Primaquine phosphate
| 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
Primaquine phosphate
1.2 Group
Antimalarial agent
8 aminoquinoline
1.3 Synonyms
primaquine diphosphate
primaquinium phosphate
1.4 Identification numbers
1.4.1 CAS number
90-346
1.4.2 Other numbers
1.5 Brand names, Trade names
Aralen with primaquine (Winthrop-Breon, USA)
To be completed by the centre.
1.6 Manufacturers, Importers
Imperial Chemical Industries PLC, Cheshire UK; Winthrop,
Canada.
To be completed by the centre.
2. SUMMARY
2.1 Main risks and target organs
Target organs are: cardiovascular, haematological system, and
gastrointestinal.
Acute, dose-dependent methaemoglobinaemia and haemolytic
anaemia occurs in persons with a deficiency of glucose-6-
phosphate dehydrogenase (G6PD); leucopenia or agranulocytosis
may also occur. Adverse effects with therapeutic doses are
usually mild.
2.2 Summary of clinical effects
Toxic manifestations include cardiovascular disturbances,
especially ventricular dysrhythmias, abdominal cramps,
vomiting, burning epigastric distress, headache, confusion,
cyanosis, methaemoglobinaemia, leucocytosis or leucopenia, and
anaemia. Granulocytopenia, acute haemolytic anaemia and acute
haemolysis may occur in individuals who are hypersensitive to
primaquine.
2.3 Diagnosis
Abdominal cramps, vomiting, burning gastric distress, cardiac
dysrhythmias, headache, confusion, impaired respiration, shock,
effects of methaemoglobinaemia such as cyanosis are the
features of acute primaquine poisoning.
There may be a moderate leucopenia or leucocytosis.
Granulocytopenia and acute haemolytic anaemia are common in
persons who are hypersensitive to primaquine.
A complete blood count may reveal haematological
abnormalities. Indicators of haemolysis may be present (for
example, a sudden darkening of the urine, sudden decrease of
haemoglobin level or leucocyte count or a severe skin
reaction).
2.4 First aid measures and management principles
Patients with primaquine overdose should be admitted as soon
as possible to an intensive care unit. Treatment is
symptomatic and must be prompt. There is no specific antidote.
Acute poisoning:
Remove swallowed drug from gastrointestinal tract by induction
of emesis with syrup of ipecacuanha and/or gastric lavage.
Convulsions should be controlled with diazepam before
attempting gastric lavage.
If methaemoglobinaemia and cyanosis occur, oxygen may be
administered and administration of methylene blue may be
considered. If collapse and hypotension or shock occur,
vasopressors may be used.
If convulsions are due to cerebral stimulation, cautious
administration of an ultrashort-acting barbiturate may be
tried, but if due to anoxia, it should be corrected by oxygen
administration, artificial respiration or, in shock with
hypotension, by vasopressor therapy. Because of the
importance of supporting respiration, tracheal intubation or
tracheotomy may also be necessary. The patient should be
observed for the possible development of leucopenia or
haemolytic anaemia.
Acidification of the urine has been proposed.
Cardiac arrhythmias, in the presence of hypokalaemia and
normal renal function, should be treated with potassium
chloride. Administer 5 g dissolved in fruit juice every hour
orally, or 20 mg in 500 ml of 5% dextrose intravenously, until
the ECG shows improvement or reveals a potassium effect as
indicated by peaking of the T wave.
Vital signs (ECG, blood pressure), fluid and electrolyte
balance, and full blood count should be monitored.
The patient should be kept in bed and warm. A patient who
survives the acute stage and is asymptomatic should be closely
observed for at least six hours.
Chronic poisoning:
Suspend the medication and apply symptomatic treatment as for
acute poisoning.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Primaquine is a synthetic antimalarial agent, an 8-
aminoquinoline derivative, introduced in 1926.
3.2 Chemical structure
Chemical name: 1,4 Pentanediamine, N4-(6-methoxy-8-
quinolinylquinyl)-, phosphate (1:2); or 8-(4-amino-1-
methylbutylamino)-6 methoxyquinoline diphosphate (1:2).
Molecular Formula: C15H21N3O.2H3PO4
Molecular Weight: 455.34
3.3 Physical properties
3.3.1 Properties of the substance
Characteristics: Primaquine is an orange-red,
odourless crystalline powder and has a bitter
taste (Reynolds, 1987).
