This antimalarial was perhaps the first drug for which a robust statistical association with AA was established.
SOME EXAMPLES OF INDIVIDUAL ADR
– PHARMACOVIGILANCE IN ACTION
This
antimalarial was perhaps the first drug for which a robust statistical
association with AA was established (Caster, 1946). It was widely administered
as prophylaxis to US troops in malarial areas in 1943– 44, and an incidence of
AA of 7–28 cases per 100 000 per year was compared with 1–2 cases per 100 000
in personnel stationed in non-malarial areas not receiv-ing the drug. A
characteristic skin rash often preceded the haematological complication.
This
broad spectrum antibiotic was introduced in 1948. Even before its clinical use,
the theoretical possibility of haematological toxicity had been raised because
of its chemical similarity to the antipyretic amidopyrine that has an
association with neutrope-nia (Smadel and Jackson, 1944). Reversible changes
affecting haemopoiesis are relatively common with prolonged use of the drug and
may be because of mito-chondrial effects principally altering iron metabolism
(Oski, 1979). Case reports and subsequent epidemi-ological studies established
a causative link with apparently idiosyncratic AA (Modan et al., 1975), the occurrence of which is not related to the dose
or duration of drug exposure. Chloramphenicol is also used topically for the
treatment of conjunctival infec-tion, and there was controversy about whether
chlo-ramphenicol eye drops may cause AA (Rayner and Buckley, 1996). Cases of AA
in patients receiving chloramphenicol eye drops have been reported, but the
incidence of AA does not appear to be above the background level to be expected
in the absence of any drug exposure. A recent study in the United Kingdom,
where chloramphenicol eye drops are still widely prescribed, failed to
demonstrate detectable serum levels of chloramphenicol after 1–2 weeks of
topical ocular treatment (Walker et al.,
1998). The authors felt that this was theoretical evidence against a potential
mechanism for toxicity with this route of administration, which together with
the absence of epidemiological evidence failed to support calls for the
abolition of topical chloramphenicol use. Indeed in the United Kingdom, it is
now obtainable ‘over the counter’ without medical prescription.
Aplastic
anaemia is a rare complication with these second line agents for the treatment
of inflammatory arthritis. Neutropenia and/or thrombocytopenia often precede
the development of AA, and regular monitor-ing allows the cessation of drug
before this complica-tion arises (Willame et
al., 1987).
This
potent non-steroidal anti-inflammatory drug (NSAID) was associated with a
significant incidence of AA and its use is now restricted in the UK to the
management of severe refractory Ankylosing Spondylitis under hospital
supervision.
This
is characterised by isolated anaemia and reticulo-cytopenia and the absence of
nucleated red cell precur-sors in an otherwise normal marrow. This reaction is
rare, but there is overlap with AA as with agranulocy-tosis in the implicated
causative agents (Ammus and Unis, 1987).
Between
1993 and 1998, there were sporadic reports of PRCA associated with neutralising
antibodies to erythropoietin presenting with resistance to therapy in patients
receiving the agent subcutaneously for renal anaemia. Between 1998 and 2000, an
increased number of cases were reported in France, and 12 of 13 patients had
received one particular subcutaneous formulation (Eprex) (Casadevall et al., 2002). In 2002, several European
regulatory authorities mandated intravenous rather than subcutaneous
administration of the Eprex product as a consequence. A detailed analysis of
reports of this ADR for all preparations of erythropoietin from the American
Food and Drug Administration (FDA) and from the manufacturers between January
1998 and April 2004 was reported in the New
England Journal of Medicine (Bennett et
al., 2004). Subcutaneous administration of proteins is known to be associated with an increased poten-tial to induce
antibody formation (Porter, 2001). In the case of subcutaneous Eprex, it seems
that stabilis-ers and lubricating oil in the plungers of the pre-filled syringe
preparations were responsible for the increased immunogenicity rather than the
erythropoi-etin itself (Locatelli et al.,
2004).
Neutropenia
is defined by the lower limit of the refer-ence range that will vary between
laboratories but becomes progressively significant in terms of infec-tion risk
below 1 5 × 109/l.
