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Azathioprine

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 Main brand names/main trade names
   1.6 Main manufacturers/main importers
   1.7 Presentation/formulation
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
         3.3.1.1 Colour
         3.3.1.2 State/form
         3.3.1.3 Description
      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
4. USES
   4.1 Indications
      4.1.1 Uses
      4.1.2 Description
   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 Others
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
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
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):
    1.  NAME
 
        1.1  Substance
 
             Azathioprine
 
        1.2  Group
 
             ATC Code: L04AX Other Immunosuppressive agents
 
        1.3  Synonyms
 
             BW 57322
             azothioprine
             NCI-C03474
             NSC-39084
             methylnitroimidazolylmercaptopurine
 
        1.4  Identification numbers
 
             1.4.1  CAS number
 
             Azathioprine 446-86-6
 
             1.4.2  Other numbers
 
             RTECS:     UO8925000
 
        1.5  Main brand names/main trade names
 
             Azamune, Azanin, Azapress, Berkaprine, Immunoprin, 
             Imuran, Imurek, Imurel, Rorasul, Thioprine.
 
        1.6  Main manufacturers/main importers
 
             To be added by the centre using the monograph.
 
        1.7  Presentation/formulation
 
             To be added by the centre using the monograph.
 
    2.  SUMMARY
 
        2.1  Main risks and target organs
 
             Azathioprine is a myelotoxic and hepatotoxic 
             immunosuppressive agent. Bone marrow and liver are the main 
             targets but gastrointestinal tract, kidney, lungs, CNS and 
             skin may also be affected. Transient gastroenteritis may be 
             observed with massive overdose. Leukopenia is the main toxic 
             effect which may occur during azathioprine therapy and in the 
             overdose patients. Liver and kidney function tests may be 
             altered but usually returned to normal after discontinuation 
             of the drug.
 
 
 
        2.2  Summary of clinical effects
 
             Oral ulceration occurs rarely with therapeutic doses but 
             may be seen with large doses. Gastrointestinal disturbances 
             such as nausea, vomiting, abdominal pain and diarrhoea can 
             appear mainly at higher doses. Acute pancreatitis was also 
             reported following long term azathioprine treatment. 
             Suppression of the bone marrow mainly leukopenia and 
             occasionally pancytopenia may be seen after therapeutic doses 
             and overdoses of azathioprine. Septic shock due to this 
             immunosuppression may occur. Hepatic dysfunction 
             (hepatocellular and cholestatic), venocclusive disease and 
             haemangioma of the liver following azathioprine therapy were 
             documented. Acute restrictive lung disease, interstitial 
             nephritis and a case of progressive leukoencephalopathy after 
             4 years azathioprine therapy were reported. Skin rash, 
             alopecia and urticaria and a case of palmar-plantar erythema 
             with desquamation and pain were also documented.
 
        2.3  Diagnosis
 
             Diagnosis of azathioprine overdose is based on history 
             of the drug taken and clinical findings mainly 
             gastrointestinal dysfunction, leukopenia and liver 
             dysfunction. Peripheral cell blood counts and liver function 
             tests are required. Estimation of 6-thioguanine nucleotide, a 
             cytotoxic metabolite of azathioprine in red blood cell may 
             confirm the diagnosis and could also be used to predict bone 
             marrow toxicity of azathioprine.
 
        2.4  First-aid measures and management principles
 
             Emesis may be indicated in substantial recent ingestion 
             of azathioprine. It is most effective if initiated within 30 
             minutes of ingestion. In massive overdose patients, gastric 
             aspiration and lavage should be performed as soon as possible 
             and within 3 to 4 hours of ingestion. Activated charcoal (1 
             to 2 g/kg every 3 to 4 hours) as slurry in water or mixture 
             with sorbitol should be given orally or through the gastric 
             tube. Haemodialysis should be used in severe azathioprine 
             overdose patients.
 
    3.  PHYSICO-CHEMICAL PROPERTIES
 
        3.1  Origin of the substance
 
             Azathioprine is a chemical analogue of the physiologic 
             purines and is of synthetic origin.
 
 
 
 
        3.2  Chemical structure
 
             6-(1-Methyl-4-nitroimidazol-5-ylthio)purine
             
             Relative molecular mass: 277.3
             
             Molecular formula: C9H7N7O2S
 
        3.3  Physical properties
 
             3.3.1  Properties of the substance
 
                    3.3.1.1  Colour
 
                             Pale yellow. 
 
                    3.3.1.2  State/form
 
                             Powder. 
 
