Amodiaquine Hydrochloride
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.2 Properties of the locally available formulation |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 CNS |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. Additional information |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
PHARMACEUTICALS
1. NAME
1.1 Substance
Amodiaquine Hydrochloride (INN)
1.2 Group
Antimalarials: 4-aminoquinolines
1.3 Synonyms
Amodiachin Hydrochloride
Amodiaquini Hydrochloridum
1.4 Identification numbers
1.4.1 CAS number
86-42-0
1.4.2 Other numbers
6398-98-7 (amodiaquine dihydrochloride, dihydrate)
69-44-3 (amodiaquine hydrochloride, anhydrous)
1.5 Brand names, Trade names
Basoquin
CAM-AQ1
Camoquin
Camoquinal
Flavoquin
Fluroquine
Miaquin
SN-10,751
Formulations containing combinations of amodiaquine and other
antimalarial drugs are also available, e.g. Camoprima Infatabs
(containing 75 mg amodiaquine + 15 mg primaquine).
1.6 Manufacturers, Importers
Basoquin (Parke, Davis, UK)
Camoquin (Parke, Davis, Spain, Switzerland, UK)
Flavoquin (Roussel, France)
2. SUMMARY
2.1 Main risks and target organs
After oral administration amodiaquine hydrochloride is rapidly
absorbed,and undergoes rapid and extensive metabolism to
desethylamodiaquine which concentrates in red blood cells. It
is likely that desethylamodiaquine, not amodiaquine, is
responsible for most of the observed antimalarial activity,
and that the toxic effects of amodiaquine after oral
administration may in part be due to desethylamodiaquine.
Chloroquine, a 4-aminoquinoline derivative which resembles
amodiaquine structurally, is widely distributed into the body
tissues, especially in liver, spleen, kidney, lungs, brain,
and spinal cord. It binds to melanin-containing cells in the
eyes and skin. In the blood, chloroquine concentrates in the
erythrocytes and binds to platelets and leucocytes. Since the
structure and spectrum of activity of these two 4-
aminoquinoline derivatives are very similar, it is likely that
the distribution of desethylamodiaquine in man mirrors that of
chloroquine.
2.2 Summary of clinical effects
Gastrointestinal tract: anorexia, nausea, vomiting, diarrhoea,
melanosis
Haematopoietic system: leucopenia, agranulocytosis, aplastic
anaemia, pancytopenia
Liver: toxic hepatitis
Skin: lichenoid reaction, urticaria, pigmentation of mucous
membranes and skin
Nervous system & muscles: hallucinations, neuronitis,
polymyositis
Eye: corneal irritation, keratitis, retinitis, retinal
degeneration
Heart: heart block
The usual signs and symptoms of an overdose are headache,
vertigo and vomiting; the more severe manifestations including
cardiac arrhythmias, convulsions and coma. The most dramatic
feature is visual disturbance, including sudden loss of vision,
which is usually transitory.
Other symptoms include itching, cardiovascular abnormalities,
dyskinesia, neuromuscular and haematological disorders, and
hearing loss.
2.3 Diagnosis
Nausea, vomiting, diarrhoea, headache, drowsiness, blurred
vision, blindness, convulsions, coma, hypotension, cardiac
arrhythmias, cardiac arrest and impaired respiration are the
characteristic features of amodiaquine poisoning.
Electrocardiography (ECG) may show inverted or flattened T
waves, widening of QRS, ventricular tachycardia and
fibrillation.
Hypokalaemia may be present.
High serum amodiaquine levels confirm the diagnosis.
2.4 First aid measures and management principles
Treatment of overdosage is supportive and must be prompt since
acute toxicity can progress rapidly, possibly leading to
vascular collapse and respiratory and cardiac arrest.
Because of the importance of supporting ventilation, early
endotracheal intubation and mechanical ventilation may be
necessary. Early gastric lavage followed by administration of
activated charcoal may provide some benefit in reducing
absorption of the drug. These should be preceded by measures
to correct cardiac and severe ardiovascular disturbances, if
present, and by respiratory support. Diazepam IV may control
seizures and other manifestations of CNS stimulation.
Seizures caused by anoxia should be corrected by oxygen and
other respiratory support. Defibrillators and cardiac
pacemakers may be required.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthesised from 4,7-dichloroquinoline and 4-acetamido- -
diethylamino-o-cresol. Alternative synthesis from 2-
aminomethyl-p-aminophenol and 4,7-dichloroquinoline (The Merck
Index, 1983).
US patents 2,474,819 : 2,474,821 (1949 to Parke, Davis)
3.2 Chemical structure
Aminodiaquine Hydrochloride is 4-[(7-chloro-4-quinolyl)amino]-
2-[(diethylamino)methyl] phenol dihydrochloride dihydrate.
Structural formula: C20H22ClN3O,2HCl,2H2O
STRUCTURAL FORMULA;pim030.bmp
Molecular weight: 464.8
3.3 Physical properties
3.3.1 Properties of the substance
A yellow crystalline powder; odourless (or
almost odourless); with a bitter taste.