Solubility: One part of primaquine is soluble
in 6 parts of water; it is practically
insoluble in alcohol,chloroform and ether. A 1%
w/v solution has a pH of 2.5 to 3.5. Solutions
are acid to litmus.
Primaquine melts at about 200°C (Reynolds,
1989).
3.3.2 Properties of the locally available formulation
Primaquine is formulated in a brown, odourless, sugar-
coated tablet with a bitter taste.
To be completed by the centre.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
The shelf-life depends on local conditions of
temperature and humidity, and exposure to sunlight.
3.4.2 Shelf-life of the locally available formulation
To be completed by the centre.
3.4.3 Storage conditions
Primaquine should be stored in airtight containers and
protected from light and moisture.
3.4.4 Bioavailability
Local data to be added.
3.4.5 Specific properties and composition
Local data to be added.
4. USES
4.1 Indications
Mainly for medical cure of Plasmodium vivax infections.
For elimination of primary and secondary exoerythrocytic
stages of P. vivax, P. malariae and P. ovale and the
primary exoerythrocytic forms only of P. falciparum.
Primaquine must always be given in conjunction with full
doses of a 4-aminoquinoline.
For elimination of gametocytes of all species.
(WHO, 1988, Goodman & Gilman, 1985, McEvoy, 1988, PDR,
1988, Reynolds, 1989, Harvey, 1980, USP DI, 1990).
4.2 Therapeutic dosage
4.2.1 Adults
Radical treatment of P. vivax and P. ovale malaria 0.25
mg/kg or 15 mg daily (calculated as the base) for 14
days following standard therapy with a 4-aminoquinoline.
If G6PD deficiency is known or suspected: 0.75 mg/kg
weekly (base) for 8 weeks.
Gametocyticidal therapy: 0.5 mg/kg (base) in a single
dose. N.B. For some strains of P. vivax (particularly
those from South East Asia), a dose of 22.5 mg (base)
daily for fourteen days may be required for radical cure
of malaria. To eliminate gametocytes of P. Falciparum,
a single dose of 45 mg (base) may be administered (USP
DI 1990).
[Note: 7.5 mg of primaquine base is equivalent to 13.2
mg of primaquine phosphate]
4.2.2 Children
0.25 mg/kg (base) daily for 14 days.
Gametocyticidal therapy: 0.5 mg/kg in a single dose.
[Note: 7.5 mg of primaquine base is equivalent to 13.2
mg of primaquine phosphate]
4.3 Contraindications
The balance of risk and benefit should be considered when
primaquine is administered under the following conditions:
- in acutely ill patients suffering from systemic disease
characterized by a tendency to granulocytopenia (for example,
patients with arthritis or lupus erythematosus).
- agents capable of depressing the myeloid elements of the
bone marrow (e.g., antineoplastic agents, colchicine, gold
salts, penicillamine, phenylbutazone, quinacrine).
- individuals who have shown previous idiosyncratic
reaction to primaquine, individuals with a history of favism
or acute haemolytic anaemia.
- individuals with G6PD deficiency or NADH methaemoglobin
reductase deficiency; primaquine should be discontinued
immediately if haemolysis occurs (see 2.3) (Goodman & Gilman,
1988, Reynolds, 1989).
5. ROUTES OF ENTRY
5.1 Oral
Oral absorption is the only common cause of intoxication.
5.2 Inhalation
No data available
5.3 Dermal
No data available
5.4 Eye
No data available
5.5 Parenteral
No data available
5.6 Other
No data available
6. KINETICS
6.1 Absorption by route of exposure
Primaquine is readily absorbed from the gastrointestinal
tract. The plasma concentration peaks within 1 to 3 h after
ingestion but is negligibly low after 24 h. Considerable
interindividual variation in peak plasma concentrations of
primaquine has been reported with the same dose of the drug
(Reynolds, 1989).
6.2 Distribution by route of exposure
Primaquine is extensively distributed into body tissues with
an apparent volume of distribution of about 150 to 250 litres
or 2.9 litre/kg or 242.9 +/- 69.5 (mean +/- standard
deviation) litre in healthy adults and the total clearance of
24.2 +/- 7.4 litre/h. About 75% of primaquine in plasma is
bound to proteins and high concentrations occur in
erythrocytes. Primaquine crosses the placenta but it is
uncertain whether significant amounts occur in breast milk
(Mihaly et al., 1985, White, 1985, Briggs et al., 1986).