                    3.3.1.3  Description
 
                             Odourless.
                             
                             Insoluble in water and very slightly soluble 
                             in ethanol.
                             
                             Solutions of azathioprine sodium for 
                             injection have a pH of 9.8 to 11.0.
 
             3.3.2  Properties of the locally available formulation
 
                    To be filled in by centre using the 
                    monograph.
 
        3.4  Other characteristics
 
             3.4.1  Shelf-life of the substance
 
                    Azathioprine tablets have a shelf-life of five 
                    years and the azathioprine injection has a shelf-life 
                    of three years (Dollery, 1991).
 
             3.4.2  Shelf-life of the locally available formulation
 
                    To be added by the centre using the 
                    monograph.
 
 
 
 
             3.4.3  Storage conditions
 
                    Azathioprine tablets should be protected from 
                    light and stored at a temperature that does not exceed 
                    35 C. The azathioprine injection should be stored in 
                    a dry place at a temperature that does not exceed 25 
                    C(Dollery, 1991).
 
             3.4.4  Bioavailability
 
                    To be added by the Center using the 
                    monograph.
 
    4.  USES
 
        4.1  Indications
 
             4.1.1  Uses
 
             4.1.2  Description
 
                    Azathioprine is used as an adjunct for the 
                    prevention of the rejection of kidney allografts. The 
                    drug is used in conjunction with other 
                    immunosuppressive therapy including local radiation 
                    therapy, corticosteroids, and other cytotoxic 
                    agents.
                    
                    Azathioprine may be used for the treatment of 
                    conditions which involve derangement of the immune 
                    system including chronic active hepatitis, severe 
                    rheumatoid arthritis, systemic lupus erythematosus, 
                    dermatomyositis, pemphigus vulgaris, polyarteritis 
                    nodosa, acquired haemolytic anaemia, Crohn's disease 
                    and idiopathic thrombocytopenia. (Dollery, 1991; 
                    McEvoy, 1993).
 
        4.2  Therapeutic dosage
 
 
             4.2.1  Adults
 
                    Prophylatic therapy is usually initiated in a 
                    dose of 3 to 10 mg/kg one or two days prior to renal 
                    transplantation, or on the day of the operation 
                    (Calabresi and Chabner, 1990). Maintenance doses are 
                    lower.
                    
                    For the treatment of conditions which involve 
                    derangement of the immune system the dose of the drug 
                    is usually decided by titration against the clinical 
                    activity of the disease, in the range of 1 to 3 mg/kg 
                    daily (Dollery, 1991).
 
 
 
             4.2.2  Children
 
                    The dose in children is the same (per kilogram 
                    body weight) as in adults.
 
        4.3  Contraindications
 
             Azathioprine is contraindicated in patients who are 
             hypersensitive to the drug. If severe, continuous rejection 
             occurs, it is probably preferable to use another agent, 
             rather than to increase the dosage of azathioprine to very 
             toxic levels (McEvoy, 1993).
             
             Azathioprine is also contraindicated in those patients with 
             renal failure, impaired hepatic function and in pregnant 
             women (Dollery, 1991).
 
    5.  ROUTES OF ENTRY
 
        5.1  Oral
 
             Azathioprine is usually administered orally.
 
        5.2  Inhalation
 
             Not known
 
        5.3  Dermal
 
             Not known
 
        5.4  Eye
 
             Not known
 
        5.5  Parenteral
 
             Following renal transplantation, azathioprine may 
             initially be given intravenously to patients unable to 
             tolerate oral medication. Oral therapy should replace 
             parenteral therapy as soon as possible.
 
        5.6  Others
 
             Not known
 
 
 
 
    6.  KINETICS
 
        6.1  Absorption by route of exposure
 
             Azathioprine is readily absorbed from the 
             gastrointestinal tract with only 12.6% of the dose being 
             detected in the stool over a 48 hour period. After oral 
             administration of 100 mg of azathioprine the peak levels of 
             azathioprine and its metabolites are equivalent to 2 mg.L-1 
             (Dollery, 1991)
 
        6.2  Distribution by route of exposure
 
             Azathioprine is rapidly distributed throughout the body 
             with peak plasma concentrations being reached at 1 to 2 hours 
             after dosing. Small amounts of azathioprine bind to plasma 
             proteins (to a maximum of 30%) and only very small amounts 
             enter the brain(Dollery, 1991).
             
             Azathioprine crosses the placenta and trace amounts of the 6- 
             mercaptopurine metabolite have been detected in foetal blood 
             (Briggs et al., 1990).
 
