Download Amodiaquine for the treatment of uncomplicated falciparum malaria

Amodiaquine for the treatment of uncomplicated falciparum malaria
Authors: Piero Olliaro & WRJ Taylor, WHO/CDS/TDR (3 April 2002)
1.
2.
3.
4.
5.
Synopsis
Background
Drug profile
Clinical data on amodiaquine
References
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1. Synopsis
Amodiaquine is a 4-aminoquinoline similar to chloroquine that has been widely in the
past to treat and prevent malaria. Following serious toxicity associated with use as
prophylaxis, it was withdrawn by the WHO from the list of drugs for the treatment of
malaria during 1990-1996 and then reinstated. However, it is still used in both West,
Central and East Africa.
Current evidence supports the continued use of amodiaquine particularly in
combination with other antimalarials, notably artesunate. Several countries,
particularly in Africa have opted for, or are considering, an amodiaquine-containing
combination. Long term tolerability data are lacking. Therefore, it is essential that
toxicity should be monitored if the drug is introduced as first-line treatment either
alone or in combination with other antimalarials.
2. Background
Amodiaquine (AQ) is a 4-aminoquinoline similar to chloroquine that has been used
widely in the past to treat and prevent malaria. It was withdrawn by the WHO from
the list of drugs for the treatment of malaria during 1990-1996 but later reinstated
(1996).
In the mid 1980’s, reports of fatal adverse drug reactions (ADRs) were
described in travellers using amodiaquine as prophylaxis 1, 2. Consequently, ParkeDavis (now Pfizer) modified the labelling and withdrew prophylaxis as an indication
and the World Health Organization (WHO) prevented its use in malaria control
programmes 3. In practice, these statements have caused considerable confusion, with
several countries banning its use altogether, whilst others have continued to use
amodiaquine as a second or a first line treatment for uncomplicated malaria.
The 19th Expert Committee on malaria modified this to say that “amodiaquine
could be used for treatment if the risk of infection outweights the potential for
ADRs”, but still did not recommend amodiaquine as first line treatment 4. To assess
comprehensively the information available on amodiaquine, a systematic review was
conducted using the Cochrane Collaboration methodology 5, 6. This review
summarised the considerable amount of published and unpublished data. The
conclusion of the review was that AQ was a valuable drug and supported its continued
use for the treatment of uncomplicated malaria, with the proviso that, due to the
partial cross-resistance with chloroquine, that monitoring of effectiveness, as well as
surveillance for evidence of toxicity, must continue. 7
1/13
Consequently, the WHO modified its recommendations to reinstate
amodiaquine as an option for the treatment of falciparum malaria. 8
In recent years, increasing attention has been given to therapies combining
antimalarial drugs with different mode of action. 9 Amodiaquine has been tested in
clinical trials in combination with artesunate or sulfadoxine/pyrimethamine with very
encouraging results. Amodiaquine in combination with artesunate is now one option
that is recommended by the WHO for use in malaria control programmes 10. Several
countries, particularly in Africa have opted for, or are considering, an amodiaquinecontaining combination. (Watkins W, personal communication).
3. Drug profile
3.1. Chemical composition. Amodiaquine is part of the 4-amino quinoline family
3.2. Structure: C20H22CIN3O
3.3. Chemical name: 4-(7-chloro-4-quinolyamino)-2-(diethylaminomethyl)
phenol.
3.4. Formulations for single-agent therapy: Amodiaquine chlorhydrate 200 mg
base per tablet (261.24mg of amodiaquine chlorhydrate) and 153 mg base per
tablet (200mg amodiaquine chlorhydrate).
3.5. Pharmacokinetics 11
3.5.1. Administration in normal human volunteers
AQ
DesethylAQ
Cmax(ng/l)
*
Tmax
(h)
AUC0-6
(ng/l/h)†
t ½β
(h)
V
l/kg
Cl
ml/h/kg
21 (11)
2 (2)
13,601±4002
204.3±42.2
0.15±0.03
0.53±0.09
0.72 ±0.07
69.4±24
268±94
219.3±71.4
Oral amodiaquine is rapidly absorbed from the gastrointestinal tract. Peak plasma
concentrations are reached after a mean of 30 minutes (healthy volunteers), and 1.75
hours in malaria patients. It is extensively metabolised in the liver to
desethylamodiaquine, the main antimalarial compound, and 2-hydroxyAQ. Peak
plasma concentrations (Cmax) of these metabolites are reached after a mean of 3.4
hours (healthy volunteers). The mean plasma concentration of desethylAQ is 6-7
times greater than amodiaquine (healthy volunteers). DesethylAQ accumulates in red
cells to give a red cell:plasma ratio of 3:1. AQ and its metabolites are >90% protein
bound and are eliminated by renal excretion. The mean terminal half life of AQ is 5.2
(+/- 1.7) hours. DesethylAQ has a longer terminal t ½ than AQ with widely reported
values ranging from 9 - 31 days.
The pharmacokinetics of intravenous amodiaquine have been studied in 7
healthy volunteers, administered as an injection of 3mg base/kg over 10 mins, and in
10 patients with uncomplicated falciparum malaria, administered as an infusion of
10mg base/kg over 4 hours.
The pertinent findings in the healthy volunteers were (means are geometric):
2/13






