Azathioprine
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 œg. 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 µg.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(95.4ñ31.0 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