6.3 Biological half-life by route of exposure
After acute and chronic oral administration to healthy
volunteers, a mean peak plasma concentration of 65.0 +/- 34.7
mg/ml is achieved within approximately 2 +/- 1 h. Primaquine
has a plasma elimination half-life of 3.7 to 9.6 h in healthy
adults (Ward et al., 1985, Bhatia et al., 1986).
6.4 Metabolism
Primaquine is not subject to extensive first pass metabolism.
However, it is readily metabolized in the liver to three
metabolites: 8-(3-carboxyl-1-methyl-propylamino)-6-methoxy-
quinoline, 5-hydroxy primaquine and 5-hydroxy-6-desmethyl-
primaquine. The carboxyl derivative is the major metabolite
found in plasma; it accumulates during repeated administration,
when the plasma concentration greatly exceeds that of
unchanged primaquine. These metabolites have appreciably less
antimalarial activity than primaquine but their haemolytic
activity, as assessed by formation of methaemoglobin in vitro,
is greater than that of the parent compound (Mihaly, 1985;
Ward, 1985; Price & Fletcher, 1986).
6.5 Elimination by route of exposure
Only 3.6% of the dose of primaquine is excreted as unchanged
drug. The principal metabolite is carboxyprimaquine.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Primaquine may cause haemolysis and methaemoglobinaemia.
Certain ethnic groups, especially those arising in the
Mediterranean basin, are more susceptible to these
effects and "primaquine sensitivity" occurs in persons
with G6PD deficiency (Alving, 1950). G6PD deficiency is
genetically acquired; there are a large number of
variants in which the extent of the deficiency differs.
The sensitivity of individuals to primaquine therefore
varies.
G6PD is an enzyme which protects the erythrocyte from
the direct oxidative effects of some drugs and chemicals
by maintaining intracellular stores of reduced
glutathione. In people who are G6PD deficient, oxidation
of haemoglobin leads to precipitation within the cell,
producing characteristic inclusions called Heinz bodies;
increased oxidation of haemoglobin also produces
methaemoglobinaemia. There is an increase in the
generation of free radicals which also contribute to
cellular damage. These effects ultimately cause
haemolysis.
7.1.2 Pharmacodynamics
The exact mechanism of antimalarial activity of
primaquine has not been determined, but the drug appears
to bind to plasmodial DNA and interfere with its
function.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
The toxicity of primaquine phosphate is dose-
dependent; weekly administration (in combination
with chloroquine) is less toxic than daily
administration. For example, in Black American
adult volunteers, a weekly dose of 45 to 60 mg
(base) is less toxic than 15 mg (base)
administered daily.
Serious haematologic reactions may occur in some
people with a G6PD deficiency even at the low
weekly doses of primaquine used in combination
with chloroquine for the prophylaxis of malaria.
This occurs primarily in patients with a family
or personal history of favism.
Methaemoglobinaemia is more common in
individuals with nicotinamide adenine
dinucleotide methaemoglobin reductase deficiency
(PDR, 1988).
About 10% of the black population with G6PD
deficiency develop anaemia due to intravascular
haemolysis at daily dose levels of 15 mg (base)
and higher. Some darker-skinned Mediterranean
populations (for example, Sephardi Jews, Greeks,
and Iranians), are more sensitive than blacks
(Goodman & Gilman, 1985).
7.2.1.2 Children
No data available
7.2.2 Relevant animal data
No data available
7.2.3 Relevant in vitro data
No data available
7.3 Carcinogenicity
No data available
7.4 Teratogenicity
No reports are available to associate primaquine with
congenital defects.
7.5 Mutagenicity
No data available
7.6 Interactions
Primaquine should not be administered concurrently with any
other drug that is likely to induce haemolysis or bone marrow
depression (see section 4.3) as this may increase the risk of
toxicity.
Concurrent use of primaquine with bone marrow depressants may
increase the risk of leucopenia. If concurrent use is
essential, close observation for myelotoxicity should be
considered. The toxicity of primaquine appears to be
potentiated by antimalarial agents that are structurally
similar (for example, quinacrine). Primaquine should not be
administered to patients who have received quinacrine within
the previous 3 months (Goodman & Gilman, 198?; Kasilo, 1988).
Although primaquine inhibits the elimination of drugs which
undergo oxidative metabolism (for example, antipyrine),
therapeutic doses have no effect on paracetamol metabolism
(Back & Tjia, 1987).