wide inter-individual Cmax: 65-1921, mean 415 ng/ml
distribution phase time (t ½ α): 1.7 (range 0.4-5.5) mins
elimination phase half life (t ½ z): 2.1 (0.5-5.7) h
total volume of distribution (Vss): 17.4 (2.3-95.9) l/ kg
central compartment volume of distribution (Vl): mean 1.1 (0.3-3.6) l/kg/h
systemic clearance (CL): mean 13.0 (4.7-56.6) l/kg/h
In the patients the pertinent findings were:

wide inter-individual, post-infusion Cmax: 82-836 ng/ml, g. mean 322 ng/ml

T ½ α: 22 (5-126) mins

T ½ z: 10.1 (2.6-33) h

Vss: 38.3 (3.7-127.9) l/ kg

Vl: 4.6 (0.5-29.3) l/kg/h

CL: 5.5 (1.6-17.3) l/kg/h, significantly less than in volunteers
General points/observations were:

desethyAQ was not detected in plasma samples, in contrast to studies with oral
amodiaquine where most of the parent compound undergoes extensive first
pass hepatic metabolism to desethylAQ

AQ, like chloroquine, has a small central compartment and should be
administered as an infusion to limit cardiovascular toxicity associated with
transiently high plasma levels

clearance was longer in the patients and suggests either impaired hepatic
metabolism or reduced liver blood flow

no serious toxicity in either group

four volunteers had a significant fall in systolic blood pressure in the early
distribution phase, and tow complained of dizziness lasting 5 minutes

two patients had nausea and vomiting

slight increase in the QRS but not the PR or QTc intervals
3.5.2. Administration to patients with uncomplicated malaria.
Table 2. Amodiaquine (10mg/kg) administered to 14 Zambian adults with
uncomplicated malaria.
AQ
DesethylAQ
Cmax ng/ml
Tmax
h
AUC0-6
ng/ml/h
t½β
h
21
2 (2)
77 (46)
3.7 (1.3)
161(72)
(1.2)
621(249)
3/13
4. Clinical data on amodiaquine presented in this paper
4.1. Updated Systematic Review (draft) of randomised & quasi-randomised
clinical trials of amodiaquine vs. chloroquine or
sulfadoxine/pyrimethamine for the treatment of uncomplicated
falciparum malaria
NB: this is a draft update of the review published in the Cochrane Library (Olliaro &
Mussano, Cochrane Database Syst Rev 2000;2:CD000016) and in Olliaro et al, The
Lancet 348:1196-1201, 1996. As such, it has not yet been fully validated through the
Cochrane system and is unpublished

Search strategy. We searched the Cochrane Infectious Diseases Group trials
register and Medline. We also contacted researchers in the field and drug
companies.

Selection criteria. Randomised and quasi-randomised trials comparing
amodiaquine with other treatment for uncomplicated malarial infections in adults
and children.
AMODIAQUINE REVIEW: STUDY ATTRITION
studies identified
n=101
Studies included
n=56
comparator CQ
asymptomatic
n=7
follow-up 7d
n=7
AQD patients=583
CLQ patients=586
comparator CQ
mild malaria
n=34
Studies excluded
n=45
comparator S/P
mild malaria
n=19
follow-up 7d
n=27
ADQ patients=1230
CLQ patients=1234
follow-up 7d
n=14
ADQ patients=824
S/P patients=818
follow-up 14d
n=18
ADQ patients=802
CLQ patients=808
follow-up 14d
n=14
ADQ patients=786
S/P patients=821
follow-up 28d
n=3
ADQ patients=254
CLQ patients=248
follow-up 28 d
n=7
ADQ patients=345
S/P patients=322
4/13
PATIENTS REPORTED FOR EFFICACY ANALYSES
Asymptomatic
D7
Add. D14
Add. D28
Total reported
AQ
108
0
0
108
CQ
101
0
0
101
Symptomatic pts.
total AQ pts in comparison
AQ CQ AQ S/P
1230 1234 824 818
258 268 342 340
50
42
0
0
1538 1544 1166 1158
CQ
1230
258
50
1538
add. S/P
549
342
0
891
Total
1779
600
50
2429

Data collection & analysis. Both reviewers independently extracted data and
assessed trial quality.

