Annex 4. Case reports, case series, and pharmacovigilance data: description CONTENTS Case reports and case series
Table 1. Case reports and case series reporting adverse events: adverse events are the main purpose of the report ………… 2 Table 2. Case reports and case series reporting adverse events: adverse events are not the purpose of the report …………. 15 Table 3. Case reports and case series: reporting no adverse events ……………………………………………………………….. 18
Pharmacovigilance data
Table 4. Summary of the adverse reactions with ‘amodiaquine (including salts/esters) in the WHO Adverse Reaction ……… 19
Draft 1
Case reports and case series Table 1. Case reports and case series reporting adverse events: adverse events are the main purpose of the report Sorted by (1) primary adverse event, (2) indication, and (3) year
First author
Year
R = case report
ID 1° adverse event1
1° adverse event: time
to onset (days)
U = unclear
2° adverse events2
Indication Gender Age (years)
U =
unclear
AQ mono or combo
U = unclear
AQ dose
U = unclear
Duration treatment
(days)
U = unclear
Outcome
U = unclear
Country Comments
Orrell 2001R 200 abnormal liverfunction test
48 Volunteer F 20 AQ-ART Twice 10 mg/kg body weight
Two doses of AQ 21 days apart
Recovered ZAF
Grupper 1957 1170 abnormalmucocutaneous and subungueal pigmentation
U Lupuserythematosus
M 58 AQ 600 mg per day U U FRA Concomitant medication: vitamin D per os and IM, oleosoluble and insoluble bismuth, vitamin E, CQ
Grupper 1957 1170 abnormalpigmentation of the palate
Approx 3 years (January 1956)
Lupuserythematosus
M 42 AQ U Since 1953 U FRA Concomitant medication: had taken oleosoluble and insoluble bismuth for a number of years, vitamin E, B12, CQ
Blecourt 1959 R 720 agranulocytosis First time 42; second time 7
Stomatitis, herpes zoster, fever
Lupus erythematosus
F 42 AQ First time: 21000 mg; second time: 3500 mg
First time 42; Second time 7
Recovered NLD Concomitant medication:prednison; had used nivaquin between the two episodes of taking AQ
Booth 1967 5750 agranulocytosis 21 Cellulites, sorethroat, fever, septic shock
Malaria prophylaxis M 20 AQ 3150 mg to 6300 mg
21 Death PNG
Booth 1967 5750 agranulocytosis 21 Fever.Epigastric and back pain
Malaria prophylaxis F 57 AQ 1200 mg 28 Recovered PNG
Booth 1967 5750 agranulocytosis 70 Sore throat,fever, ear infection
Malaria prophylaxis M 65 AQ 3000 mg 70 Recovered PNG
Lind 1973 R 1300 agranulocytosis 50 Cellulites,septicaemia, deep venous thrombosis
Malaria prophylaxis F 26 AQ 2400 mg 56 Normalisation of bone marrow and resolving of DVT
AUS Concomitant disease:recurrent respiratory tract infection; Concomitant medication: erythromycin or penicillin, oral contraceptives and chlordiazepoxide, vaccination against typhoid and cholera
Lepeu 1981 R 6340 agranulocytosis 49 Throat angina, Malaria prophylaxis M 44 AQ 600 mg per week 42 Blood tests FRA
1 The objective of the case report 2 Other reported adverse events
Draft 2
fever returned to
normal Douer 1985 R 6220 agranulocytosis 49 Skin rash and
haemorrhagic bullae (Pseudomanas on culture), fever, Klebsiella on blood culture, anaemia
Malaria prophylaxis F 63 AQ-P 2400 mg 42 Recovered ISR Concomitant medication:dipyrone for back pain
Neftel 1986 6180 agranulocytosis 49 septicaemia,abscesses
Malaria prophylaxis M 76 AQ 3600 mg 49 Death CHE
Neftel 1986 6180 agranulocytosis 42 pseudomonassepticaemia,
Malaria prophylaxis
raised bilirubin
M 71 AQ 3200 mg 49 Death CHE
Neftel 1986 6180 agranulocytosis 51 septicaemia,abscesses, abnormal liver function tests
Malaria prophylaxis F 52 AQ 3200 mg 49 U CHE
Neftel 1986 6180 agranulocytosis 57 recurrentpulmonary embolism, abscesses, abnormal liver function tests
Malaria prophylaxis F 63 AQ 3600 mg 49 Death CHE
Neftel 1986 6180 agranulocytosis 48 septicaemia,abscesses, toe gangrene, necrotic angina
Malaria prophylaxis F 17 AQ 6000 mg 63 U CHE
Neftel 1986 6180 agranulocytosis 38 abnormal liverfunction tests
Malaria prophylaxis M 39 AQ 1800 mg 34 U CHE
Rhodes 1986 R 3580 agranulocytosis 84 Malaria prophylaxis F 21 AQ-PG 2400 mg 12 Recovered IND, GBR Steed 1986 R 2900 agranulocytosis u Malaria prophylaxis F 34 AQ-PG 400 mg per week U recovered TZA,GBR Aymard 1987 6130 agranulocytosis 59 Fever,
hepatomegaly, anaemia
Malaria prophylaxis F 60 AQ 4200 mg 49 Recovered FRA
Aymard 1987 6130 agranulocytosis “over twomonths”
Facial cellulites, throat angina, bulleous toxidermia, leg phlebitis, dyspnoea, renal failure
Malaria prophylaxis F 47 AQ 2800 mg 49 Death FRA
Aymard 1987 6130 agranulocytosis 30 Fever, intraoralulcerations
Malaria prophylaxis M 53 AQ U (400 mg per week)
U Recovered FRA
Aymard 1987 6130 agranulocytosis 49 Febrile throatangina, lumbar pain
Malaria prophylaxis M 41 AQ 3600 mg 42 Recovered FRA
Rouveix 1989 6110 agranulocytosis 47 febrile facialcellulitis, shock, pulmonary oedema
Malaria prophylaxis F 47 AQ 2800 mg 49 Death FRA
Rouveix 1989 6110 agranulocytosis Fever, Malaria prophylaxis M 53 AQ 1600 mg 28 recovered FRA
Draft 3
fusobacterium isolated from blood culture
Booth 1967 5750 agranulocytosis 28 Diarrhoea,infected haemorrhoid, fever, sore throat
Malaria prophylaxis & malaria therapy
M 30 AQ 4650 mg 33 Recovered PNG allergic to Penicillin
Booth 1967 5750 agranulocytosis 70 Cellulites,gingivitis, pharyngitis, otitis externa, thrombocytopenia
Malaria prophylaxis & malaria therapy?