Soluble 1 in 22 parts water
1 in 70 parts ethanol (96%)
Practically insoluble in benzene, chloroform and
ether.
A 2% solution in water has a pH of 2.6 - 4.6.
pH of 1% aqueous solution : 4.0 to 4.8 (Merck,
1989)
Decomposition: 150-160 °C
3.3.2 Properties of the locally available formulation
To be added by the Poison Control Centre.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Shelf-life of the locally available formulation
To be added by the Poison Control Centre.
3.4.3 Storage conditions
Store in an air-tight container, in child-resistant
packaging out of the reach of children.
3.4.4 Bioavailability
To be added by the Poison Control Centre.
3.4.5 Specific properties and composition
To be added by the Poison Control Centre.
4. USES
4.1 Indications
For treatment of acute malarial attacks in non-immune
subjects. It is at least as effective as chloroquine,
and is effective against some chloroquine-resistant
strains, although resistance to amodiaquine has been
reported.
Amodiaquine hydrochloride has been tried in the
treatment of giardiasis and hepatic amoebiasis. It has
also been tried, with variable success, in the treatment
of lepra reactions, lupus erythematosus, rheumatoid
arthritis, and urticaria (Martindale, 1989).
4.2 Therapeutic dosage
4.2.1 Adults
For the treatment of acute malarial attacks in non-
immune subjects: 600 mg of the base, followed by 200 mg
after 6 hours, then 400 mg daily on each of the
subsequent two days. Doses may be taken with meals to
lessen gastric upset.
A number of variations of this regimen have been used.
For partially immune subjects a single dose of 600 mg of
the base is often sufficient (Martindale, 1989).
Prophylactic dose: for children 15 years of age and
younger: 7 mg base/kg body weight to be given once
weekly and continued for six weeks after the last
exposure.
Because of the narrow margin between the therapeutic and
toxic concentrations in children, amodiaquine should not
be administered parenterally in this age group (AHFS,
1988) (see section 7.2.1.2).
4.2.2 Children
4.3 Contraindications
The US Center for Disease Control (CDC) has stated that any
possible prophylactic advantage that amodiaquine may afford is
not justified by the possible risk of agranulocytosis
associated with the use of the drug (CDC, 1985).
The manufacturer of Camoquin (Parke-Davis) has advised in a
data sheet to health professionals that the prophylactic use
of amodiaquine as a first line agent has been restricted to
chloroquine-resistant areas (Neftel et al., 1986). They have
also stated that agranulocytosis has occurred in association
with the use of amodiaquine in malaria prophylaxis. Although
agranulocytosis has been reported following the sole use of
amodiaquine, most cases have occurred when other anti-
malarials have been taken concurrently. Therefore, the
prescribing physician should assess the advantages and
disadvantages of amodiaquine in malaria prophylaxis but if the
decision is made to so prescribe the drug, concomitant use
with other anti-malarials should be performed to assure that
blood values and liver function tests remain within normal
limits.
Because amodiaquine may concentrate in the liver, the drug
should be used with caution in patients with hepatic disease
or alcoholism, and in patients receiving hepatotoxic drugs.
Children are especially sensitive to 4-aminoquinoline
derivatives (see Section 7.2.1.2). Because of the narrow
margin between the therapeutic and toxic concentrations in
children, amodiaquine should not be administered parenterally
in this age group (AHFS, 1988).
Amodiaquine is contraindicated in patients who are
hypersensitive
5. ROUTES OF ENTRY
5.1 Oral
This is the usual route of administration for therapeutic use.
5.2 Inhalation
Unknown.
5.3 Dermal
Unknown.
5.4 Eye
Unknown.
5.5 Parenteral
Amodiaquine has been given by both constant rate intravenous
injection and constant rate infusion in volunteers and
patients (White et al., 1987).
Because of the narrow margin between the therapeutic and toxic
concentrations in children, amodiaquine should not be
administered parenterally in this age group (AHFS, 1988).
5.6 Other
Unknown.
6. KINETICS
6.1 Absorption by route of exposure
Oral
After oral administration amodiaquine hydrochloride is rapidly
absorbed, and undergoes rapid and extensive metabolism to
desethylamodiaquine which concentrates in blood cells. It is
likely that desethylamodiaquine, not amodiaquine, is
responsible for most of the observed antimalarial activity,
and that the toxic effects of amodiaquine after oral
administration may in part be due to desethylamodiaquine
(Winstanley et al., 1987).
6.2 Distribution by route of exposure
Oral
After oral administration of amodiaquine (600 mg) to 7 healthy
adult males, amodiaquine underwent rapid conversion to
desethylamodiaquine. The peak concentration of amodiaquine was
32 + 3 ng/ml at 0.5 + 0.03h. The peak concentrations of
amodiaquine in whole blood and packed cells were 60 + 10 and
42 + 6 ng/ml respectively, reached at 0.5+ 0.1h in both.
Thereafter the concentration of amodiaquine declined rapidly,
and was detectable for no more than 8 h.
