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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 200C (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 
    Lactation, Second Edition, Williams & Wilkins, Baltimore, p. 368.
    
    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 
    Pharmaceutical Sciences, 2: 1163-1164.
    
    Jaeger A, Saunders P, Kopferschmitt J & Flesch F (1987).  
    Clinical features and management of poisoning due to antimalarial 
    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. 
    Geneva, 2(2): 89-90.
    
    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



    See Also:
       Toxicological Abbreviations