        6.3  Biological half-life by route of exposure
 
             The plasma half-life of azathioprine is 3 to 5 hours 
             (Dollery, 1991).
 
        6.4  Metabolism
 
             Azathioprine is metabolized  in vivo to mercaptopurine, 
             apparently by sulphydryl compounds such as glutathione. 
             Mercaptopurine is oxidised and methylated to several 
             derivatives among which 6-thiouric acid predominates; the 
             proportion of metabolites varies amongst individuals. The 
             fate of the nitromethylimidazole portion of azathioprine has 
             not been completely elucidated. Small amounts of azathioprine 
             are also split to give 1-methyl-4-nitro-5-thioimidazole 
             (McEvoy, 1993). The active metabolites, 6-thioguanine 
             nucleotides, responsible for the therapeutic action, are 
             formed intracellularly and appear to have very long half- 
             lives (Maddocks et al., 1986).
 
        6.5  Elimination by route of exposure
 
             The metabolites of azathioprine are excreted by the 
             kidneys; only small amounts of azathioprine and 
             mercaptopurine are excreted intact (McEvoy, 1993). In the 24 
             hour period after administration up to 50% of the dose is 
             excreted in the urine with 10% as the parent drug. There is 
             no data concerning azathioprine excretion in breast milk 
             (Briggs et al., 1990).
 
 
 
 
    7.  PHARMACOLOGY AND TOXICOLOGY
 
        7.1  Mode of action
 
             7.1.1  Toxicodynamics
 
                    The principal toxic effect of azathioprine is 
                    bone marrow depression manifested by leukopenia, 
                    macrocytic anaemia, pancytopenia, and 
                    thrombocytopenia, which may result in prolongation of 
                    clotting time and eventual haemorrhage (McEvoy, 1993). 
 
                    In a concentration of 50 g. mL-1, azathioprine 
                    produced cytogenetic damage to human lymphocytes  in 
                     vitro (Dollery, 1991).
 
             7.1.2  Pharmacodynamics
 
                    The exact mechanism of immunosuppressive 
                    activity of azathioprine has not been determined. 
                    Azathioprine which is an antagonist to purine 
                    metabolism, may inhibit RNA and DNA synthesis. The 
                    drug may also be incorporated into nucleic acids 
                    resulting in chromosome breaks, malfunctioning of the 
                    nucleic acids, or synthesis of fraudulent proteins. 
                    The drug may also inhibit coenzyme formation and 
                    functioning, thereby interfering with cellular 
                    metabolism. Mitosis may be inhibited by the drug.
                    
                    In patients who undergo renal transplantation, 
                    azathioprine suppresses hypersensitivities of the 
                    cell-mediated type and causes variable alterations in 
                    antibody production (McEvoy, 1993).
 
        7.2  Toxicity
 
             7.2.1  Human data
 
                    7.2.1.1  Adults
 
                             Severe pancytopenia has been 
                             observed in about 1% of patients who receive 
                             more than 2.5 mg.kg-1. A renal patient who 
                             took 7500 mg of azathioprine with 1000 mg of 
                             prednisone developed leucopenia and the drug 
                             was discontinued for 11 days (Carney et al., 
                             1974).
 
 
 
 
                    7.2.1.2  Children
 
                             Lymphopenia, decreased IgG and IgM 
                             concentrations, cytomegalovirus infection, 
                             and a decreased thymic shadow were observed 
                             in one infant whose mother had received 150 
                             mg of azathioprine and 30 mg of prednisone 
                             daily throughout pregnancy; most of these 
                             findings had apparently normalised by 10 
                             weeks of age. Pancytopenia and severe 
                             immunodeficiency were reported in a premature 
                             infant whose mother received 125 mg of 
                             azathioprine and 12.5 mg of prednisone 
                             throughout pregnancy (McEvoy, 
                             1993).
 
             7.2.2  Relevant animal data
 
                    Studies with animals have shown that the 
                    haemopoietic system is affected by azathioprine with 
                    depression of granulopoiesis, megakaryocytes and, 
                    hence, platelet formation. Reversible hepatoxicity has 
                    been observed in dogs at doses of 5 mg.kg-1 
                    (Dollery, 1991).
                    
                    Various teratogenic effects have been observed in 
                    rabbits, showing skeletal abnormalities at doses of 5 
                    to 15 mg.kg-1 given daily on days 6 to 14 of 
                    pregnancy, and in mice where azathioprine was lethal 
                    to the embryos at doses of 1 to 2 mg.kg-1 on days 3 
                    to 12 of pregnancy (Dollery, 1991).
 