Mean peak plasma concentration of the metabolite
(desethylamodiaquine) was 181 + 26 ng/ml respectively. Times
to peak for whole blood and packed cells were 2.2 + 0.5 and
3.6 + 1.1 h respectively (Winstanley et al., 1987).
Although in use for more than 40 year, there exists little
information regarding the disposition of amodiaquine in man.
Chloroquine, a 4-aminoquinoline derivative which resembles
amodiaquine structurally, is widely distributed into the body
tissues, especially in liver, spleen, kidney, lungs, brain,
and spinal cord. It binds to melanin-containing cells in the
eyes and skin. In the blood, chloroquine concentrates in the
erythrocytes and binds to platelets and leucocytes. Since the
structure and spectrum of activity of these two 4-
aminoquinoline derivatives are very similar, it is likely that
the distribution of desethylamodiaquine (the major active
metabolite of amodiaquine) in man mirrors that of chloroquine.
Parenteral
The distribution half times observed after intravenous
injection (3 mg base per kg over 10 minutes) to seven healthy
adult male volunteers (geometric mean 1.7; range 0.4 to 55
minutes) were significantly faster than those observed after
intravenous infusion (10 mg base per kg over 4 hours) to 10
adult patients with falciparum malaria (geometric mean 22.2;
range 5 to 126 minutes). The plasma concentration time
profiles were biphasic.
After bolus injection the apparent volume of the central
compartment (1.1; range 0.3 to 3.6 l/kg) was one-quarter of
that estimated after the infusion (4.6; range 0.5 to 29.3
l/kg).
The authors of the study suggested that there was probably an
additional distribution phase in the malaria patients obscured
by the slower rate of infusion: it was possible that had the
volunteers been able to tolerate a larger dose, a triphasic
elimination profile may have become apparent (White et al.,
1987).
6.3 Biological half-life by route of exposure
Oral
Amodiaquine 600 mg was given by mouth (see section 6.2), the
apparent terminal half-life of amodiaquine was 5.2 + 1.7
(range 0.4 to 5.5) minutes and the geometric mean of the
estimated elimination phase half-lives was 2.1 (range 0.5 to
5.7) hours (White et al., 1987).
6.4 Metabolism
When amodiaquine is given orally relatively little of the
parent compound is present in the blood. Hepatic
biotransformation to desethylamodiaquine (the principal
biologically active metabolite) is the predominant route of
amodiaquine clearance with such a considerable first pass
effect that very little orally administered amodiaquine
escapes untransformed into the systemic circulation
(Winstanley et al., 1987).
6.5 Elimination by route of exposure
Amodiaquine and desethylamodiaquine have been detected in the
urine several months after administration (Winstanley et al.,
1987).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Amodiaquine, a 4-aminoquinoline similar to chloroquine
in structure and activity, has been used as both an
antimalarial and an anti-inflammatory agent for more
than 40 years.
The mode of action of amodiaquine has not yet been
determined. 4-Aminoquinolines depress cardiac muscle,
impair cardiac conductivity, and produce vasodilatation
with resultant hypotension; they depress respiration
and cause diplopia, dizziness and nausea.
7.1.2 Pharmacodynamics
In general, 4-aminoquinoline derivatives appear to bind
to nucleoproteins and inhibit DNA an RNA polymerase.
High drug concentrations are found in the malaria
parasite's digestive vacuoles (AFHS, 1988).
After oral administration amodiaquine hydrochloride is
rapidly absorbed, and undergoes rapid and extensive
metabolism to desethylamodiaquine which concentrates in
blood cells. It is likely that desethylamodiaquine, not
amodiaquine, is responsible for most of the observed
anti-malarial activity, and that the toxic effects of
amodiaquine after oral administration may, in part, be
due to desethylamodiaquine (Winstanley et al., 1987).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
TDLo (male, oral) 34 mg/kg over a 6 week
interval; agranulocytosis
TDLo (female, oral) 160 mg/kg over a 14 week
interval; agranulocytosis
(Ref. RTECS, 1985-1986)
It is likely that the fatal dose for amodiaquine
would be similar to that of chloroquine
phosphate (2 to 3 g, adult) (Ellenhorn and
Barceloux, 1988) since amodiaquine appears to
completely parallel the adverse effects of those
seen with chloroquine when equivalent doses are
used.
7.2.1.2 Children
Children are especially sensitive to 4-
aminoquinoline derivatives; fatalities have been
reported following accidental ingestion of
relatively small doses of chloroquine (a 4-
aminoquinoline derivative similar in structure
and activity to amodiaquine). The toxic dose
range for oral chloroquine phosphate in children
is 0.75 to 1 g (Ellenhorn & Barceloux, 1988).
Severe reactions and fatalities have also
occurred in children following parenteral
administration of chloroquine (AFHS, 1988) (see
section 4.2.2).
