annex 4. case reports, case series, and...

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


3 Hypotension,leucocytosis

Malaria treatment M 5.5 AQ-PQ 4 tablets (?300 mg AQ)

2 Recovered PAK


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)


2 Malaria treatment M 3.5 AQ-PQ 4 tablets (300 mg?)

2 Recovered PAK


3 Malaria treatment M 13 AQ-PQ u U Recovered PAK


2 hypotension Malaria treatment F 17 AQ-PQ 6 tablets 3 Recovered PAK


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


U Malaria prophylaxis U U U 600 mg weekly Between one and 22 months

U GUF


U Malaria prophylaxis U U U 600 mg weekly Between one and 22 months

U GUF


U Malaria prophylaxis U U u 600 mg weekly Between one and 22 months

U GUF



U GUF



U GUF


u Malaria prophylaxis U U u 600 mg weekly Between one and 22 months

U GUF

Dedet 1986 3650 Cutaneousleishmaniasis


U GUF



U GUF


U Malaria prophylaxis U U u 600 mg weekly Between one and 22

U GUF

Draft 5

months



U GUF



U GUF



U GUF



U GUF



U GUF



U GUF



U GUF



U GUF



U GUF



U GUF


u Malaria prophylaxis U U u 600 mg weekly Between one and 22 months

U GUF



U GUF



U GUF



U GUF



U GUF



U GUF



U GUF


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







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)


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)


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



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)


42 Fever, asthenia,vomiting



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)



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



U U u Between 3000 mg and 13000 mg

Between 35 and 105




U U u Between 3000 mg and 13000 mg

Between 35 and 105




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


About 45 Prostration Malaria prophylaxis M 38 AQ About 2893 mg base




20 Recovered Those with an acute febrile episode alluding a hepatitis were excluded from the study in the initial

Draft 8

stage














About 250 Fever, prostration

Malaria prophylaxis M 55 AQ About 16071 mg base


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


80 Melanosis,asthenia, arthralgias, thrombopenia


FRA


105 Fever, asthenia,vomiting, chills, thrombopenia


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


U Malaria prophylaxis U U AQ 150 mg (AQ base chlorhydrate) every other day

U Recovered FRA


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


U Rheumatoid arthritis U U AQ U u Notdescribed as serious

USA


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


Hatton 1986 6210 neutropenia 81 Dental abscess,febrile pharyngitis, thigh ulcer


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)


AUS

McAllan 1986 4060 Palatalpigmentation

U Asthma suppressive F 13 AQ 97821 mg (at diagnosis 375 mg weekly)


AUS


U Malaria prophylaxis F 2 AQ U (at diagnosis 50 mg weekly)


AUS


U Malaria prophylaxis F 6 AQ U (at diagnosis 150 mg weekly)


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


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)


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


”)

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


”)

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")


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")


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


IND

Hamilton 1950iv 160 nauseavomiting


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))


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

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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

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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


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’

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(2) F 25 Camoquin 300 mg per oral

weekly from 3 Sept 1981 to 9 Oct 1981


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


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


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

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sequelae

Malaise 2 (1) F 25 Camoquin 300 mg per oral weekly from 3 Sept 1981 to 9 Oct 1981


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


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

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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


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


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


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

annex 4. case reports, case series, and...

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