The combination of chloroquine and primaquine with dapsone may
prevent haemolysis in G6PD deficient subjects (Tester-Dalderup,
1988). The antimalarial effects of quinacrine and primaquine
in various test organisms are synergistic with many
antibiotics (Tester-Delderup, 1988).
The effects of primaquine on the pharmacokinetics of
antipyrine have been studied in volunteers. Primaquine 45 mg
(base) given 2 h before antipyrine, 300 mg orally, increases
the half-life of antipyrine (calculated over 24 h) from 12.7
+/- 3.2 (mean +/- SD) to 25.3 +/- 3.9 h and decreases the
clearance from 3.01 +/- 0.67 to 1.32 +/- 0.32 litres/h. There
is no change in apparent volume of distribution. The half-
life of antipyrine changes with time in the presence of
primaquine and, when calculated between 24 to 48 h, returns to
baseline values. After administration of primaquine, the
metabolism of antipyrine (calculated from 0 to 24 h) to its 3
main metabolites, 3 hydroxymethyl-antipyrine, 4 hydroxy-
antipyrine and norantipyrine, is significantly reduced. There
is no selective effect on a particular metabolic pathway.
7.7 Main adverse effects
Gastrointestinal tract
Dose-related gastrointestinal symptoms include anorexia,
nausea, vomiting, epigastric distress, and abdominal cramps
(Reynolds, 1989).
Haematological system
Acute haemolytic anaemia occurs most frequently in G6P
Ddeficient individuals. It is usually self-limiting but in
severe cases blood transfusion may be necessary.
Methaemoglobinaemia, agranulocytosis, granulocytopenia and
leucopenia are also reported. Methaemoglobinaemia can be
severe in people who are nicotinamide dinucleotide (NADH)
methaemoglobin reductase deficient.
Cardiovascular system
Hypertension and arrhythmias have been reported.
Other
Headache, interference with visual accommodation and pruritus
have been reported with primaquine. Adverse CNS effects,
including depression and confusion, can also occur.
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
Toxic manifestations such as methaemoglobinaemia and
cyanosis occur in most subjects; adverse
gastrointestinal effects occur at higher doses (60 to
240 mg/day). These doses also cause severe haematologic
reactions such as leucopenia, anaemia and intravascular
haemolysis.
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
No data available.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
The adverse effects associated with chronic
administration are similar to those which occur in acute
poisoning.
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
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Course
Commonly, symptoms of overdoses are nausea, abdominal pain,
sometimes vomiting and jaundice. Haemolytic anaemia may occur
in G6PD deficiency but is usually self-limiting.
Prognosis
If patient survives for 48 h recovery is likely.
Death
Cardiocirculatory arrest may occur within 1 to 2 h of
ingestion due to ventricular dysrhythmia or asystole.
Hypotension is common and may progress rapidly to cardiogenic
shock with increased central venous pressure (Poisindex,
1990). Hypertension and cardiac arrhythmias have been reported
on rareoccasions (Reynolds, 1993).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Based on its anti-arrhythmic activity in mice,
primaquine is predicted to have quinidine-like
cardiotoxicity (Gosselin et al., 1984). Hypertension
and cardiac arrhythmias have been reported on rare
occasions (Reynolds, 1993).
9.4.2 Respiratory
Respiratory arrest secondary to circulatory arrest or
severe shock may occur within 1 to 2 h following
overdose.
9.4.3 Neurological
9.4.3.1 CNS
In severe cases, headache, mental depression and
confusion occur, especially in persons with
prior exposure to chloroquine.
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Abdominal cramps and epigastric distress have been
reported (Tester-Dalderup, 1988).
9.4.5 Hepatic
Hepatic function is unaffected.
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Pruritus and urticaria.
9.4.9 Eye, ear, nose, throat: local effects
Diplopia; visual disturbances; blurred vision;
irreversible changes to the cornea and retina; optic
neuritis.
9.4.10 Haematological
Toxic doses of primaquine induce marked bone marrow
depression, methaemoglobinaemia, agranulocytosis and
haemolytic anaemia. Haemolytic anaemia is commonest in
persons with G6PD deficiency. The effects are more
pronounced in the B-type G6PD deficiency (the
Mediterranean type) than in the A-type (the type mainly
present among black American and African populations)
(Tester-Dalderup, 1988).
9.4.11 Immunological
Primaquine may also cause immunosuppression (Reynolds,
1989).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
Hypokalaemia is common in severe intoxication.