7.2.2 Relevant animal data
LD50 (mouse, intraperitoneal) 225 mg/kg
LD50 (mouse, oral) 550 mg/kg
LDLo (mouse, intraperitoneal) 137 mg/kg
(as dihydrochloride; no toxic effect noted)
(RTECS, 1985-1986).
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Although no data are available for amodiaquine, chloroquine, a
structurally similar 4-aminoquinoline with the same spectrum
of activity and similar adverse reaction profile, is known to
cross the placental barrier.
A woman during four of her eight pregnancies was given
chloroquine (250 mg daily from the sixth week after
conception); two of these children were congenitally deaf with
instability of gait. One of these children had
chorioretinitis of the type associated with chloroquine
toxicity in the adult. A third exposed child had
hemihypertrophy and developed a Wilm's tumour (Shepard, 1986).
A 1985 report summarized the results of 169 infants exposed in
utero to 300 mg of chloroquine base once weekly throughout
pregnancy. The control group consisted of 454 non-exposed
infants. Two infants (1.2%) in the study group had anomalies
(tetralogy of Fallot and congenital hypothyroidism) compared
to four control infants who had defects (0.9%). Based on
these data the authors concluded that chloroquine does not
have a strong teratogenic effect, but a small increase in
birth defects could not be excluded (Wolfe & Cordero, 1985).
It is generally believed that the benefits of chloroquine
therapy in pregnant women exposed to malaria outweigh the
potential risks of the drug to the foetus.
Chloroquine does not appear to be excreted in appreciable
amounts in the breast milk (Anderson, 1977).
7.5 Mutagenicity
No data available.
7.6 Interactions
Since magnesium trisilicate and kaolin are known to decrease
the gastrointestinal absorption of chloroquine when
administered simultaneously, it is likely that this also
follows for amodiaquine (Ellenhorn & Barceloux, 1988).
Concomitant administration of chloroquine at recommended doses
for malaria suppression of chemoprophylaxis during pre-
exposure prophylaxis of rabies with intra-dermally
administered rabies vaccine may interfere with the antibody
response to the vaccine. However, the clinical significance
of this interaction remains to be clearly established but
should be considered and may have relevance in the case of
amodiaquine (AHFS, 1988).
7.7 Main adverse effects
Oral administration of a single dose of amodiaquine may be
followed by abdominal discomfort, nausea, vomiting, headache,
dizziness, blurring of vision, mental and physical weakness,
and fatigue. These symptoms are usually mild and transient.
More severe adverse reactions include itching, cardiovascular
abnormalities, dyskinesia, ocular damage, neuromuscular
disorders and hearing loss. There have been several reports
of agranulocytosis and these have limited its use in
prophylaxis.
Hepatitis and peripheral neuropathy have also been reported
(Reynolds, 1989) (see section 9.4).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Amodiaquine (a 4-aminoquinoline derivative), exhibits
symptoms of overdosage typical of the 4-aminoquinoline
class of anti-malarial drugs. Symptoms include headache,
drowsiness, visual disturbances, vomiting, hypokalaemia,
cardiovascular collapse and cardiac and respiratory
arrest. Hypotension, if not treated, may progress
rapidly to shock. Electrocardiograms (ECG) may reveal
atrial standstill, nodal rhythm, prolonged
intraventricular conduction time, broadening of the QRS
complex, and progressive bradycardia leading to
ventricular fibrillation and/or arrest (AFHS, 1988).
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
See section 9.1.1 (oral exposure). Cardiovascular
effects may be more commonly observed.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Adverse reaction include itching, cardiovascular
abnormalities, dyskinesia, ocular damage, neuromuscular
disorders and hearing loss. There have been several
reports of agranulocytosis and these have limited its
use in prophylaxis. Hepatitis and peripheral neuropathy
have also been reported (Reynolds, 1989) (see section
9.4).
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
No data available.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
See section 9.2.1 (oral exposure). Cardiovascular
effects may be more commonly observed.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Because the 4-aminoquinoline derivatives are rapidly and
completely absorbed from the Gl tract, symptoms of acute
toxicity may occur within 30 minutes following ingestion of
the drug. Death has occurred within two hours following
vascular collapse and respiratory and cardiac arrest.
Children are especially sensitive to 4-aminoquinoline
derivatives; however, reports of suicides have indicated that
the margin of safety in adults is also small. Without prompt
effective therapy, acute ingestion of 5 g or more of
chloroquine in adults has usually been fatal, although death
has occurred with smaller doses. Fatalities have been
reported following ingestion of relatively small doses of
chloroquine (e.g., 750 mg or 1 g of chloroquine phosphate in a
three-year-old child).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Chronic
T-wave changes and prolongation of the QT-interval are
not uncommon during high-dose treatment with 4-
aminoquinoline congeners. These are probably not
significant in themselves (Tester-Dalderup, 1984).