M 47 AQ 5100 mg 75 Death PNG Concomitant medication: Aspro and tetracycline. Recently had two boils and paronchia
Perry 1962 R 380 agranulocytosis 18 Hepatitis Malaria treatment M 33 AQ 2800 mg 10 Hospitalization, recovered
USA
Neftel 1986 6180 agranulocytosis 69 Abnormal liverfunction tests
Malaria treatment F 64 AQ 4000 mg 62 U CHE
Glick 1957 470 agranulocytosis 65 Febriletonsillitis, anisocytosis of red blood cells in sternal marrow, hepatomegaly with hyperbilirubinaemia and hypoproteinaemia, suspected meningitis
Photosensitive skin reaction
F 53 AQ 11000 mg 55 Death GBR
Krayenbuhl 1998 7450 agranulocytosis In the 19 patients who were included in the study, the average duration of the granulocutosis(imrovement to values over 500/mm3 was 4.9 days)
U U between 29
and 89
U U U In the 19 patients who were included in the study, the average duration of the granulocutosis (improvement to values over 500/mm3 was 4.9 days)
CHE
Khandakar 1968 100 anaemia (acutehaemolytic)
0 Hypotension Malaria treatment M 14 AQ-PQ 2 tablets (possibly 150 mg of AQ)
1 Recovered PAK
Khandakar 1968 100 anaemia (acutehaemolytic)
3 Hypotension,leucocytosis
Malaria treatment M 5.5 AQ-PQ 4 tablets (?300 mg AQ)
2 Recovered PAK
Khandakar 1968 100 anaemia (acutehaemolytic)
1 Hypotension,leucocytosis
Malaria treatment M 2.5 AQ-PQ U 1 Recovered PAK
Khandakar 1968 100 anaemia (acute 1 Hypotension, Malaria treatment M 3.5 AQ-PQ 2 tablets (possibly 2 recovered PAK
Draft 4
haemolytic) leucocytosis 150 mg of AQ)
Khandakar 1968 100 anaemia (acutehaemolytic)
2 Malaria treatment M 3.5 AQ-PQ 4 tablets (300 mg?)
2 Recovered PAK
Khandakar 1968 100 anaemia (acutehaemolytic)
3 Malaria treatment M 13 AQ-PQ u U Recovered PAK
Khandakar 1968 100 anaemia (acutehaemolytic)
2 hypotension Malaria treatment F 17 AQ-PQ 6 tablets 3 Recovered PAK
Khandakar 1968 100 anaemia (acutehaemolytic)
U Leucocytosis Malaria treatment M 25 AQ-PQ 3 tablets U Recovered PAK
Baran 1960 R 1160 confusion 2 abdominal pain,fever, red urine, vomiting and diarrhoea, aggravation of diabetes
Porphyria cutanea tarda
M 74 AQ “4 tablets” (?800 mg)
2 Notdescribed as serious
Unknown
Scales 1960 R 770 corneal changes 13th Aug 1958
Glaucoma Lupuserythematosus
M 38 AQ 200 mg daily from May 1958 to 26th Aug 1959 and from Jan 1059 for around 11 weeks
from May 1958 to 26th Aug 1959 and from Jan 1059 for around 11 weeks
Not described as serious
AUS Had chloroquine treatment before
Hirst 1982 R 5670 corneal,conjunctival and skin changes
420 Visualdisturbances
Pain F 24 AQ 336000 mg 420 Improved USA Concomitant medication: carisoprodol
Dedet 1986 3650 cutaneousleishmaniasis
U Malaria prophylaxis U U U 600 mg weekly
Between one and 22 months
U GUF
Dedet 1986 3650 cutaneousleishmaniasis
U Malaria prophylaxis U U U 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 cutaneousleishmaniasis
U Malaria prophylaxis U U U 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 cutaneousleishmaniasis
u Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22
U GUF
Draft 5
months
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
u Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months
U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u U u U GUF
Draft 6
Dedet 1986 3650 Cutaneous
leishmaniasis U Malaria prophylaxis U U u U u U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u U u U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u U u U GUF
Dedet 1986 3650 Cutaneousleishmaniasis
U Malaria prophylaxis U U u U u U GUF
Biagini 1957 750 drowsiness Startedbetween day 7 and 13
Lupuserythematosus
M 13 AQ 3200 mg in first 14 days, then 200 mg daily (continuing)
>=30 Recovered ARG
Manor 1981 4480 Gingivalpigmentation
112 Pigmentation onlips and fingernail beds
Malaria prophylaxis M 19 AQ U (at least 6400 mg) (400 mg per week)
U (at least 112)
Recovered ISR
Manor 1981 4480 Gingivalpigmentation
168 Malaria prophylaxis M 20 AQ U (at least 9600 mg) (400 mg per week)
U (at least 168)
Recovered ISR
Mevel 1986 3230 haemolyticanaemia, thrombocytopenia, rhabdomyolysis
Around 1095 bipalpebral oedema, chest infection, malaria
Malaria prophylaxis M 36 AQ 400 mg (AQ chlorhydrate) per week
Around 1095
Recovered FRA