             7.2.3  Relevant  in vitro data
 
                    Cytogenetic damage was observed in human 
                    lymphocytes  in vitro at a dose of 50 g.mL-1 
                    (Dollery, 1991).
 
        7.3  Carcinogenicity
 
             Azathioprine is carcinogenic in animals and may increase 
             the risk of neoplasia in humans. The exact risk of neoplasia 
             asscoiated with azathioprine use has not been defined; 
             however, evidence suggests that the risk may be elevated both 
             in patients with rheumatoid arthritis and in renal allograft 
             recipients receiving the drug. Acute myelogenous leukemia and 
             solid tumours have occurred in patients with rheumatoid 
             arthritis who received the drug (McEvoy, 1993).
 
 
 
 
        7.4  Teratogenicity
 
             Azathioprine is teratogenic in rabbits and mice when 
             given in dosages equivalent to the human dosage (5 mg/kg 
             daily). Abnormalities included skeletal malformations and 
             visceral anomalies.
             
             Immunologic and other abnormalities have been reported in 
             newborn infants who were exposed to azathioprine during 
             pregnancy. However, the association that may exist between 
             these abnormalities and azathioprine has not been determined 
             (Briggs et al., 1990).
 
        7.5  Mutagenicity
 
             Azathioprine is mutagenic in animals and humans. 
             Chromosomal abnormalities have been documented in humans 
             receiving azathioprine, but the abnormalities were reversed 
             following discontinuance of the drug (McEvoy, 1993). 
             Azathioprine is mutagenic in the Ames test (Dollery, 
             1991).
 
        7.6  Interactions
 
             Azathioprine dose should be reduced 75% when 
             administered with allopurinol, as allopurinol affects the 
             metabolism of mercaptopurine, a metabolite of azathioprine 
             (Dollery, 1991).
             
             Azathioprine may reduce the effect of certain neuromuscular 
             blocking agents including curare and related non-depolarizing 
             drugs (Dollery, 1991).
             
             Certain cytotoxic agents may be additive or synergistic in 
             producing toxicity when used in conjunction with azathioprine 
             (Dollery, 1991).
             
             The Committee on Safety of Medicines have advised that 
             azathioprine and penicillamine should not be used 
             concurrently (Dollery, 1991).
             
             The effects of azathioprine and corticosteroids could be 
             synergistic (Dollery, 1991).
             
             Azathioprine may reduce the anticoagulant effect of warfarin 
             (Reynolds, 1993).
 
 
 
 
        7.7  Main adverse effects
 
             The principal toxic effect of azathioprine is bone 
             marrow depression.
             
             Adverse GI effects (nausea, vomiting, anorexia and diarrhoea) 
             caused by azathioprine may be minimized by giving the drug in 
             divided doses and/or after meals.
             
             Hepatoxicity may occur in patients receiving azathioprine 
             principally in allograft patients. Rare, but life-threatening 
             hepatic veno-occlusive disease has occurred during chronic 
             azathioprine therapy.
             
             Azathioprine may also cause rash, infection, drug fever, 
             serum sickness, alopecia, arthralgia, retinopathy, Raynaud's 
             disease, and pulmonary edema. Some of these adverse effects 
             can occur as manifestations of rare hypersensitivity 
             reactions. (McEvoy, 1993).
 
    9.  CLINICAL EFFECTS
 
        9.1  Acute poisoning
 
             9.1.1  Ingestion
 
                    Oral ingestion of azathioprine tablets is the 
                    primary route of its administration. It may affect 
                    taste and smell (Ellenhorn & Barcelux,1988). It is 
                    well absorbed from the GI tract (Dorr & Fritz,1980). 
                    The oral bioavailability of therapeutic doses is 
                    approximately 60%. Acute overdosage with 850 mg of 
                    azathioprine has been tolerated by an adult without 
                    producing symptoms. An overdose of 7500 mg 
                    azathioprine produced mild transient alteration of 
                    liver enzymes and leukopenia which was delayed. The 
                    usual therapeutic dose of azathioprine is about 1 to 5 
                    mg/kg/day (Calabresi and Chabner, 1991).
 
             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
 
                    Acute poisoning due to parenteral exposure of 
                    azathioprine has not been reported. However, transient 
                    side effects following therapeutic intravenous 
                    administration of 100 mg azathioprine may occur. There 
                    has been no specific toxic effects following 
                    parenteral exposure of azathioprine. Idiosyncratic 
                    reactions such as dizziness, nausea, vomiting and 
                    reversible shock may appear during and or right after 
                    I.V. injection of azathioprine (Reynolds, 
                    1989).
 