Acute on chronic
Acute intoxication with chloroquine, a 4-aminoquinoline
congener structurally similar to amodiaquine, is
associated with cardiac arrest. Complete heart block
was observed in a Nigerian male treated with high doses
for about two years. First degree right bundle-branch
block was recorded in another male who had taken 8 to 10
tablets of 250 mg chloroquine weekly for about three
years; sudden death was attributed to a Stoke-Adams
attack. Focal convulsions followed by irregular heart
action and cardiac arrest were reported during the iv
administration of 250 mg chloroquine over a five-minute
period. Acute overdosing is reputed to be particularly
dangerous if the drug is given intravenously or if taken
by young children (Tester-Dalderup, 1984).
Sudden hypotension may occur, with absence of peripheral
pulses, vasodilatation, cyanosis of the lips and face,
arrhythmias and cardiac arrest often seen early. The
ECG may reflect bradycardia, atrial standstill, a
widened QRS, prolonged intraventricular conduction time,
inverted or flattened T waves, S-T segment depression,
ventricular tachycardia, nodal rhythm, prolongation of
QT interval, complete heart block, ventricular
fibrillation, and cardiac arrest (Ellenhorn & Barceloux,
1988).
9.4.2 Respiratory
Acute
Rapid superficial breathing, Cheyne-Stokes breathing,
sudden apnoea, respiratory failure, or, terminally,
respiratory arrest may be observed (Ellenhorn &
Barceloux, 1988).
9.4.3 Neurological
9.4.3.1 CNS
Chronic
Four patients experienced involuntary movements,
usually with speech difficulty after large, but
not excessive, doses of amodiaquine (Akindele &
Odejide, 1976).
Lethargy and drowsiness have been reported as
early side effects following therapeutic doses
(Glickman, 1959).
Additional neurological effects following other
4-aminoquinoline derivatives have been
described. These may occur with amodiaquine
therapy but have not been reported. A range of
mental changes attributed to the use of
chloroquine has been described namely agitation,
aggressiveness, confusion, personality changes,
psychotic symptoms and depressions (Tester-
Dalderup, 1984).
Acute
Abnormal involuntary movements similar to those
that occur in Parkinsonism have been reported in
some patients treated with amodiaquine. The
movements mainly affected the tongue and the
facial muscles. In some patients the limbs were
affected with tremor and ataxia. The symptoms
usually started within 24 hours of taking the
drug. Left untreated, the disturbance remitted
spontaneously with 48 hours, but it could be
terminated within two hours by giving
anticholinergic drugs like benzhexol and
benztropine (Salako, 1984).
9.4.3.2 Peripheral nervous system
Chronic
Peripheral neuritis has also been described in
association with chloroquine (Tester-Dalderup,
1984).
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
Chronic
Neuromyopathy, and myopathy have also been
described in association with chloroquine
(Tester-Dalderup, 1984).
9.4.4 Gastrointestinal
Chronic
Nausea, vomiting and diarrhoea have been reported
(Glickman et al., 1959).
9.4.5 Hepatic
Chronic
Hepatitis developed in seven patients taking amodiaquine
for malaria prophylaxis for 4 to 15 weeks. Liver
dysfunction recurred in two patients when amodiaquine
was administered subsequently (Larrey et al., 1986) (see
section 9.4.11).
9.4.6 Urinary
9.4.6.1 Renal
Chronic
Although no data are available for amodiaquine,
it should be noted that haemolysis and acute
renal failure reportedly occurred in a few
patients with glucose-6-phosphate dehydrogenase
deficiency receiving chloroquine (AFHS, 1988).
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Chronic
A mild degree of itching with or without a rash can
follow the use of amodiaquine in all races. However, in
Africans, a more severe itching has been reported (see
below). The itching has a curious biting or pricking
character, and affects all parts of the body including
the scalp, the palms of the hands, and the soles of the
feet. It is often unassociated with urticaria or any
other kind of rash. It begins within a few hours of
taking the drug and often continues for between 48 and
72 hours. It is usually severe enough to make sleep
impossible for as long as it lasts. The itching occurs
in all age groups but it is unusual for it to be
experienced on the first exposure to the drug.
Once itching has started, it usually runs it course of
48 to 72 hours, irrespective of treatment with
antihistamines. However, prophylactic administration of
an antihistamine usually prevents or reduces the
severity of the reaction (Salako, 1984).
Pruritus occurred in 14 (27%) of 52 patients with
malaria treated with amodiaquine (25 mg/kg) over three
days. Although the pathogenesis of this adverse
reaction is still unknown, it occurs mainly in Blacks,
and appears to run in families, suggesting a genetic
basis (Sowunmi et al., 1989).
Other dermatological effects have been reported for
chloroquine, which may also occur following amodiaquine
therapy. These include pigmentary changes of the skin
and mucous membranes, skin eruptions resembling lichen
planus, and various dermatoses which may be aggravated
by exposure to ultraviolet light. Additionally,
bleaching of hair has been reported occasionally with
chloroquine and occurs most frequently in light-haired
individuals. Hair bleaching may affect eye leases and
axillary, pubic, scalp, and body hair, and is usually
evident after 2 - 5 months post-therapy (AFHS, 1988).