Main results. Fifty-six trials were included. Allocation was adequately concealed
in three trials. Amodiaquine was more effective than chloroquine for parasite
clearance on days 7, 14 and 28. The combined results of parasite clearance at 14
days from 18 trials was 89% for amodiaquine and 45% for chloroquine (odds ratio
6.44, 95% confidence interval 5.09 to 8.15). Amodiaquine and
sulfadoxine/pyrimethamine showed similar results for parasite clearance on day 7
and 14, but sulfadoxine/pyrimethamine appeared to be more effective on day 28.
The combined results of parasite clearance at 14 days from 14 trials was 84% for
amodiaquine and 86% for sulfadoxine/pyrimethamine (odds ratio 0.86, 95%
confidence interval 0.64 to 1.14). No significant difference for adverse events was
observed between amodiaquine and chloroquine and sulfadoxine/pyrimethamine.
There were no serious ADRs; all reported adverse effects were considered to be of
mild or moderate severity.
SUMMARY TABLE
Comparison day #studies nonAfrica #ADQ Succ %Succ #comp Succ %Succ OR (95%CI)
African
AQ AQ
Comp Comp
CQ
CQ
CQ
CQ1
SP
SP
SP
7
14
28
7
7
14
28
1

27
18
3
9
14
14
7
2
1
0
0
2
0
1
25
17
3
9
12
14
6
1230
802
254
543
824
786
345
1043
716
193
493
716
661
243
85
89
76
91
87
84
70
1234
808
248
586
818
821
322
718
453
122
422
735
705
273
58
56
49
72
90
86
85
4.42(3.65,5.35)
6.44(5.09,8.15)
3.62(2.49,5.29)
3.64(2.65,5.00)
0.73(0.53,1.01)
0.86(0.64,1.14)
0.41(0.28,0.61)
asymptomatic malaria patients
Reviewers' conclusions. There is evidence to support the continued use of
amodiaquine in the treatment of uncomplicated malaria, although drug resistance
and erosion of efficacy in case of increased use should be considered. Monitoring
for toxicity should also continue.
4.2. Combined analysis of three double-blinded, randomised, placebocontrolled clinical of amodiaquine vs. amodiaquine + artesunate for the
5/13
treatment of paediatric uncomplicated falciparum malaria in Kenya,
Sénégal, and Gabon
NB: unpublished data –manuscript submitted

Methods. These randomised, double blind, placebo controlled trials were
conducted in 941 children up to age 10 years with uncomplicated P. falciparum
malaria. Amodiaquine (10mg/kg/d for 3 days) and artesunate/placebo (4mg/kg/d
were administered under supervision. The primary end points were parasitological
cure rates at Days 14 and 28. Analysis was by intention to treat and an evaluability
method.

Findings. Both regimens were equally well tolerated. Six patients in the AQ-AS
group and five in the AQ group developed early, drug-induced vomiting,
necessitating alternative treatment. Nine of 153 [6% (95% CI 3-11)] children from
both groups developed neutropenia (<1000/microL) by Day 28. Gametocyte
carriage was significantly lower in the AQ-AS group only on Days 7 and 14 in
Kenya. AQ-AS led to significantly increased parasite clearance rates on Days 1, 2
and 3 in all sites.
By ITT analysis, 415/446 (93%) of the AS-AQ group and 373/441 (85%) of the
AQ group were cured by Day 14. The Day 14 and 28 cure rates for AQ-AS vs AQ
.
were, respectively: Kenya: 175 (91%) vs
7 (95% CI 9.3-24.1),
.
P
3 (17.5-37.2), P<0.0001], Sénégal:
.
.
.
148 (93%)
-1 1 (-6 7-4 5), P=0.7], and 130 (82%) vs 123 (79%)
.
.
9 (-5.9-11.7), P= 0.5], and Gabon
3 (1.5-15.1),
.
.
.
.
.
P=0 02], and 80 (85%) vs 70 (71%),
7 (2 2-25 2), P=0 02].