Pomeroy 1959ii 660 hepatic coma,biliary cirrhosis
16th week Rheumatoid arthritis F U AQ U U Death USA some suggestion of pre-existing liver disease" on microscopic examination of the liver
Neftel 1986 6180 Hepatic failure 90 Malaria prophylaxis & treatment
F 36 AQ 9400 mg 126 Death CHE
Desaint 1986 2970 Hepatitis 40 Pruritus,vomiting
Malaria prophylaxis F 41 AQ 1600 mg 26 Recovered FRA
Desaint 1986 2970 hepatitis Around 90 Anorexia,prostration, epigastric pain, vomiting
Malaria prophylaxis F 35 AQ 600 mg per week October 1984 to 28/3/1985
Recovered FRA
Amouretti 1986 R 3420 hepatitis About 51 Malaria prophylaxis F 38 AQ 3600 mg 3000mg over 35 days, 2 weeks later single dose of 600 mg
Death FRA
Raymond 1989 R 2380 hepatitis 42 pruritus,vomiting
Malaria prophylaxis F 38 AQ 4200 mg over 49 days then 600 mg day 66
49 days, then single dose day 66
Death GAB, FRA
Christie 1988i 50 hepatitis U u F u u U U U GBR Christie 1989 (ID 6100) contains duplicate data from Christie 1988 (ID50)
Bernuau 1988 240 Hepatitis(fulminant)
110 Confusion Malaria prophylaxis F 12 AQ 16100 mg 161 Recoveredafter liver transplantation
FRA Contains duplicate data from Larrey 1987 (ID 2850)
Bernuau 1988 240 Hepatitis(fulminant)
380 Asthenia,asterixis
Malaria prophylaxis M 41 AQ 6000 mg in 30 weeks, then 11200 in 28 weeks
406 Death FRA daily consumption of 60 g of alcohol Paper contains duplicate data from Larrey 1987
Draft 7
(ID2850)
Bernuau 1988 240 Hepatitis(fulminant)
125 Somnolenceand confusion, UTI, bacteraemia, vomiting
Malaria prophylaxis M 51 AQ 13200 mg 154 Death FRA
Larrey 1986 3760 Hepatitis (minorform)
56 Skin rash,asthenia, vomiting
Malaria prophylaxis M 38 AQ 8000 mg 63 Recovered FRA
Larrey 1986 3760 Hepatitis (minorform)
28 Vomiting,abdominal pain
Malaria prophylaxis F 38 AQ 3000 mg 35 Recovered FRA Concomitant medication:oral contraceptives, diphenoxylate. We suspect this reported case is identical to one patient reported in Larrey 1989 (ID 1560)
Larrey 1986 3760 Hepatitis (minorform)
42 Fever, asthenia,vomiting
Malaria prophylaxis M 64 AQ 4200 mg 42 Recovered FRA
Larrey 1986 3760 Hepatitis (minorform)
37 Fever, asthenia,abdominal pain, chills, arthralgias
Malaria prophylaxis M 36 AQ 1200 mg 35 Recovered FRA We suspect this reported case is identical to one patient reported in Larrey 1989 (ID 1560)
Larrey 1986 3030 Hepatitis (non-fulminant)
U U (? Malaria prophylaxis)
u u u Between 3000 mg and 13000 mg
Between 35 and 105
U FRA AQ discontinued less than two weeks after onset of jaundice. The cases of fulminant hepatitis are described under Bernuau 1988 (ID 240)
Larrey 1986 3030 Hepatitis (non-fulminant)
U U (? Malaria prophylaxis)
U u u Between 3000 mg and 13000 mg
Between 35 and 105
U FRA AQ discontinued less than two weeks after onset of jaundice
Larrey 1986 3030 Hepatitis (non-fulminant)
U U (? Malaria prophylaxis)
U U u Between 3000 mg and 13000 mg
Between 35 and 105
U FRA AQ discontinued less than two weeks after onset of jaundice
Larrey 1986 3030 Hepatitis (non-fulminant)
U U (? Malaria prophylaxis)
U U u Between 3000 mg and 13000 mg
Between 35 and 105
U FRA AQ discontinued less than two weeks after onset of jaundice
Larrey 1986 3030 Hepatitis (non-fulminant)
U U (? Malaria prophylaxis)
u U u 16000 mg 189 U FRA AQ discontinued less than two weeks after onset of jaundice
Charmot 1987 3210 Hepatitis (non-severe)
About 25 Prostration Malaria prophylaxis F 39 AQ About 1071 mg base
25 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Charmot 1987 3210 Hepatitis (non-severe)
About 45 Prostration Malaria prophylaxis M 38 AQ About 2893 mg base
45 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Charmot 1987 3210 Hepatitis (non-severe)
About 20 Prostration Malaria prophylaxis F 56 AQ About 857 mg base
20 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial
Draft 8
stage
Charmot 1987 3210 Hepatitis (non-severe)
About 50 Prostration Malaria prophylaxis M 21 AQ About 3214 mg base
50 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Charmot 1987 3210 Hepatitis (non-severe)
About 35 Prostration Malaria prophylaxis F 28 AQ About 2250 mg base
35 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Charmot 1987 3210 Hepatitis (non-severe)
