroin in that sudden discontinuation is not followed by severe withdrawal