Interpretation. The addition of AS to AQ did not affect tolerability. The
combination of artesunate and amodiaquine improved treatment efficacy in Gabon
and Kenya, and was equivalent in Sénégal. AQ-AS is a potential combination for
use in Africa. Further investigations to assess the potential impact on the evolution
of drug resistance, disease transmission, and safety of AQ-AS are warranted.
SUMMARY TABLE
Kenya
AQ/AS
AQ
N = 200 *
N = 200
Cure rate Day 14
Cure rates Day 28
 PCR uncorrected

PCR corrected†
Sénégal
AQ/AS
AQ
N=160
N=161
Gabon
AQ/AS
AQ
N=110
N=110
175/192
(91%)1
140/188
(75%)
148/160
(93%)
147/157
(94%)
92/94
(98%)2
86/96
(90%)
123/180
(68%)3
144/180
(80%)5
75/183
(41%)
98/183
(54%)
130/159
(82%)
123/156
(79%)
80/94
(85%)4
85/94
(89%)6
70/98
(71%)
77/98
(77%)
* N = number recruited
† Missing PCR data = failures
6/13
Significant P values: 1<0.0001, 2=0.016, 3<0.0001, 4=0.019, 5<0.0001, 6=0.02
4.3. Phased scaling of artesunate-amodiaquine combination therapy for
acute, uncomplicated falciparum malaria in the Oussouye District,
southern Sénégal
NB: unpublished data

Methods. During the transmission seasons (July to November) of 2000 and 2001,
artesunate-amodiaquine was prescribed as first-line treatment for all
parasitologically confirmed cases attending the Mlomp dispensary. Artesunate
50mg tablets and amodiaquine 200mg base tablets were administered together at a
daily dose of 4 mg/kg (AS) and 10 mg/kg (AQ) for 3 days, rounded to the nearest
half tablet. Because of occasional shortages of artesunate, amodiaquine
monotherapy was used for short periods of time. The end point was the Day 28
cure rate. Analysis was by a modified intention to treat.