About 300 Prostration Malaria prophylaxis M 52 AQ About 12857 mg base
300 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Charmot 1987 3210 Hepatitis (non-severe)
About 26 Prostration Malaria prophylaxis F 34 AQ About 1671 mg base
26 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Charmot 1987 3210 Hepatitis (non-severe)
About 250 Fever, prostration
Malaria prophylaxis M 55 AQ About 16071 mg base
250 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial stage
Larrey 1986 3760 Hepatitis(severe)
45 Asthenia,thrombopenia
Malaria prophylaxis M 51 AQ 7200 mg 77 Still abnormal liver function tests after 27 months
FRA Concomitant medication:Lorazepam
Larrey 1986 3760 Hepatitis(severe)
80 Melanosis,asthenia, arthralgias, thrombopenia
Malaria prophylaxis M 44 AQ 6400 mg 105 Still abnormal liver function tests after 26 months
FRA
Larrey 1986 3760 Hepatitis(severe)
105 Fever, asthenia,vomiting, chills, thrombopenia
Malaria prophylaxis M 34 AQ 9600 mg 105 Still abnormal liver function tests after 7 months
FRA
Hirschel 1986 1040 Hepatitis? 30 Thrombocytopenia, malaria
Malaria prophylaxis M 32 AQ 1400 mg 24 Recovered CHE
Hirschel 1986 1040 Hepatitis? 31 Thrombocytopenia, malaria
Malaria prophylaxis F 31 AQ 1400 mg 24 Recovered CHE
Neftel 1986 6180 Hepatotoxicity 54 neutropenia Malaria prophylaxis M 55 AQ 2200 mg 42 U CHE Schievink 1960 760 Hyperproteinaem
ia and hyperglobulinaemia
Around 21 Lupus erythematosus
M 53 AQ 400 mg per day u (probably a month)
Recovered NLD
Pomeroy 1959ii 660 jaundice,liver biopsy showed "areas of necrosis and proliferation of round cells"
4th week Rheumatoid arthritis U U AQ u U Recoved completely with no evidence of residual liver damage
USA
Love 1953ii 600 Leukopenia U Sarcoidosis U U AQ 4800 mg to 5600 30 Not USA
Draft 9
mg described as
serious Love 1953ii 600 Leukopenia U Sarcoidosis U U AQ 4800 mg to 5600
mg 30 Not
described as serious
USA
Wade 1981 5620 Maculopathywith central scotoma
266 Rheumatoid arthritis F 39 AQ 13890 mg 420 The control was conducted 2 months after stop of AQ. The visual acuity and the lesions of the fundus oculi were stabilized.
SEN
Nicolas 1994 1480 Malaria U Malaria prophylaxis U U AQ U u u FRASimon 1988 1720 Malaria (causing
death) U Malaria prophylaxis U U AQ U irregular
intake of AQ Death FRA
Charmot 1986 3530 Malaria (falciparum, multidrug resistant)
About 365 Malaria prophylaxis U U AQ 150 mg (AQ base chlorhydrate) every other day
presumably about 365
Recovered FRA
Charmot 1986 3530 Malaria (falciparum, multidrug resistant)
U Malaria prophylaxis U U AQ 150 mg (AQ base chlorhydrate) every other day
U Recovered FRA
Charmot 1986 3530 Malaria (falciparum, multidrug resistant)
U Malaria prophylaxis U U AQ 150 mg (AQ base chlorhydrate) every other day
u Recovered FRA
Schuurkamp
1989 R 1170 malaria(worsening, with development of mixed infection)
31st Jan 1989
Bronchitic changes on CXR
Malaria therapy F 0.67 (8 months
)
AQ, AQ-PG
history of treatment: -7 July 1988: AQ (50 mg x 3 d (third dose given 20 d after second)) -24 Oct 1988: AQ (100 mg x 3 d) -2 Nov 1988: AQ (100 mg x 3 d (second and third doses given 15 and 16 d after first)) -5 Jan 1989 (P. vivax): AQ (50 mg x 3 d) + PQ (3.8 mg x 1 d) -19 Jan 1989 (P. falciparum): CQ (75 mg x 3 d) + PQ (3.8 mg x 1 d) -31 Jan 1989 (P. vivax + P. falciparum): CQ (75 mg x ?d) + PQ (3.8 mg x 1 d) -3 Feb 1989 (P. vivax): CQ (100 mg x 3 d) + PQ (3.8 mg x 1 d) -10 Feb 1989: S (250 mg) + P (12.5 mg) See dose
Hospitalization
PNG Had 4 antimalarials
Hamilton 1950iii 160 Nausea U giddiness Malaria treatment F U AQ 500 mg 1 Not described as
IND
Draft 10
serious
Hamilton 1950iii 160 Nausea U giddiness Malaria treatment F U AQ 500 mg 1 Not described as serious
IND
Pomeroy 1959ii 660 Nausea andvomiting
U Rheumatoid arthritis U U AQ U U Notdescribed as serious
USA
Pomeroy 1959ii 660 Nausea andvomiting
U Rheumatoid arthritis U U AQ U u Notdescribed as serious
USA
Pomeroy 1959ii 660 Nausea andvomiting
U Rheumatoid arthritis U U AQ U U Notdescribed as serious
USA
Wittes 1984 R 2410 Neuromyopathy 280 Malaria prophylaxis F 42 AQ Approx. 34320 mg (salt)
Approx. 330 Improving NER, CAN
