example several reports coming from the same
doctor or practice (is the so-called hepatotoxi-
city really a local outbreak of viral hepatitis or
due to some strange doctor still giving aspirin to
children and causing Reye syndrome).- Carefully reassess the balance of benefit
and risk and determine if this has changed
and, if so, in what way. The ADR data (yellow
cards in the United Kingdom) form the
numerator. The company is in the best position
to know the number of patients treated (the
denominator). Has the ratio changed? What is
the indication for the drug (rare, severe
adverse effects may be acceptable in an effec-
tive anticancer agent, whereas almost total
safety would be demanded for an oral con-
traceptive used in fit, healthy people early in
adult life). If the drug is withdrawn what
remedies remain for the management of the
indication – and what is the picture of their
comparative toxicity? Make quite sure that
the problem is not arising from some new,
previously undescribed iatrogenic disease
(e.g. the oculomucocutaneous syndrome with
practolol); in a similar way rule out long-
latency adverse reactions (e.g. sclerosing peri-
tonitis – again with practolol). Be careful to
determine what other drugs the patients
were receiving (is the problem a drug–drug
interaction). - Consider whether the current pharmacovigi-
lance program is adequate to deal with the
new issues arising. The situation may have
greatly changed – new data may focus attention
on one specific adverse effect and, for example,
a case control study on that reaction might need
to be established with the General Practitioner
ResearchDatabase (GPRD),orsome other data-
base, as a matter of extreme urgency. It is now
known what the cases must be in such a study
and that changes the picture completely. Any
such study must almost always need to be con-
ducted in an existing database as time and the
urgency of the situation will not permit any
study which requires the prospective acquisition
of data.
44.4 Escaping from the maze
Although escape may be impossible, and the drug
has to be withdrawn in the best interests of the
patients, there have been survivors. The techniques
used have included the following:1.Focussed surveillance:The classic example is
clozapine and the Clozaril Patient Monitoring
Service. Clozapine is a valuable antischizophre-
nic agent used in patients unresponsive to other
antipsychotic agents. Its side-effect profile
includes fatal agranulocytosis, myocarditis
and cardiomyopathy. Because the drug can be
effective in severe schizophrenia when other
remedies have failed it was desired to maintain
it in clinical use despite the known incidence of
uncommon blood dyscrasias and cardiac
adverse reactions. This was accomplished by
establishing the Clozaril Patient Monitoring
Service with which the patient, prescriber and
supplying pharmacist must be registered before
the drug will be supplied. The monitoring ser-
vice ensures that leukocyte and differential
blood counts, plus other observations, are
undertaken at suitable intervals. The scheme
has been highly effective and similar schemes
have been established by other pharmacutical
houses supplying the drug. Clearly, this kind of
intense focussed management can be used only
when it will prevent withdrawal of a uniquely
valuable therapeutic agent active against life-
threatening disease.2.Contraindication in a susceptible subpopula-
tion:Aspirin (acetylsalicylic acid) has been
associated with the occurrence of Reye syn-
drome and, as a result, the Committee on
Safety of Medicines has advised that aspirin-
containing preparations should not be given
to children and adolescents under 16 years of
age unless specifically indicated, for example
for Kawasaki syndrome. Establishing this con-
traindication, relating to what is probably the
most widely used medicine known, involved
educating the whole community and repre-
sented one of the most remarkable therapeutic
achievements of the late twentieth century. The582 CH44 DRUG WITHDRAWALS FROM THE MARKET – CAUSES AND CONSEQUENCES