Results. A total of 624 patients were recruited into the study. There were only 11
study withdrawals. Outcomes were known for 267 (2000) and 346 (2001) patients.
The median doses administered were 4mg/kg/d (AS) and 10.4 mg/kg/d (AQ).
All patients from both groups initially cleared their parasites. All second
episodes of malaria occurred between Days 14 and 28. By Day 28, the cure rates
of AS-AQ were 98.1 (2000) and 96.7% (2001). Corresponding rates for
amodiaquine alone were 98.1 and 95.7%.
4.4. Tolerability
Martindale BPS12 states that the adverse effects of usual doses of amodiaquine are
similar to chloroquine but the incidence of hepatitis and agranulocytosis is higher.
4.4.1. Systematic review of controlled trials of amodiaquine single-agent
treatment
The details of reported toxicity (symptoms, laboratory parameters) vary
considerably between clinical trials which have primarily assessed drug efficacy.
Toxicity data from the systematic review show that of 588 patients treated with
amodiaquine in randomised trials, adverse events were reported in 52 (10.7%)
patients. The most common symptoms were nausea, vomiting, and pruritus, all
considered mild or moderate in severity. There were no severe or life threatening
adverse events. Data from 24 non-randomised/non-comparative trials involving 776
amodiaquine recipients, recorded 450 mild adverse events in 219/776 (28%) patients.
# patients with AE/# treated (%)
comparison
# studies
Amodiaquine
comparator
OR(95%CI)*
chloroquine
8
33/413 ( 8)
36/411 (8.8)
0.85 (0.43-1.67)
S/P
3
33/127 (26 )
15/105 (14.3)
1.68 (0.67-4.21)
7/13
* Odds Ratio (95% Confidence Intervals) amodiaquine:comparator drug. NB: the total
number of patients with Adverse Events on amodiaquine is 52/488 (10.7%) due to patients
enrolled in 3-arm studies with both chloroquine and S/P
Neutrophyl counts
country
units
Côte d'Ivoire 10^3/cumm
mean+/-std
Kenya
%
mean+/-std
drug
amodiaquine
chloroquine
amodiaquine
chloroquine
S/P
n
62
59
191
22
116
day0
5.12+/-4.46
5.13+/-3.13
48.0+/-15.7
48.5+/-15.6
47.6+/-14.6
day7
4.38+/-1.97
4.04+/-1.48
43.1+/-12.7
43.9+/-15.1
43.1+/-12.9
paired change
(-0.75+/-4.76)
(-0.91+/-3.45)
(-4.8+/-14.8)
(-4.6+/-14.6)
(-4.5+/-14.2)
4.4.2. Double-blinded, randomised, placebo-controlled clinical trials of
amodiaquine combination treatment
The results of the tolerability analyses of the randomised-controlled trials reported in
Section 4.2 are summarised below. AQ = amodiaquine; AS = artesunate
 Safety, Toxicity & Tolerability
AQ and AQ-AS were well tolerated. Early drug induced vomiting necessitating
alternative treatment occurred in 11 patients: 6 on AQ-AS (D0=4, D1=2), and 5 on
AQ (D0=2, D1=2, D2=1). The reporting of any symptom combined or a specific
symptom (weakness, headache, dizziness, anorexia, nausea, vomiting, abdominal
pain, diarrhoea) within the first week and during follow up was similar between the
arms, as were the total number of reported AEs: 165 (AQ-AS) vs 133 (AQ). Nine
patients had dermatological complaints: eight (AQ) reported itching, and one
developed an itchy rash (AQ-AS).
There was one death (AQ) and 13 other serious adverse events (AQ-AS=7,
AQ=6): (i) Kenya: convulsion (n=3), pneumonia (n=2), anaemia (n=2), meningitis
(n=1), (ii) Sénégal: convulsion (n=1), (iii) Gabon: asthma (n=1), convulsion (n=1),
vomiting on Day 0 (n=1), and gastroenteritis (n=1). Apart from the vomiting on Day
0, all serious adverse events were considered unrelated to study drugs.
The death occurred in a four years old Kenyan male from Migori who
received AQ alone. He became acutely breathless with foaming at the mouth some six
hours after the first dose of AQ. He died in hospital 6 hours after the development of
dyspnoea. The cause of death was unclear (no post mortem was done). The history is
consistent with acute pulmonary oedema or convulsions. He was classified as
treatment failure due to severe malaria.
Mean values of routine haematological and biochemical parameters were
similar in the two arms at each time interval. By Day 28, cured patients had similar
increases in mean haemoglobin levels compared to baseline (AQ-AS vs AQ): 1.5
(SD=1.9) g/dL (n=184) vs 1.4 (2.0) g/dL (n=133). Liver enzymes (n=192) tended to
fall during follow up but mean changes were not significantly different compared to
baseline between the arms (details not shown). Changes in serum creatinine values
were also unremarkable (n=201). By Day 28, a total of 153 [n=140 (Gabon), n=13
(Kenya)] patients had paired Day 28/Day 0 white cell counts. Of these, nine [6%
(95% CI 3-11)] children, developed neutropenia (absolute neutrophil count
8/13
<1000/µL); their neutrophil counts ranged from 306-900/µL (median = 780). Three
were AQ-AS and six were AQ recipients; all had normal neutrophil counts on Day 0.
There was a significant decline in mean neutrophil counts for all patients comparing
each time interval with baseline with no differences between the two treatment arms
(details not shown). Mean total white cell counts and mean changes in white cell
counts compared to Day 0 were unremarkable between the two arms.



Comparison of rates of Adverse Events (AE)
 All AEs are all treatment-emerging signs or symptoms recorded by the
treating physician in double-blind conditions, independent of whether drugrelated or not
 Serious AE are defined as potentially life-threatening or requiring
hospitalisation
 AE requiring treatment discontinuation
4.4.3. Other treatment studies
One case of acute asymptomatic rise in liver enzymes was detected in a healthy
normal volunteer exposed to 2 oral doses of amodiaquine and artesunate received
[artesunate (day 0), amodiaquine (day 7), followed by the combination (day 28)].
The enzymes increased on day 42 and decreased spontaneously by day 72. 13
Treatment with amodiaquine+artesunate and amodiaquine alone reported in
Section 4.3 was well-tolerated. There were no significant changes in the mean
haematocrit or biochemical (AST, ALT, bilirubin, creatinine) parameters;
although, there was a downward trend in the latter.
9/13
Blood Chemistry and Haematology
Year
Plasma AST (IU/L)
Plasma ALT (IU/L)
Bilirubin (µmol / l)
Plasma creatinine (µmol / l)
Haematocrit (%)
2000
Mean difference*
- 0.2
-2
- 9. 9
- 3. 54
+ 0.3
n†
28
29
29
27
23
2001
Mean difference*
- 14. 5
- 9. 6
- 6. 67
- 12. 4
+ 0. 7
n†
32
33
33
32
34
* mean difference between admission (D0) and last study day (D28)
† n = number of evaluated patients