Agranulocytosis refers to severe neutropenia < 0 5×109/l. The principal
mech-anism in drug-induced agranulocytosis is immune, and a degree of
peripheral neutrophil destruction is involved as well as myelosuppression. The
cellular-ity of the marrow, and the degree of representation of early myeloid
cells, may help to predict recovery time and response to colony-stimulating
factor (CSF) therapy (Julia et al.,
1991; Sprikkelman, de Wolf and Vellenga, 1994). There is considerable overlap
with drugs implicated in the aetiology of idiosyncratic AA. Some drugs merit
further individual consideration.
This
antipsychotic agent clozapine was introduced in the late 1960s as an effective
therapy for schizophre-nia without the extrapyramidal side effects associated
with other major tranquillisers. In Finland in 1975, 16 patients taking
clozapine developed neutropenia, an estimated incidence of 2% (Amsler et al., 1977). Half of them died of
infective complications. Because of its unique therapeutic advantages, the drug
has not been withdrawn, but mechanisms for ensuring careful monitoring were
established. The use was restricted to patients registered with the Clozaril
Patient Moni-toring Service (CPMS) run by the original drug manu-facturer,
Novartis Pharmaceuticals. With subsequent generic availability, similar
monitoring systems have been set up by generic manufacturers. Regular blood
count specimens are required to be sent to the central laboratory of the
monitoring service, which requires to confirm that the total white cell count
is > 3 0 × 109/l
and the neutrophil count > 1 5 × 109/l and that
signif-icant downward trends in values above these levels are not occurring
before drug supply is issued just to last until the next count is due. All
instances of agran-ulocytosis are therefore reported, and large
epidemio-logical studies (Alvir et al.,
1993; Munro et al., 1999) have
subsequently accurately confirmed an incidence of approximately 1% for this complication
and have helped to identify potential risk factors, as described above. Early
discontinuation and prompt recognition enabling immediate appropriate
supportive care have markedly reduced the incidence and morbidity of this
severe reaction to acceptable levels.
Propylthiouracil,
carbimazole and methimazole (the active ingredient to which carbimazole is
metabolised) are associated with an incidence of agranulocytosis of 3/100 000
per year. The highest incidence is in the first 3 months of treatment, perhaps
as susceptible individuals identify themselves (Cooper et al., 1983).
Agranulocytosis
was found to have an incidence in 1/700 patients within the first 3 months of
treat-ment, following which the risk was low (Keisu and Ekman, 1992).
Nomifensine
was introduced in Europe in 1976 as a new tricyclic antidepressant with fewer
anticholiner-gic and sedative effects than its older counterparts. The
problematic toxicity of standard tricyclics in over-dosage made it an
attractive alternative. Autoimmune haemolytic anaemia (AIHA) had not been
observed during pre-licensing studies. Four cases were reported in the United
Kingdom in 1978–79 (Stonier, 1992), but the incidence was thought to be very
rare. An increase in reports between 1983 and 1986, including a fatal case, led
to the withdrawal of the drug from the market by the manufacturer.
Many
patients receiving anticoagulation with heparin will demonstrate mild,
transient, clinically insignifi-cant and non-immune minor thrombocytopenia. The
rarer immune-mediated heparin-induced thrombocy-topenia (HIT) is caused by an
immunoglobulin G (IgG) autoantibody directed against a complex of heparin and
platelet factor 4 (PF4), a platelet surface protein, which may appear after
7–10 days of heparin therapy (or earlier if the patient has been exposed
previously). Although more frequent with unfraction-ated heparin, it can also
occur with low molecu-lar weight heparin (LMWH) preparations (Warkentin, Chong
and Greinacher, 1995). Unlike with other drug-induced immune thrombocytopenias
(ITP), numeri-cally severe thrombocytopenia is not usual, and the platelet
nadir is typically around 50×109/l.
It however induces a highly prothrombotic state because of immune-mediated
platelet activation. New venous or arterial thrombosis occurs in some 50% of
cases, and there is a high morbidity/mortality. Patients receiv-ing heparins should
have regular platelet count moni-toring. If significant thrombocytopenia and/or
new thromboembolic events occur in heparinised patients, then heparin should be
discontinued and tests for platelet/PF4 antibodies undertaken. If continuing
anti-coagulant treatment is required, then a direct thrombin inhibitor such as
hirudin or argatroban is appropriate (Schiele et al.,1995).
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