9.4.9 Eye, ear, nose, throat: local effects
Chronic: 4-Aminoquinolines cause two typical effects
involving the eye, namely keratopathy and retinopathy.
Both are associated with the administration of the drug
over longer periods of time; the level of daily doses
and total doses is of importance.
Retinopathy, sometimes irreversible, was reported
following treatment with amodiaquine hydrochloride 200
mg daily (Grant, 1986).
Ototoxicity has been reported in association with the
use of the 4-aminoquinoline derivative chloroquine
(Tester-Dalderup, 1984).
9.4.10 Haematological
Chronic
Amodiaquine has reportedly caused blood dyscrasias at
therapeutic doses.
Sporadic cases of severe neutropenia were reported as
early as 1953, but occurred more commonly in patients
receiving amodiaquine in anti-inflammatory doses for
rheumatoid arthritis. However, in 1986, seven cases
were described in travellers returning to the UK who
were taking amodiaquine for malaria prophylaxis. The
frequency of neutropenia among these has been estimated
at about 1 in 2000. Similar findings were reported in
Switzerland. In all, 23 cases of agranulocytosis
associated with the use of amodiaquine were reported in
the 12-month period ending in March 1986, seven of
which were fatal. Most cases involved a dosage of 400
mg weekly over periods of three to 24 weeks (WHO,
1987).
9.4.11 Immunological
Chronic
The mechanism for amodiaquine hepatotoxicity is
unknown. It has been postulated that an immunoallergic
mechanism is consistent with some extra-hepatic
manifestations possibly due to hypersensitivity and
with the prompt increase in serum aminotransferase
levels after re-challenge (Larry et al., 1986).
However, other co-workers favour a toxic rather than an
immune mediated mechanism (Neftel et al., 1986) (see
section 9.4.5).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
Hypokalaemia has been reported.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Chronic
The pathogenesis of the itching (see section 9.4.8) may
be a hypersensitivity or genetic reaction, but is still
a matter of debate (Salako, 1984; Sowunmi et al.,
1989).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
Although no data are available for amodiaquine,
chloroquine is known to cross the placental barrier.
A 1985 report summarized the results of 169 infants
exposed in utero to 300 mg of chloroquine base once
weekly throughout pregnancy. The control group
consisted of 454 non-exposed infants. Two infants
(1.2%) in the study group had anomalies (tetralogy of
Fallot and congenital hypothyroidism) compared to four
control infants who had defects (0.9%). Based on these
data the authors concluded that chloroquine does not
have a strong teratogenic effect, but a small increase
in birth defects could not be excluded (Wolfe & Cordero,
1985).
It is generally believed that the benefits of
chloroquine therapy in pregnant women exposed to
malaria outweigh the potential risks of the drug to the
foetus.
Breast feeding
Chloroquine does not appear to be excreted in
appreciable amounts in the breast milk (Anderson,
1977).
Enzyme deficiencies
Since haemolysis and acute renal failure has been
reported to occur in a few patients with glucose-6-
phosphate dehydrogenase deficiency receiving
chloroquine, this should also be considered when using
amodiaquine (AHFS, 1988).
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Treatment of overdosage is supportive and must be prompt
since acute toxicity can progress rapidly, leading to
vascular collapse and respiratory and cardiac arrest.
Because of the importance of supporting ventilation, early
endotracheal intubation and mechanical ventilation may be
necessary. Early gastric lavage followed by administration
of activated charcoal may provide some benefit in reducing
absorption of the drug, but should be preceded by measures
to correct cardiac and severe cardiovascular disturbances,
if present, and by respiratory support. Diazepam iv may
control seizures and other manifestations of CNS
stimulation. Seizures caused by anoxia should be corrected
by oxygen and other respiratory support. Defibrillators and
cardiac pacemakers may be required.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood should be collected on EDTA and centrifuged at
2000 g for 15 minutes within two hours of collection
and the plasma should be frozen at -20 to -40°C.
The blood sample should be transported under
refrigerated and separated within two hours of
collection.
10.2.2 Biomedical analysis
Regular laboratory investigations should be performed
to assure that blood cell counts remain within normal
limits.
Perform liver function tests and monitor serum
electrolytes.
Arterial blood gases should be determined.
Electrocardiography is helpful assess cardiotoxicity.
10.2.3 Toxicological analysis
Measuring the blood levels of amodiaquine and its
major metabolite desethylamodiaquine is not
considered to be of practical assistance in the
clinical management of amodiaquine poisoning.
Both simple qualitative and quantitative tests may be
found in the USP (1974).
A sensitive and selective HPLC method for the
determination of amodiaquine in plasma has been
reported by Mihaly et al., 1985). This has been
modified to permit the determination of both
amodiaquine and the major active metabolite,
desethylamodiaquine, in plasma, urine, whole blood
and packed red blood cells (Winstanley et al., 1987).
10.2.4 Other investigations
No data available.