             9.1.6  Other
 
                    No data available.
 
        9.2  Chronic poisoning
 
             9.2.1  Ingestion
 
                    Chronic poisoning due to oral ingestion of 
                    azathioprine has not been reported. However, long term 
                    oral therapeutic administration to 64 patients 
                    revealed reversible leukopenia in 22%, macrocytosis in 
                    20%, systemic illness (vomiting, abdominal pain, 
                    anorexia, rash or urticaria) in 12% and hepatotoxicity 
                    in 9% (Kissel et al, 1986).
 
             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
 
                    Parenteral administration of azathioprine may 
                    induce toxic effects such as dizziness, nausea, 
                    vomiting, allergic reactions, hypotension and delayed 
                    leukopenia (Reynolds,1989). Parenteral overdose cases 
                    of azathioprine has not been reported.
 
 
 
 
             9.2.6  Other
 
                    No data available.
 
        9.3  Course, prognosis, cause of death
 
             Based on very limited reports and experience on 
             azathioprine overdose, it seems that single overdose up to 
             850 mg is asymptomatic. In a case of massive overdose with 
             7500 mg of azathioprine, immediate toxic reactions were 
             nausea, vomiting and diarrhoea followed by mild leukopenia, 
             mild abnormalities in liver and kidney function on the third 
             day after the overdose. On the 6th day of admission white 
             blood cell (WBC) count, liver and kidney function tests 
             returned to normal. The oral azathioprine of 50 mg daily was 
             resumed on this kidney transplant patient, WBC had dropped to 
             2,800/mm3 on the third day after administration. 
             Azathioprine therapy was again discontinued, and WBC 
             increased to 11,000/mm3 after 11 days. Azathioprine therapy 
             was resumed at 50 mg/day without further suppression of 
             peripheral WBC and the patient survived (Carney et al, 
             1974).
             
             There has been no report of mortality due to azathioprine 
             poisoning. However, several cases of azathioprine induce 
             hepatic venocclusive disease in renal transplant patients 
             with high mortality (6 out of 7 patients) was reported by 
             Katzka et al (1986). Severe bone marrow depression and its 
             complication such as septic shock may also be a cause of 
             death.
 
        9.4  Systematic description of clinical effects
 
             9.4.1  Cardiovascular
 
                    Arterial hypertension after renal 
                    transplantation in patients treated with azathioprine 
                    in 72% of the cases compared with cyclosporin (64%) 
                    was investigated (Gordjani et al, 1990). Cases of 
                    portal hypertension in renal transplant patients after 
                    long term azathioprine therapy were reported 
                    (Yanagisawa et al, 1990 and Lorenz et al, 
                    1992).
 
             9.4.2  Respiratory
 
                    A single case of acute restrictive lung disease 
                    following long term azathioprine at a dose of 100 
                    mg/day which resolved after the drug was discontinued 
                    has been reported (Dorr & Fritz, 1980). A case of 
                    pulmonary manifestation (pulmonary infiltrations with 
                    haemoptysis) of Goodpasture's syndrome following 
                    azathioprine therapy in a renal patients has also been 
                    reported (Stetter et al, 1994).
 
 
 
             9.4.3  Neurological
 
                    9.4.3.1  CNS
 
                             A case of progressive 
                             leukencephalopathy (PML) after a four year 
                             azathioprine therapy with difficulty in 
                             urinating, articulation, spastic hemiplegia 
                             and eye movement malfunction was reported 
                             (Schnider,1991).
 
                    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
 
                             There is only a report of artralgia 
                             among many othertoxic effects (Osol, 
                             1980).
 
             9.4.4  Gastrointestinal
 
                    Oral ulceration occur rarely with therapeutic 
                    doses but may be seen with large doses (Dorr & Fritz, 
                    1980). Metallic or bitter taste following azathioprine 
                    ingestion has been reported (Ellenhorn & Barcelux, 
                    1988). Gastrointestinal disturbances such as nausea, 
                    vomiting, abdominal pain and diarrhoea have been 
                    reported and appear to occur mainly at higher doses 
                    (Assini et al, 1986). The authors classified this as a 
                    definite adverse reaction based on a positive 
                    rechallenge. Acute pancreatitis with severe vomiting 
                    following long term therapeutic administration of 
                    azathioprine was also reported (Roblin et al, 
                    1990).
 