Considering published and unpublished information, haematological and
biochemical data have not shown any significant changes compared to baseline
values or compared to other antimalarial drugs eg atovoquone/proguanil,
chloroquine, and S/P.
In a recent report of the cardiovascular effects of amodiaquine in adults with
falciparum malaria, there was significant prolongation of the mean PQ, QRS, QTc
intervals on Day 2 compared to baseline and a significant bradycardic effect in
most patients. 14 These effects did not cause clinical symptoms.
4.4.4. Use in prophylaxis
4.4.4.1.White cell toxicity
Toxicity data reported to the WHO Collaborating Centre for International
Drug Monitoring during 1970-94, show that 115 adverse events were reported in 66
patients, including two deaths. Data quality varied from the reporting sources and .
were incomplete in some cases. There were 17 cases of agranulocytosis and 7 of
granulocytopaenia. Adults of both sexes were affected and the duration of treatment
on amodiaquine ranged from 3-360 days, mean 9 weeks. The time to onset of
granulocytopaenia varied from 48-98 days. Company reports (Parke-Davis) from
1985-1991 on amodiaquine prophylaxis use, reveal 42 cases of adverse events which
included 28 cases of agranulocytosis (9 deaths), and 14 cases of hepatitis (3 deaths).
Amodiaquine consumption ranged form 200-700 mg per week for 3-48 weeks.
4.4.4.2.Hepatic toxicity
Amodiaquine-induced hepatitis during malaria prophylaxis is well described
and may be associated with neutropenia. 2 15 16 17 18 19 Hepatitis has occurred from as
early as 3 weeks (exposure to 3 weekly doses) to as late as 10 months of prophylaxis.
Clinically, reported cases have ranged from a mild, transient elevation of liver
enzymes with few symptoms to fulminant hepatitis with either slow recovery of
function or death. Patients with severe amodiaquine induced hepatitis may remain
jaundiced for 3-6 months and have raised liver enzymes for between 7-27 months.
Data on hepatic toxicity and amodiaquine use in malaria endemic areas are
few. Amodiaquine appears to be safer as treatment rather than as prophylaxis.
However, we are unable to identify any studies examining delayed onset hepatitis
following treatment, or longitudinal studies of repeated treatments.
4.4.5. AQ dose and serious AQ toxicity
10/13
The prophylaxis dose is 400mg weekly for adults. The recommended
treatment dose of 10mg/kg per day for 3 days (1.8g for a 60kg person). Hepatitis and
agranulocytosis causing death have been associated with total mean doses (SD) of
amodiaquine of 3.44 (1.2) g accumulated over 7.7 (2.3) weeks.
4.4.6. Mechanism of toxicity
The mechanism of bone marrow and hepatic toxicity is thought to be mediated
via antibodies to amodiaquine. IgG anti-AQ antibodies have been found in patients
with agranulocytosis or hepatitis who had been taking amodiaquine prophylaxis
400mg weekly for several weeks but not in patients who had taken amodiaquine for
treatment. 20
4.4.7. Remaining issues
Multiple, intermittent treatment doses of amodiaquine would resemble
prophylaxis and, in theory, could result in similar toxicity to prophylactic dosing.
There is minimal data of multiple treatment doses of amodiaquine.
11/13
5. REFERENCES
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Hatton C, Peto T, Bunch C, Pasvol G, Russel S, Singer C, Edwards G, Winstanley P
(1986) Frequency of severe neutropenia associated with amodiaquine prophylaxis
against malaria. Lancet 1986;I: 411-413.
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Neftel K, Woodtly W, Schmidt R, Frich P, Fehr J. Amodiaquine to induced
agranulocytosis and liver damage. B M J 1986; 292:721-723.
3
World Health Organization. Practical chemotherapy of malaria. Report of a WHO
Scientific Group. Geneva: World Health Organisation, 1990: Technical Report Series
No 805.
4
World Health Organisation. 19th Expert Committee on malaria. Geneva: World
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Olliaro & Mussano, Cochrane Database Syst Rev 2000;2:CD000016
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Olliaro P, Nevill C, LeBras J, Ringwald P, Mussano P, Garner P, Brasseur P.
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