10.3 Life supportive procedures and symptomatic/specific
treatment
Treatment is largely supportive. Cardiac and respiratory
arrest may quickly supervene, therefore preparations should
be made for tracheal airway protection (endotracheal
intubation) and mechanical ventilation. Defibrillators and
cardiac pacemakers may be required. Check adequacy of tidal
volume (normal 10 to 15 ml/kg). Control seizures, if
present, before emptying stomach. The seizures may result
from the following:
- anoxia: administer 100% oxygen, begin assisted
ventilation;
- CNS stimulation: diazepam (up to 10 mg iv slowly in
adults; 0.1 to 0.2 mg/kg iv slowly in children). If
unresponsive: phenytoin (15 mg/kg iv slowly, at up to 0.5
mg/kg/minute, with ECG monitoring);
- hypotension: intravenous fluids. If unresponsive,
administer dopamine: 5 to 15 µg/kg/minute (after correction
of hypovolemia); watch for ventricular arrhythmias.
10.4 Decontamination
Emesis may be induced if there is evidence of overdose, if
the patient is not comatose, is not convulsing, and has not
lost the gag reflex. It is preferable that gastric emptying
be performed more rapidly by gastric lavage with prior
endotracheal intubation. The drug is rapidly absorbed, and
if symptoms are already present, gastric aspiration may not
be effective. It should be attempted in any case.
Activated charcoal (adults, 60 to 100 g; children, 30 to 60
g) may be placed as a slurry with a cathartic into the
gastric lavage tube.
10.5 Elimination
Forced diuresis and/or urinary acidification may increase
excretion of unchanged amodiaquine, but neither procedure
can be recommended at present on the basis of clinical
evidence.
Peritoneal dialysis and haemodialysis are not effective. In
the case of chloroquine as a comparison, dialysis and
haemoperfusion techniques are limited by the high apparent
volume of distribution of chloroquine in the tissue.
Charcoal haemoperfusion may be effective if begun very early
after ingestion in a severely toxic patient. Clinical
studies have not established its usefulness. The total body
clearance of chloroquine (a 4-aminoquinoline similar to
amodiaquine), is increased only slightly after haemodialysis
and haemoperfusion.
10.6 Antidote treatment
10.6.1 Adults
There are no antidotes. Although diazepam has been
shown to have a protective effect in diminishing
chloroquine (a related 4-aminoquinoline) toxicity in
animals this, however, has not been clearly
established for humans (Crouzette et al., 1983).
10.6.2 Children
There are no antidotes. Although diazepam has been
shown to have a protective effect in diminishing
chloroquine (a related 4-aminoquinoline) toxicity in
animals this, however, has not been clearly
established for humans (Crouzette et al., 1983).
10.7 Management discussion
Despite the widespread therapeutic use of amodiaquine for
the past 40 years, there remains a paucity of both clinical
and experimental data on this drug. In particular, there
appear to be no useful literature reports from acute
amodiaquine poisoning.
Further research into the possible role that diazepam may
play as an antagonist in acute amodiaquine poisoning is
indicated (see section 10.6).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Children, oral ingestion
A report (WHO 1979) cites a case in June 1965 from Pakistan.
Severe haemoglobinuria had occurred in seven children
following ingestion of an unknown amount of Camoprima
Infatabs (each tablet containing 75 mg amodiaquine + 15 mg
primaquine). No details could be obtained regarding the
approximate number of tablets ingested, the age of the
children and the circumstances in which the tablets had been
taken. However, certain indications strongly suggested that
the reported toxic reactions were not related to any regular,
supervised drug administration, but were accidents in that
the children had got hold of the drug and surreptitiously
swallowed a number of tablets.
11.2 Internally extracted data on cases
To be added by the Poison Control Centre.
11.3 Internal cases
To be added by the Poison Control Centre.
12. Additional information
12.1 Availability of antidotes
No specific antidotes are available.
12.2 Specific preventive measures
Store in an air-tight container, in child-resistant
packaging out of the reach of children.
The manufacturer of Camoquin (Parke-Davis) has advised in a
data sheet to health professionals that the prophylactic use
of amodiaquine as a first line agent has been restricted to
chloroquine-resistant areas. If the decision is made to so
prescribe the drug, concomitant use with other anti-
malarials should be avoided and regular laboratory
investigations should be performed to assure that blood
values and liver function tests remain within normal limits.
Because amodiaquine may concentrate in the liver, the drug
should be used with caution in patients with hepatic disease
or alcoholism, and in patients receiving hepatotoxic drugs.
Amodiaquine is contraindicated in patients who are
hypersensitive to other 4-aminoquinolines.
Since haemolysis and acute renal failure has been reported
to occur in a few patients with glucose-6-phosphate
dehydrogenase deficiency receiving chloroquine, this should
also be considered when using amodiaquine.
Children are especially sensitive to 4-aminoquinoline
derivatives. Because of the narrow margin between the
therapeutic and toxic concentrations in children,
amodiaquine should not be administered parenterally in this
age group.