             9.4.5  Hepatic
 
                    Hepatic dysfunction (hepatocellular and 
                    cholestatic), manifested by elevation of liver 
                    function tests and onset of jaundice and also hepatic 
                    venocclusive disease in renal transplant patients 
                    given azathioprine therapy have been reported (Read et 
                    al,1986; Barrowman et al,1986; Katzka et al,1986; 
                    Jeurissen et al,1990; Sternek et al,1991). Hepatic 
                    hemangiomas in a patient with rheumatoid arthritis 
                    treated with azathioprine was reported by Linana- 
 
 
 
                    Santafe et al (1992). Reversible cholestasis with bile 
                    duct injury following azathioprine therapy was also 
                    described (Horsmans et al,1991). A patient with 
                    dermatomyositis developed peliosis hepatis after 
                    treatment by azathioprine and corticosteroids. Liver 
                    enlargement with signs of portal hypertension 
                    disappeared progressively following discontinuation of 
                    azathioprine (Lorcerie et al, 1990).
 
             9.4.6  Urinary
 
                    9.4.6.1  Renal
 
                             There has been no report of the 
                             direct toxic effects of azathioprine on the 
                             kidneys. However, fever, hepatitis and acute 
                             interstitial nephritis in a rheumatic patient 
                             as concurrent manifestations of azathioprine 
                             hypersensitivity was reported (Meys et 
                             al,1992).
 
                    9.4.6.2  Other
 
                             No data available.
 
             9.4.7  Endocrine and reproductive systems
 
                    No data available.
 
             9.4.8  Dermatological
 
                    A severe palmar-plantar erythema with 
                    desquamation and pain was reported in a case receiving 
                    allupurinol as well. This was successfully treated by 
                    discontinuation of the drugs and initiation of topical 
                    steroid therapy. Skin rash, alopecia and urticaria 
                    after azathioprine therapy were also reported (Dorr 
                    and Fritz,1980; Kissel et al,1986).
 
             9.4.9  Eye, ear, nose, throat: local effects
 
                    There has been no report on the local effects 
                    of azathioprine on the above organs. However, 
                    retinophathy among the other toxic effects of 
                    azathioprine was reported (Osol, 1980).
 
             9.4.10 Haematological
 
                    Myelosuppression is an important and 
                    potentially lethal complication of azathioprine 
                    treatment (Connell et al, 1993). Leukopenia is the 
                    primary haematologic finding following azathioprine 
 
 
 
                    therapy. A mild leukopenia (4,100/mm3) was found on 
                    the third day after a massive azathioprine overdose. 
                    It was increased to 7300/mm3 on the 6th day (Carney 
                    et al,1974). However, severe bone marrow depression 
                    was reported in a 55 year old woman with severe oral 
                    lichen planus treated with azathioprine 100 mg/day 
                    orally for 28 days. Her white blood count (WBC) 
                    continued to fall down to 200/mm3 one week after 
                    azathioprinediscontinuation. Her Hb reduced to 8.4 
                    g/dL over this period. Bone marrow aspirated 12 days 
                    after the drug withdrawal showed reduced cellularity 
                    mainly of WBC precursors. Erythropoiesis was 
                    normocellular with megaloblastic change and 
                    megacaryocytes werenormal (Maddocks et al, 1986). In a 
                    study of 739 patients who were treated with 2 
                    mg/kg/day azathioprine for a median of 12.5 months, 37 
                    patients (5%) developed bone marrow toxicity. 
                    Leukopenia (WBC< 3000 /mm3) occurred in 28 (3.8%) 
                    patients and 3 of them were pancytopenic of which 2 
                    died from sepsis (Connell et al,1993). Pure red blood 
                    cell aplasia was found in a renal transplant patient 
                    who was treated by azathioprine. Discontinuation of 
                    azathioprine was associated with complete recovery 
                    from anaemia as well (Agarwal et al,1993).
 
             9.4.11 Immunological
 
                    Azathioprine is an immunosuppressive agent 
                    which induce myelosuppression. However, 
                    hypersensitivity reactions and shock have been 
                    observed during azathioprine treatment (Wilson et 
                    al,1993; Jones and Ashworth,1993). Gastrointestinal 
                    type I hypersensitivity to azathioprine with a massive 
                    duodenal eosinophilia without peripheral blood 
                    eosinophilia was reported (Riedel et al, 
                    1990).
 
             9.4.12 Metabolic
 
                    No data available.
 
                    9.4.12.1 Acid-base disturbances
 
                             No data available.
 
                    9.4.12.2 Fluid and electrolyte disturbances
 
                             No data available.
 