9.4.12.3 Others
Hypo- or hyperthermia and hypo- or
hyperglycaemia have been reported.
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
Primaquine should be withheld from women with G6PD
deficiency who are pregnant. If prophylaxis or
treatment is essential, the possible benefits should
outweigh the potential risks (Briggs et al., 1986,
Kasilo, 1988).
Transplacental transfer of primaquine to a foetus with
G6PD deficiency may result in life-threatening anaemia
and methaemoglobinaemia in utero.
Breast-feeding
It is not known whether primaquine is excreted in
breast milk. However, problems in man have not been
documented.
Enzyme deficiency
Primaquine should be used with caution in patients with
G6PD deficiency who are receiving other drugs likely to
induce haemolysis, (for example, nitrites,
sulphonamides).
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Patients with suspected primaquine overdose should always be
admitted to an intensive care unit. Treatment depends on
the dose ingested, the symptomatology and the delay
following ingestion. It includes gastric lavage,
administration of activated charcoal, supportive treatment,
treatment of methaemoglobinemia and cardiac effects.
Cardiac monitoring is essential.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood samples for primaquine should be drawn in
plastic tubes with heparin. Primaquine may be
analyzed in whole blood or plasma. Biological
samples (blood, plasma, urine) should be stored in
airtight conditions and protected from light.
10.2.2 Biomedical analysis
Treatment with primaquine:
Obtain full blood count and measure haemoglobin at
weekly intervals during treatment with primaquine
(anaemia and leucopenia have been reported following
administration of large doses). Primaquine should be
discontinued immediately if a sudden decrease in
haemoglobin concentration, erythrocyte count, or
leucocyte count occurs.
Acute poisoning with primaquine:
Biomedical analysis with glucose should include
haematological and coagulation studies. Glucose, BUN,
electrolytes, creatinine, a full blood count and
blood enzymes should be obtained on admission and
repeated every 12 h.
10.2.3 Toxicological analysis
To be completed.
10.2.4 Other investigations
G6PD determination is recommended prior to therapy in
all non-caucasians and caucasians of Mediterranean
origin (USP DI, 1990).
10.3 Life supportive procedures and symptomatic/specific
treatment
Systematically monitor vital signs and blood pressure.
Isolate the patient if there is evidence of bone marrow
depression; infusion of white blood cells may be necessary.
If cardiac arrhythmias are present, correct any significant
degree of hypokalaemia; the use of anti-arrhythmic agents,
for example phenytoin, may be indicated.
Acute haemolytic anaemia is usually self-limiting but in
severe cases blood transfusion may be necessary.
10.4 Decontamination
Gastric lavage: early gastric lavage is indicated because it
may remove 7 to 25% of the dose ingested if performed within
6 hours.
Emesis: emesis may be useful only in cases of recent
ingestion but may be contraindicated because of cardiac
complications.
10.5 Elimination
Little unchanged drug is excreted in urine, especially
during the 24 h following ingestion. Early forced diuresis
should not be instituted. Sufficient ammonium chloride (8 g
daily in divided doses in adults) may be administered for a
few days to acidify the urine to help promote urinary
excretion in cases of both overdosage or hypersensitivity
reactions. (Gosselin et al., 1984; McEvoy, 1988; Barnhart,
1987).
No data on the value of haemoperfusion or haemodialysis have
been reported. However, the low primaquine plasma
concentrations reported in acute poisoning indicate that
haemoperfusion or haemodialysis are unlikely to be useful.
10.6 Antidote treatment
10.6.1 Adults
No antidote is available.
10.6.2 Children
No antidote is available.
10.7 Management discussion
Any patient with suspected primaquine overdose should be
observed in an intensive care unit. The patient is at risk
for up to 24 hours following ingestion.
The value of attempting to prevent further absorption of
primaquine by emesis is uncertain because of the risk of
secondary cardiac effects.
In cases of methaemoglobinaemia with haemoglobinuria,
intravenous infusion of sodium bicarbonate prevents blockage
of renal tubules (Gosselin, 1976).
The value of diazepam in the treatment of primaquine
overdose is unproven.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
No information available.
11.2 Internally extracted data on cases
To be added by the Centre.
11.3 Internal cases
To be added by the Centre.
12. Additional information
12.1 Availability of antidotes
No antidote available.