Carr 1986 6200 Neutropenia U suppuratingwound on foot
Malaria prophylaxis M 18 AQ-PG u (400 mg weekly) u Death GBR
Carr 1986 6200 Neutropenia 42 anaemia Malaria prophylaxis M 71 AQ-PG 2400 mg 42 Remains profoundly neutropenic, but well
GBR Concomitant medication:co-trimoxazole
Hatton 1986 6210 neutropenia 42 Jaundice,febrile, axillary abscess
Malaria prophylaxis M 51 AQ-PG U (at least 2400 mg)
U (at least 42)
Recovered GBR
Hatton 1986 6210 neutropenia 101 Febrilepharyngitis, anaemia
Malaria prophylaxis F 49 AQ 7600 mg 101 Dischargedfrom hospital
GBR
Hatton 1986 6210 neutropenia 42 Fever, chestpain
Malaria prophylaxis M 62 AQ-PG 3600 mg 63 Recovered GBR
Hatton 1986 6210 neutropenia 40 Sepsis,gastroenteritis
Malaria prophylaxis F 63 AQ-PG U U Recovered GBR
Hatton 1986 6210 neutropenia 49 Febrile otitismedia, perianal sepsis
Malaria prophylaxis M 35 AQ-PG 2800 mg 49 Recovered GBR
Hatton 1986 6210 neutropenia 81 Dental abscess,febrile pharyngitis, thigh ulcer
Malaria prophylaxis M 49 AQ-PG 4000 mg 70 Recovered GBR
Hatton 1986 6210 neutropenia U Renal failure,pharyngitis, stomatitis, neurological illness
Malaria prophylaxis F 62 AQ-PG 2800 mg 7 Died GBR
Ellis 1987 R 6120 neutropenia Between 49and 55
Tonsillitis, chills, myalgia, arthralgia
Malaria prophylaxis F 26 AQ-PG 3200 mg 56 Recovered GBR
Gillespie 1977 R 6380 neutropenia 70 Hepatitis, sorethroat with fever, bilateral axillary infection (Proteus species), localized cutaneous
Malaria prophylaxis and therapy
F 26 AQ 3450 mg 70 Transferredto another hospital after infection had subsided with normal blood count and normal
PNG
Draft 11
gangrene, anaemia, hypotension, septicaemia
hepatic function for surgical treatment of axillary condition
Kennedy 1955 R 490 Neutropenia(absolute neutrophil leucopenia)
5 tonsillarinfection, anaemia
Malaria treatment (self medication)
F 2 AQ 1300 mg 7 Recovered ZWE 3 months earlier child had been given sulfadimidine for pyuria, she then had leucocyte count of 6900 per cmm
Carr 1986 6200 Neutropenia,agranulocytosis
63 pharyngitis Malaria prophylaxis M 54 AQ-PG 3200 mg 56 White cell count had risen
GBR
McAllan 1986 4060 palatalpigmentation
U skinpigmentation
Asthma suppressive F 10 AQ 117,375? mg (at diagnosis 375 mg weekly)
2191 Notdescribed as serious
AUS
McAllan 1986 4060 Palatalpigmentation
U Asthma suppressive F 13 AQ 97821 mg (at diagnosis 375 mg weekly)
1826 Notdescribed as serious
AUS
McAllan 1986 4060 palatalpigmentation
U Malaria prophylaxis F 2 AQ U (at diagnosis 50 mg weekly)
730 Notdescribed as serious
AUS
McAllan 1986 4060 palatalpigmentation
U Malaria prophylaxis F 6 AQ U (at diagnosis 150 mg weekly)
2191 Notdescribed as serious
AUS
Schloeder 1961 R 370 pigmentation 110 muscleweakness, myalgias, corneal oedema, anorexia, muscle degeneration
Photosensitive skin reaction
M 33 AQ 49600 mg 124 Hospitalization, later returned to work with some muscle weakness
USA Had chloroquine before
Duperrat 1959 R 750 pigmentation offace, buccal mucosa and nails
Dec 1958 anaemia Lupus erythematosus
M Between 35
and 39
AQ 350000 mg 1068 (AQ was started in January 1956, initially 600 mg per day for 3 months and then 400mg per day until September 1956. Then was stopped because of improvement of the skin lesions. In March 1957, the treatment
U U Concomitant medication:disulfiram; before the use of AQ the patient had been on chloroquine
Draft 12
was resumed with dose of 400mg per day. During the winter 1957-1958, AQ was stopped. AQ was restarted in spring 1958)
Van Riel 1961 610 Pigmentation of fingers and palate (toxidermia)
1095 Dyspnoea,“digital syncope”
Malaria prophylaxis M 39 AQ 70285 mg (at least)
400mg/week of AQ base from 1955 to October 1959 (with a 5 months interuption)
Recovered BEL
Watson 1974 R 5140 Pigmentation ofpalate, face and neck
U Sjorgren'sdisease
Lupus erythematosus
F 36 AQ u Frequentcourses over 8 years
Not described as serious
GBR
Bleil 1958 R 760 pigmentation ofskin and sclerae, partial blindness with opaqueness of cornea
18 lethargy,amenorrhoea, anorexia
Lupus erythematosus
F 42 AQ u 18? Recovered USA
Van Riel 1961 610 Pigmentation of skin, palate and nails (toxidermia)
u Malaria prophylaxis M 56 AQ at least 135000 mg
from 1954 to April 1961