                    9.4.12.3 Others
 
                             No data available.
 
 
 
 
             9.4.13 Allergic reactions
 
                    Dermatologic and gastrointestinal allergic 
                    reaction such as rash, urticaria and gastroentritis 
                    during azathioprine therapy were reported (Jeurissen 
                    et al,1990; Riedel et al, 1990).
 
             9.4.14 Other clinical effects
 
                    No data available.
 
             9.4.15 Special risks
 
                    Pregnancy & Lactation:
                    
                    There has been no report of bona fide cases of human 
                    malformations attributed to maternal treatment with 
                    azathioprine. There are 77 cases of normal infants 
                    born under azathioprine treatment (Schardein,1985). 
                    Despite the lack of foetal damage associated with 
                    azathioprine, it seems prudent to avoid its use in 
                    pregnancy if possible. There has been no report of 
                    azathioprine excretion in breast milk (Briggs et al., 
                    1990).
 
        9.5  Other
 
             No data available.
 
    10. MANAGEMENT
 
        10.1 General principles
 
             Special attention should be given to the haemopoietic 
             system and liver function. In severe intoxication with 
             azathioprine, respiratory and cardiovascular functions 
             shouldbe monitored and supported.
 
        10.2 Relevant laboratory analyses
 
             10.2.1 Sample collection
 
                    Blood and urine samples should be collected 
                    for analyses. Gastric contents may also be used for 
                    toxicological analysis (presence of azathioprine) in 
                    azathioprine overdose patient who was admitted early 
                    after ingestion. Blood samples should be collected in 
                    different tubes with and without anticoagulant (EDTA) 
                    for haematological, biochemical and toxicological 
                    tests. Red blood cells have been used in one case for 
                    the estimation of a cytotoxic metabolite of 
                    azathioprine (6-thioguanine nucleotide) (Maddocks et 
                    al., 1986).
 
 
 
             10.2.2 Biomedical analysis
 
                    Regular white blood cell count monitoring is 
                    required during and 1 to 2 weeks after taking 
                    azathioprine therapy and after overdose as leukopenia 
                    is the most common toxic effect of azathioprine in 
                    humans. Liver and kidney function tests should also be 
                    performed to detect the azathioprine toxicity on these 
                    organ.
 
             10.2.3 Toxicological analysis
 
                    Estimation of azathioprine and its metabolites 
                    concentrations in blood and urine may be required. 
                    Concentration of 6-thioguanine nucleotide (TGN) a 
                    cytotoxic metabolite of azathioprine was assayed in 
                    red blood cells 12, 44 and 55 days after intoxication 
                    which were much higher than the control group. The 
                    authors concluded that this active metabolite which is 
                    also produced with 6-mercaptopurine and 6- thioguanine 
                    therapy is related to neutropenia and can be used to 
                    predict bone marrow toxicity of these drugs (Maddocks 
                    et al., 1986).
 
             10.2.4 Other investigations
 
                    In severe azathioprine intoxicated patient, 
                    other paramedical investigations such ECG and chest X- 
                    ray may be required and should be performed whenever 
                    indicated.
 
        10.3 Life supportive procedures and symptomatic/specific treatment
 
             Treatment should be supportive and symptomatic. Make a 
             proper assessment of airway, breathing, circulation and 
             neurological status of the patient. Open and maintain at 
             least one intravenous route. Administer intravenous fluid. 
             Monitor vital signs in severe intoxicated patients. Monitor 
             fluid and electrolytes and acid-base balance. Haemodialysis 
             has been reported to remove azathioprine and its metabolites. 
             It can therefore be used in severe overdose patients (Bennett 
             et al,1980).
 
        10.4 Decontamination
 
             Emesis may be indicated in substantial recent ingestion 
             of azathioprine. It is most effective if initiated within 30 
             minutes of ingestion. If emesis is unsuccessful following 2 
             doses of ipecac, the decision to gastric lavage should be 
             made on an individual basis. In massive overdose patients, 
             gastric aspiration and lavage may be performed as soon as 
             possible. Activated charcoal (1-2 g/kg every 3-4 h) as slurry 
 
 
 
             in water or mixed with sorbitol should be given orally or 
             through the gastric tube. Cathartics should not be used in 
             patients with an ileus or impaired renal function. In case of 
             skin and eye exposure, irrigate with copious amounts of water 
             and saline.
 