It is generally believed that the benefits of chloroquine (a
4-aminoquinoline congener similar to amodiaquine in both its
structure and activity spectrum) therapy in pregnant women
exposed to malaria outweigh the potential risks of the drug
to the foetus. The risk to the foetus is greater if it is
glucose-6-phosphate dehydrogenase deficient. Chloroquine
does not appear to be excreted in appreciable amounts in the
breast milk.
12.3 Other
No data available.
13. REFERENCES
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information 88. McEvoy G K (ed). American Society of Hospital
Pharmacists. Bethesda, MD, 2222 pp.
Akinedale MO & Odejide AO (1976) Amodiaquine-induced involuntary
movements. Br Med J, 2: 214-215.
Anderson PO (1977) Drugs and breast feeding. Drug Intell Clin
Pharm, 11: 210-211.
CDC (1985) Health information for travel, Atlanta, Georgia; US
Public Health Service, Department of Health and Human Services,
CDC Publication Number 85-8280; 73-82.
Crouzette J, Vicaut E, Palombo S, Girre C & Fournier PE (1983)
Experimental assessment of the protective activity of diazepam on
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20(3): 271-279.
Ellenhorn MJ & Barceloux DG (1988) Medical toxicology. Diagnosis
and treatment of human poisoning. Elsevier Science Publishing
Company, Inc. New York, New York, 1512 pp.
Glickman FS, Shatin H & Canizares O (1959) Anti-malarial
preparations in treatment of cutaneous disorders. New York J Med,
59: 3946-3954.
Grant WM (1986) Toxicology of the eye. 3rd Edition, Springfield,
Ill: Charles C. Thomas.
Katzung BG (ed) (1987) Basic and clinical pharmacology.
Appleton & Lange, Norwalk, Connecticut, USA, 905 pp.
Larrey D, Castot A, Pessayre D, Merigot P, Machayekhy J-P,
Feldmann G, Lenoir A, Rueff B & Benhamou J-P. (1986)
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Reynolds JEF (1989) Martindale The extra pharmacopoeia. The
Pharmaceutical Press, London. 1896 pp
Mihaly G, Nicholl D, Edwards G, Ward S, Orme M, Warrell D &
Breckenridge A (1985). High performance liquid chromatographic
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171.
Neftel KA, Woodtly W, Schmid M, Frick PG & Fehr J (1986)
Amodiaquine induced agranulocytosis and liver disease. Br Med J.
292: 721-723.
Perry HO, Bartholomew LG & Hanlon DG (1962) Nearly fatal
reaction to amodiaquine. J A M A, 179(8): 598-601.
RTECS (1986-1986) Registry of toxic effects of chemical
substances.
Salako LA (1984) Toxicity and side effects of antimalarials in
Africa: a critical review. Bulletin of the WHO, 62 (Suppl.): 63-
68.
Shepard TH (1986)(ed) Catalogue of teratogenic agents. 5th
edition, The Johns Hopkins University Press, Baltimore MD, 710
pp.
Sowunmi A, Walker O & Salako LA (1989) Pruritus and
antimalarial drugs in Africans. The Lancet, p.213.
Tester-Dalderup, DBM (1984) Antiprotozoal drugs. In: Dukes MNG
(ed) Meyler's side effects of drugs. 10th edition. Elsevier
Science Publishers BV, Amsterdam, 966 pp.
The Merck Index (1983) An encyclopedia of chemicals, drugs and
biologicals. Windholz M, Budavari S, Blumetti RF & Otterbein ES
(eds). Merck & Co., Inc., Rahway, NJ, USA, 1463 pp. plus
Appendices.
USP (1974) United States Pharmacopoeia XIX. The United States
Pharmacopoeial Convention, Inc., Mack Publishing Company, Easton,
Pa.
White NJ, Looareesuwan S, Edwards G, Phillips RE, Karbwang J,
Nicholl DD, Bunch C & Warrell DA (1987) Pharmacokinetics of
intravenous amodiaquine. Br J. Clin. Pharmac. 23: 127-135.
WHO (1979) Toxicity and side effects of primaquine and other 8-
aminoquinolines. Weniger H. WHO/MAL/79.905, 33 pp.
Winstanley PA, Edwards G, Orme M & Breckinridge AM (1987) The
disposition of amodiaquine in man after oral administration. Br
J. Clin. Pharmacol., 23: 1-7
Wolfe MS & Cordero JF (1985) Safety of chloroquine in
chemosuppression of malaria during pregnancy. Br Med. J. 290:
1466-1467.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Authors: Dr Wayne A. Temple
National Poisons and Hazardous Chemicals Information
Centre
University of Otago Medical School
P.O. Box 913
Dunedin
New Zealand
Tel: 64-3-4797248
Fax: 64-3-4770509
Dr Nerida A. Smith
Department of Pharmacy
University of Otago Medical School
P.O. Box 913
Dunedin
New Zealand
Date: 31 January 1990
Update: Dr R. Fernando
National Poisons Information Centre
Faculty of Medicine
Kynsey Road
Colombo 8
Sri Lanka
Tel: 94-1-686143
Fax: 94-1-691581
Date: July 1993