Improved BEL
Limbos 440 1960 Pigmentation ofthe nails, the palate and the edge of nostril
Around 730 Eosinophilia (? Filariasis)
Malaria prophylaxis M 34 AQ 62400 mg (base) 1095 Improved BEL Concomitant disease:filariasis (Loa loa, perstans, streptocerca)
Limbos 1960 440 Pigmentation ofthe nails, the palate, the edge of nostril and the skin of the feet
Around 850 Digestive problems (? Parasitic infection)
Malaria prophylaxis M 28 AQ 62400 mg (base) 1095 Not followed up
BEL Concomitant disease:current or past history of hook worm, schistosoma mansoni, amoebic dysentery
Shee 1963 R 270 pigmentation ofthe skin and buccal mucosa
365 (approx) Malaria prophylaxis M 43 AQ 31200 mg (approx) 1095 (approx)
Not described as serious
MOZ
Schievink 1960 760 Polyneuritis Around 21 hyperproteinaemia
Lupus erythematosus
F 30 AQ 26000 mg 95 (approx) Recovered NLD
Schievink 1960 760 Polyneuritis Around 21 Lupuserythematosus
M 39 AQ 35400 mg 111 Recovered NLD
Akindele 1976 1250 protrudingtongue
U u M 7 AQ 800?mg (4 tablets) 2 Rapidly improved
NGA
Akindele 1976 1250 protrudingtongue, fasciculation of the tongue and facial muscles,
3 excessivesalivation
Malaria therapy F U (“young woman
”)
AQ 1800?mg (9trablets)
3 Recovered NGA Known history of AE with previous AQ use, concomitant medication: aspirin
Draft 13
difficulty in speaking
Young 1958 1700 skin discoloration 117 Lupuserythematosus
M 43 AQ u300 mg to 400 mg daily (35100 mg to 46800 mg)
117 Improving NLD
Young 1958 1700 skin discoloration 56 Lupuserythematosus
M 47 AQ 400 mg daily (at least 22400 mg)
u (at least 56)
U NLD
Young 1958 1700 skindiscoloration, abnormal pigmentation
104 dullness & tremors
Lupus erythematosus
M 47 AQ 300 mg per day (at least 32100 mg)
u (at least 107 d)
Improving NLD Duplication of data in Young 1958 (ID 1690; Dutch)
Akindele 1976 1250 tremor, difficulty with speech
Day 0 (3 hours)
excessive salivation
Malaria therapy F U (“young woman
”)
AQ 600? mg (3 tablets)
1 Recovered NGA Known history of AE with previous AQ use
Hamilton 1950iii 160 Uterinecontractions
U Nausea Malaria treatment F U AQ 500 mg 1 Not described as serious
IND
Akindele 1976 1250 Wobbly gait,intention tremor, stammering, tongue protuded
Day 0 Nausea, dizziness
Malaria therapy F U (“young woman
”)
AQ 600? mg (3 tablets)
1 Rapidlyimproved
NGA Chloroquine use before AQ
AQ, amodiaquine: ART, artesunate; P, pyrimethamine; PG, proguanil; PQ, primaquine,
ARG, Argentina; AUS, Australia; BEL, Belgium; CAN, Canada; CHE, Switzerland; FRA, France; GAB, Gabon; GBR, United Kingdom; GUF, French Guiana; IND, India; ISR, Israel; MOZ, Mozambique; NER, Niger; NGA, Nigeria; NLD, Netherlands; PAK, Pakistan; PNG, Papua New Guinea; SEN, Senegal; TZA, Tanzania; USA, United States of America; ZAF, South Africa; ZWE, Zimbabwe
Draft 14
Table 2. Case reports and case series reporting adverse events: adverse events are not the purpose of the report Sorted by (1) primary adverse event, (2) indication, and (3) year
First author
Year
R = case
report
ID 1° adverse event1
1° adverse event: time
to onset (days)
U = unclear
2° adverse events2
Indication Gender Age (years)
U =
unclear
AQ mono
or combo
U =
unclear
AQ dose (mg)
Duration treatment
(days)
U = unclear
Outcome
U = unclear
Country Comments
Pappenfort 1956 400 anorexia andnausea
U Lupuserythematosus
U 37 AQ (1) Initially200 mg twice daily
16
(2) Then 200 mg every other day (after adverse events occurred)
Improvementon reduced dose
USA
Pappenfort 1956 400 anorexia andnausea
u Lupuserythematosus
F 56 AQ 200 mgtwice daily for 7 days, then 200 mg once daily for 2 days, then stopped taking the drug, approx 3 months later: 100 mg twice daily for 1 week, then dose increased to 200 mg twice daily for 2 weeks and then changed to a "maintenance dose" of 100 mg daily
See dose continues to use the drug with no report of AE
USA
1 The objective of the case report 2 Other reported adverse events
Draft 15
Arias 1989 1510 Dyspepsia
with epigastric pain
u Malaria treatment M Between19 and 72
AQ + primaquine
1500 3 Notdescribed as serious
COL It is not stated whether the patient with dyspepsia and epigastric pain had AQ and primaquine or chloroquine and primaquine.