        10.5 Elimination
 
             Azathioprine and its metabolites are haemodialysable. 
             About 44% of the total amount of Azathioprine in 3 men and 3 
             women on chronic haemodialysis(95.431.0 ml/min) was removed 
             during 8 hours. Haemodialysis should be used in severe 
             azathioprine intoxicated patients (Schusziarra et al, 
             1976).
 
        10.6 Antidote treatment
 
             There is no antidote for azathioprine toxicity.
 
             10.6.1 Adults
 
             10.6.2 Children
 
        10.7 Management discussion
 
             There have been reports only on two azathioprine 
             overdose cases. One had taken 850 mg and was asymptomatic and 
             other who had taken 7500 mg, revealed mild transient 
             gastroenteritis, leukopenia and hepatic function and 
             survived. However, azathioprine toxicity has mainly been 
             reported in patients already taking this immunosuppressive 
             agent. Regular monitoring of peripheral blood count and liver 
             function is required to detect the toxicity in advance. In 
             severe azathioprine intoxicated patients, Supportive and 
             critical care management including barrier nursing, 
             particularly in those with severe leukopenia <1000/Cub.mm or 
             septic shock, is required (Carney et al, 1974; Connel et al, 
             1993). Administration of granulocyte colony stimulating 
             factor (GCS-F) may reduce morbidity in patients with severe 
             neutropenia after cytotoxic chemotherapy, and would be 
             expected to reduce the severity and duration of neutropenia 
             after azathioprine poisoning.
 
    11. ILLUSTRATIVE CASES
 
        11.1 Case reports from literature
 
             There is two case reports from the medical literature. 
             First was asymptomatic who had taken 850 mg azathioprine. The 
             second is as follows:
             
 
 
 
             A 44 year old disable heavy equipment operator who had 
             suffered from chronic renal failure. He received a cadaver 
             kidney transplantation on September 18, 1970 and went under 
             azathioprine and corticosteroid treatment. On February 8, 
             1972 at 18h ingested 200 x 5mg prednisolone tablets as 
             instructed and 150 x 50 (7500)mg tablets of azathioprine by 
             mistake. He vomited 6 and again 8 hours later and noticed 
             diarrhoea. He was then hospitalised on the following morning 
             for observation. The patient was asymptomatic thereafter for 
             6 days. His white blood cell counts (WBC) decreased from 
             7500/Cub.mm on the first day to 4100/Cub.mm on the third day 
             after overdose and returned to 7300/Cub.mm on the 6th day. 
             There was also a mild transient liver enzymes transaminase 
             alteration. He received no treatment for his overdosage. 
             Azathioprine oral administration, 50 mg/day was resumed. 3 
             days later, the total WBC decreased to 2800/Cub.mm. 
             Azathioprine therapy was again discontinued for 11 days when 
             his WBC increased to 11,000/Cub.mm. Azathioprine was resumed 
             again at 50 mg daily and subsequently to 100 mg daily without 
             further suppression of WBC and the patient survived (Carney 
             et al, 1974).
 
        11.2 Internally extracted data on cases
 
             To be added by the Center using the monograph.
 
        11.3 Internal cases
 
             To be added by the Center using the monograph.
 
    12. Additional information
 
        12.1 Availability of antidotes
 
             No antidote is available.
 
        12.2 Specific preventive measures
 
             Azathioprine is a myelotoxic and hepatotoxic agent. It 
             is therefore advisable to monitor the peripheral blood counts 
             and liver function regularly to detect the early toxic 
             effects. Estimation of 6-thioguanine nucleotide, a cytotoxic 
             metabolite of azathioprine was assayed in red blood cell of a 
             patient 12, 14 and 55 days after stopped taking azathioprine. 
             It was found much higher than the controls. The authors 
             believed that this metabolite is responsible for neutropenia 
             and could be used to predict bone marrow toxicity of 
             azathioprine (Maddocks et al, 1986).
 
 
 
 
        12.3 Other
 
             No data available.
 
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    14. AUTHOR(S):
 
        M. Balali-Mood, M.D., Ph.D.,
        Professor of Medicine and Clinical Toxicology,
        Director, Poisons Control Centre,
        Imam Reza Hospital,
        Mashhad University of Medical Sciences,
        Mashhad 91735, I.R.Iran.
        
        Tel: 9851 - 93043 / 889301
        Fax: 9851 - 93038 / 883714
        
        Peer reviewed: Berlin, October 1995
        
        Finalised: IPCS, September 1996
    



    See Also:
       Toxicological Abbreviations
       Azathioprine  (IARC Summary & Evaluation, Supplement7, 1987)
       Azathioprine (IARC Summary & Evaluation, Volume 26, 1981)