12.2 Specific preventive measures
Primaquinine should be administered cautiously to: acutely
ill patients with a tendency to granulocytopenia (e.g.
rheumatoid arthritis, lopus erythematosus), patients with
G6PD deficiency (Reynolds, 1993).
12.3 Other
No data available.
13. REFERENCES
[Alving references required]
Back DJ & Tjia JF (1987). Single dose primaquine has no effect
on paracetamol clearance. Eur J Clin Pharmacol, 32(2) 203-205.
Barnhart ER (1987). Primaquine Phosphate. Physician's Desk
Reference, 2112-2113.
Bhatia SC, Saraph YS, Revanker SN, Doshi KJ, Bharucha ED, Desai
NK, Vaidya AB, Subrahmanyam D, Gupta KC, Satoskar RS (1986).
Pharmacokinetics of Primaquine in patients with P. vivax malaria -
Eur J Clin Pharmacol, 31(2): 205-210.
British Medical Association and the Pharmaceutical Society of
Great Britain (1988). British National Formulary, No 15.
Briggs GG, Freeman RK, Yaffe SJ (1986). Primaquine. Drugs in
pregnancy and lactation. Reference Guide in Pregnancy and
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Dreisbach RH & Robertson WO (1987). Anti-infective drugs. In:
Handbook of Poisoning. Prevention, diagnosis and treatment. 12th
edition, Appleton & Lange, p 408.
Goodman & Gilman (1985). Drugs used in the chemotherapy of
malaria - The Pharmacological Basis of Therapeutics, 7th edition,
pp 1038-1041.
Gosselin RE, Smith RP, Hodge HC (1984). Clinical Toxicology of
Commercial Products, Williams & Wilkins, (eds) Baltimore II, p
1516.
Harvey SC (1980). Antimicrobial drugs. Remington's
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Jaeger A, Saunders P, Kopferschmitt J & Flesch F (1987).
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drugs. Med Toxicol, 2: 242-273.
Kasilo OJ (1988). Current information on Malaysia, Part II
Issue No... Drug and Toxicology Information Service (DATIS).
Department of Pharmacy, University of Zimbabwe.
McEvoy GK (1988). Primaquine phosphate. American Hospital
Formulary Service Drug Information 88. American Society of
Hospital Pharmacists, pp 404-405.
Mihaly GW, Ward SA, Edwards G, Nicholl DD, Orme ML, Breckenridge
AM (1985). Pharmacokinetics of primaquine in man. I. Studies
of the absolute bioavailability and effects of dose size. Br J
Clin Pharmacol 19(6): 745-750.
Poisindex (1990) Micromedex, Denver, Colo. USA. B. Rumack (ed).
Price AH & Fletcher KA (1986). The metabolism and toxicity of
primaquine. Prog Clin Biol Research 214: 261-278.
Reynolds JEF (1989). The Extra Pharmacopoeia. London, The
Pharmaceutical Press.
Reynolds JEF (1993) 30th ed. Martindale, the Extra
Pharmacopoeia. London, The Pharmaceutical Press.
Tester-Dalderup CBM (1988). Antimalarial drugs. In: Dukes MNG,
Meyler's side effects of drugs. 11th edition, Elsevier,
Amsterdam, pp 581-602.
United States Pharmacopoeial Convention, Inc. (1990).
Primaquine. Drug Information for the Health Care Professional USP
DI vol 1B, pp 2301-2302.
Ward SA, Mihaly GW, Edwards G, Looareensuwan S, Phillips RE,
Chanthavanich P, Warrell DA, Orme ML, Breckenridge AM (1985).
Pharmacokinetics of primaquine in man. II. Comparison of acute
vs chronic dosage in Thai subjects. Br J Clin Pharmacol, 19(6):
751-755.
WHO (1988). Essential drugs: Malaria. Who Drug Information.
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White NJ (1985). Clinical pharmacokinetics of antimalarial
drugs. Clinical Pharmacokinetics, 10(3):187-215.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Authors: Dr O.J. Kasilo
Drug and Toxicology Information Service (DATIS)
Department of Pharmacy
University of Zimbabwe Medical School
Harare
Zimbabwe
Dr C.F.B. Nhachi
Department of Clinical Pharmacology
University of Zimbabwe Medical School
Harare
Zimbabwe
Telephone: 263-4-790233 or 791631 ext. 117/172
Telefax: 263-4-303 292
Telex: 265801 UNIVZ ZW
Date: March 1990
Peer Review: Strasbourg, France, April 1990
Finalized IPCS: May 1994