Peter 1954i 500 vomiting U Malaria treatment U U AQ 600("reduced accordingly for children")
1 Notdescribed as serious
ZAF dose was repeated "it was ascertained that vomiting had occurred shortly after the drug had been taken, and on repeating the dose both responded in the same manner as the others"
Peter 1954i 500 vomiting U Malaria treatment U U AQ 600("reduced accordingly for children")
1 Notdescribed as serious
ZAF dose was repeated "it was ascertained that vomiting had occurred shortly after the drug had been taken, and on repeating the dose both responded in the same manner as the others"
Peter 1954ii 500 nausea ("afew people", "slight nausea") lassitude ("several complained")
u Malariaprophylaxis
U U AQ 600("reduced accordingly for children")
every 14 days Not described as serious
ZAF
Hamilton 1950iv 160 nausea vomiting
U Malaria treatment U U (adult) AQ 500 1 Not described as serious
IND
Hamilton 1950iv 160 nauseavomiting
U Malaria treatment U U (adult) AQ 500 1 Not described as serious
IND
Hamilton 1950iv 160 nauseavomiting
U Malaria treatment U U (adult) AQ 500 1 Not described as serious
IND
Hamilton 1950iv 160 nausea U Malaria treatment U U(children)
AQ (50 mg per year of life up to the age of 10 years (adult dose))
1 Notdescribed as serious
IND
Hutet 1952ii 580R
lassitude u giardiasis u u AQ 600 1 Notdescribed as serious
FRA
Nonclercq 1955R
360 Loss ofappetite
42 Lupuserythematosus
F 45 AQ at least25200mg
63 The appetitereturned as soon as AQ was stopped
FRA
Draft 16
Chowdhury 1965 5830 headache U giddiness,
yellow coloration of conjunctiva and urine, nausea & vomiting
Acute lepra reaction
M 42 AQ 6000? (30tablets of Camoquin)
10 recovered IND
Chowdhury 1965 5830 headache U Acute leprareaction
M 60 AQ 6000? (30tablets of Camoquin)
10 recovered IND
Chowdhury 1965 5830 "Camoquinintolerance"
U Acute leprareaction
F 30 AQ 1200? (3tablets daily for 48 hours)
2 recovered IND
Chowdhury 1965 5830 "Camoquinintolerance"
U Acute leprareaction
M 49 AQ u u recovered IND
Draft 17
Table 3. Case reports and case series: reporting no adverse events
First author Year ProCite ID Study design
Indication for AQ use No. cases having taken AQ
How many people in the same study taking AQ had an adverse event? 1
Pappenfort 1956 400 Case series Lupus erythematosus 9 2 Peter 1954i 500 Case series Malaria treatment 71 2 Rolfe 1988R 2890 Case report Malaria treatment 1 0 Shute 1970 5360 Case series Malaria treatment 7 0 Pomeroy 1959 660 Case series Rheumatoid arthritis 32 5 Wallace 1951 250 Case series Malaria treatment 100 0 Blasco 1992 1960 Case series Malaria treatment 7 0 Neel 1955R 410 Case report Giardiasis 1 0Soulayrol 1985 3490 Case series Malaria treatment 1 0 van Grunderbeeck 1954ii 100 Case series Taenia saginata 2 0 Charmot 1985 3970 Case series Malaria treatment 1 0 Jame 1954iiR 540 Case report Malaria treatment u 0 Biagini 1957 750 Case series Lupus erythematosus 12 1 Glick 1957 470 Case series unknown 31 1Chowdhury 1965 5830 Case series Acute lepra reaction 10 4 Schievink 1960 760 Case series Lupus erythematosus 28 3 Charmot 1987 3350 Case series Malaria treatment 1 0
1 Reported in Table 1 or 2, Annex 3
Draft 18
Pharmacovigilance data Table 4. Summary of the adverse reactions with ‘amodiaquine (including salts/esters) in the WHO Adverse Reaction Database on 16 August 20021 Adverse drug reaction No.
Reports
Gender Age (years)
AQ info (AQ is suspected drug) Indication Other drugs (in bold if also a suspected drug)
Outcome Country National Centre
‘relationship’
Comment
(1) M 19 AQ hydrochloride 200 mg per oral daily for 1 year
Diagnostic x-ray; late effects of poliomyelitis
Unknown Israel Notspecified
Also had ‘anaemia aplastic’
(2) F 51 Camoquin 150 mg per oral daily from 18 March 1975 to 29 May 1975 Camoquin 300 mg per oral daily from 10 March 1975 to 17 March 1975
Psoriatic arthropathy
Aspirin “Bayer” (acetylsalicylic acid); prednisone
Recovered without sequelae
Australia Notspecified
Agranulocytosis 18
(3) F 50 Camoquin 150 mg per oral daily from Feb 1974 to May 1975
Gold (for ‘other rheumatoid arthritis’); prednisone (for ‘other rheumatoid arthritis’); valium (diazepam)
Not specified
Australia Notspecified
Anaemia aplastic 1 (1) M 19 AQ hydrochloride 200 mg per oral daily for 1 year
Diagnostic x-ray; late effects of poliomyelitis
Unknown Israel Notspecified
Also had ‘agranulocytosis’
Anorexia 2 (1) F 25 Camoquin 300 mg per oral weekly from 3 Sept 1981 to 9 Oct 1981
Diagnostic x-ray (44(08))
Not yetrecovered
Australia Possible Also had‘coughing’, ‘fever’, ‘malaise’, ‘rash’, ‘somnolence’
Ascites 1 Asthenia 2 Ataxia 1
Draft 19
1 Caveat statement: Data released from the WHO Adverse Reaction Database, the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring. This information is not homogenous at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction. This information does not represent the opinion of the World Health Organization.
