Monograph: |
AMODIAQUINE
Adverse Effects and Precautions
As for Chloroquine, but amodiaquine was associated
with hepatitis and a much higher incidence of agranulocytosis
when it was used for the prophylaxis of malaria.
Earlier isolated reports of amodiaquine causing severe neu-
tropenia were usually when it had been used in anti-inflam-
matory doses for rheumatoid arthritis, but there was a cluster
of cases in 1986 associated with its use in malaria prophylax-
is.' In all. 23 cases of agranulocytosis, 7 of which were fatal.
were reported in the UK. USA. and Switzerland during a 12-
month period ending March 1986. Nearly all of these patients
had used the drug at a dosage of 400 mg weekly and the peri-
ods of exposure ranged from 3 lo 24 weeks.' Some of these
patients also had evidence of liver damage' and there have
been other reports of hepatotoxicity associated with the pro-
phylactic use of amodiaquine.' Examination of data submit-
ted to the UK Committee on Safety of Medicines' suggested
that the frequency of adverse reactions to amodiaquine was
about 1 in 1700 for serious reactions. 1 in 2200 for blood dis-
orders. 1 in 15650 for serious hepatic disorders, and 1 in
15 650 for fatal reactions. In contrast the frequency ofagran-
ulocytosis in users in France"* has been estimated to be I in
25 000. Worldwide"* the risk of severe reactions appears to be
between I in 1000 and I in 5000. The manufacturers report-
edly had 42 cases of serious adverse effects during amodi-
aquine prophylaxis, between 1985 and 1991; there were 28
cases of agranulocytosis (9 deaths) and 14 of hepatitis (3
deaths). Whether there was significantly less risk when amo-
diaquine was given for treatment of malaria rather than
prophylaxis was not certain.
It has been suggested that an immunological reaction to amo-
diaquine quinone imine. which can be produced by autoxida-
tion among other processes, may partially account for
omodiaquine's greater tendency to induce agranulocytosis
compared with chloroquine.
The acute toxicity of amodiaquine appears to differ from that
of chloroquine in that there have been no reports of cardiovas-
cular symptoms following overdosage with amodiaquine' but
intoxication with amodiaquine is also far less frequent than
chloroquine poisoning. However, large doses of amodiaquine
have been reported to produce syncope, spasticity. convul-
sions, and involuntary movements.
Pharmacokinetics
Aroodiaquine hydrochloride is readily absorbed from the gas'
tro-intestinal tract. Amodiaquine is rapidly converted in the
liver to the active metabolite desethylamodiaquine, only a
negligible amount of amodiaquine being excreted unchanged
in the urine. The plasma elimination half-life of desethylamo-
diaquine has varied from I to 10 days or more. Amodiaquine
and desethylamodiaquine have been detected in the urine sev-
eral months after administration.
Uses and Administration
Amodiaquine is a 4-aminoquinoline antimalarial with an ac-
tion similar to that of chloroquine. It is as effective as
chloroquine against chloroquin sensitive strain* of Plasmo-
dium falciparum and is also etiective against somechloro-
quine-resistant strains, although resistance to amodiaquine
has developed and there may be partial cross-resistance be-
tween amodiaquine and chloroquine. Because of resistance
and the risk of major toxicity amodiaquine is not recommend-
ed for the prophylaxis of malaria.
Amodiaquine is given by mouth as the hydrochloride, but
doses are expressed in terms of amodiaquine base. For the
treatment of falciparum malaria a total dose of 35 mg/ kg body wt. Has been given over three days.
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