M 3
months
AQ hydrochloride (dose not specified)
Azathioprine; prednisolone
Unknown Australia PossibleBlindness 2
M 3months
AQ hydrochloride 150 mg systemic (if route not specified)
Azathioprine; prednisolone
Unknown Australia Possible
Cardiomyopathy 1 Chest pain 1 Concentration impaired
1
Convulsions 1 Convulsions grand mal
1
Coughing 1 (1) F 25 Camoquin 300 mg per oral weekly from 3 Sept 1981 to 9 Oct 1981
Diagnostic x-ray (44(08))
Not yetrecovered
Australia Possible Also had‘anorexia’, ‘fever’, ‘malaise’, ‘rash’, ‘somnolence’
Death 2 Dermatitis exfoliative 1 F 52 Camoquin 300 mg per oral
daily Not
specified Canada Not
specified Also had ‘oedema dependent’ and ‘rash erythematous’
Dermatitis lichenoid 1 Dyskinesia tardive 1
M 49 AQ hydrochloride 600 mg per oral twice from 26 Nov 1985 to 5 Dec 1985
Diagnostic x-ray; 49 (08)
Unknown Sweden Probable Also had‘hepatocellular damage’
Eosinophilia 2
F 70 AQ hydrochloride 400 mg per oral weekly from 21 Feb 1987 to 19 March 1987
Diagnostic x-ray; 49(08)
Unknown Sweden Unlikely Also had‘SGOT increased’ and ‘SGPT increased’
Fever 3 (1) M 46 Camoquin 1.6 g per oral total Recovered without sequelae
Israel Notspecified
Also had ‘hepatocellular damage’ and ‘pain’
Draft 20
(2) F 25 Camoquin 300 mg per oral
weekly from 3 Sept 1981 to 9 Oct 1981
Diagnostic x-ray (44(08))
Not yetrecovered
Australia Possible Also had‘coughing’, ‘anorexiar’, ‘malaise’, ‘rash’, ‘somnolence’
Granulocytopenia 7 (1) M 60 Camoquin 400 mg per oral weekly for 2 months
diagnostic x-ray; late effects of acute poliomyelitis
Daraprim (pyrimethamine) A.P.C; acetylsalicylic acid; caffeine; phenacetin; septrin; sulfamethoxazole; trimethoprim
Recovered without sequelae
Israel Notspecified
predisposing condition (diabetes mellitus) Also had ‘infection bacterial’
Hepatic necrosis 2 Hepatitis 9 (1) M 23 Camoquin 0.2 g per oral
weekly from 27 May 1981 to July 1981
Unclear (0846 (08))
Daraprim (pyrimethamine) Sedistal (atropine sulfate; diphenoxylate hydrochloride)
Unknown Israel Certain
Hepatitis cholestatic 1 M 46 Camoquin 1.6 g per oral total Recovered
without sequelae
Israel Notspecified
Also had ‘fever and ‘pain’
Hepatocellular damage
2
M 49 AQ hydrochloride 600 mg per oral twice from 26 Nov 1985 to 5 Dec 1985
Diagnostic x-ray; 49 (08)
Unknown Sweden Probable Also had‘eosinphilia’
Hysteria 1 Infection bacterial 1 M 60 Camoquin 400 mg per oral
weekly for 2 months diagnostic x-ray; late effects of acute poliomyelitis
A.P.C; acetylsalicylic acid; caffeine; phenacetin; septrin; sulfamethoxazole; trimethoprim
Recovered without sequelae
Israel Notspecified
predisposing condition (diabetes mellitus Also had ‘granulocytopenia
Jaundice 3 Leucopenia 2 (1) ? ? Camoquin per oral daily (no
other information) Recovered
without USA Not
specified
Draft 21
sequelae
Malaise 2 (1) F 25 Camoquin 300 mg per oral weekly from 3 Sept 1981 to 9 Oct 1981
Diagnostic x-ray (44(08))
Not yetrecovered
Australia Possible Also had‘coughing’, ‘fever’, ‘anorexia’, ‘rash’, ‘somnolence’
Myopathy 1 Nausea 2 Neuropathy 1 Oculomotor nerve paralysis
1
Oedema 1 Oedema dependent 1 F 52 Camoquin 300 mg per oral
daily Not
specified Canada Not
specified Also had ‘dermatitis exfoliative’ and ‘rash erythematous’
Oedema peripheral 1 Pain 1 M 46 Camoquin 1.6 g per oral total Recovered
without sequelae
Israel Notspecified
Also had ‘hepatocellular damage’ and ‘fever’
Phosphatase alkaline incre
2
Pigmentation abnormal
2
Prothrombin increased
1
Rash 1 (1) F 25 Camoquin 300 mg per oral weekly from 3 Sept 1981 to 9 Oct 1981
Diagnostic x-ray (44(08))
Not yetrecovered
Australia Possible Also had‘coughing’, ‘fever’, ‘malaise’, ‘anorexia’, ‘somnolence’
F 71 Camoquin (AQ hydrochloride) 1 dosage form (strength not known) for 2 weeks
aldometmethyldopa; digoxine digoxin; potassium chloride; rastinon tolbutamide
unknown outcome
Netherlands
-- Also had‘oedema dependent’ and ‘dermatitis exfoliative’
Rash erythematous 2
F 52 Camoquin 300 mg per oral daily
Not specified
Canada Notspecified
Draft 22
Draft 23
Rash maculo-papular 1 SGOT increased 9 (1) F 70 AQ hydrochloride 400 mg per
oral weekly from 21 Feb 1987 to 19 March 1987
Diagnostic x-ray; 49(08)
Unknown Sweden Unlikely Also had‘SGPT increased’ and ‘eosinphilia’
SGPT increased 10 (1) F 70 AQ hydrochloride 400 mg per oral weekly from 21 Feb 1987 to 19 March 1987
Diagnostic x-ray; 49(08)
Unknown Sweden Unlikely Also had‘SGOT increased’ and ‘eosinphilia’
Skin discolouration 1 F 52 Camoquin unknown dose
solvex; benzoicacid; chlorothymol; salicylic acid; thymol
recovered without sequelae
Netherlands
Not specified
Somnolence 2 (1) F 25 Camoquin 300 mg per oral weekly from 3 Sept 1981 to 9 Oct 1981
Diagnostic x-ray (44(08))
Not yetrecovered
Australia Possible Also had‘coughing’, ‘fever’, ‘malaise’, ‘rash’, ‘anorexia’
Speech disorder 1 Sweating increased 1 Thrombocytopenia 1 Tremor 1 Urticaria 1 Vertigo 1