Imuran

Azathioprine.

Pharmacology: Pharmacodynamics: Mechanism of Action: Azathioprine is a prodrug of 6-mercaptopurine (6-MP). 6-MP is inactive but acts as a purine antagonist and requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGNs) for immunosuppression. The TGNs and other metabolites eg, 6-methly-mercaptopurine ribonucleotides) inhibit de novo synthesis and purine nucleotide interconversions. The TGNs are also incorporated into nucleic acids and this contribute to the immunosuppressive effects of the drug. Other potential mechanisms of azathioprine include the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.
Because of the mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment.
The activity of the methylnitroimidazole moiety, a metabolite of azathioprine but not 6-MP, has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.
Pharmacodynamic Effects: Plasma levels of azathioprine and 6-MP do not correlate well with the therapeutic efficacy or toxicity of azathioprine, and therefore have no prognostic value.
Pharmacokinetics: Absorption: The absorption of azathioprine is incomplete and variable. The median (range) absolute bioavailability of 6-MP after administration of azathioprine 50 mg is 47% (27-80%). The extent of absorption of azathioprine is similar across the gastrointestinal tract, including the stomach, jejunum and cecum. However, the extent of 6-MP absorption, after azathioprine administration is variable and differs between the sites of absorption, with the highest extent of absorption in the jejunum, followed by the stomach and then the cecum.
Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-MP have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-MP was approximately 26% lower following administration with food and milk compared to an overnight fast. 6-MP is not stable in milk due to presence of xanthine oxidase (30% degradation within 30 min) (see Metabolism as follows). Azathioprine should be administered at least 1 hr before or 3 hrs after food or milk (see Dosage & Administration).
Distribution: The volume of distribution at steady state (V_dss) of azathioprine is unknown. The mean (±SD) apparent V_dss of 6-MP is 0.9 (±0.8) L/kg, although this may be an underestimate because 6-MP is cleared throughout the body (and not just in the liver).
Concentration of 6-MP in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration of 6-MP.
Metabolism: Azathioprine is rapidly broken down in vivo by glutathione-S-transferase into 6-MP and a methylnitroimidazole moiety. The 6-MP readily crosses cell membranes and is extensively metabolized by many multi-step pathways to active and inactive metabolites, with no 1 enzyme predominating. Because of the complex metabolism, inhibition of 1 enzyme does not explain all cases lack of efficacy and/or pronounced myelosuppression. The predominant enzymes responsible for the metabolism of 6-MP or its downstream metabolites are: Polymorphic enzyme thiopurine S-methyltransferase (TPMT) (see Monitoring under Precautions and Aminosalicylates under Interactions), xanthine oxidase (see Absorption as previously mentioned and Allopurinol/Oxipurinol/Thiopurinol under Interactions), inosine monophosphate dehydrogenase (IMPDH) (see Ribavirin under Interactions), and hypoxanthine guanine phosphoribosyltransferase (HPRT). Additional enzymes involved in the formation of active and inactive metabolites are: Guanosine monophosphate synthetase (GMPS, which from TGNs) and inosine triphosphate pyrophosphatase (ITPase). Azathioprine itself is also metabolized by aldehyde oxidase to form 8-hydroxy azathioprine, which may be active. There are also multiple inactive metabolites formed via other pathways.
There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of azathioprine may predict adverse drug reactions to azathioprine therapy.
Thiopurine S-Methyltransferase (TPMT): TPMT activity is inversely related to red blood cell 6-MP derived thioguanine nucleotide concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations.
Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles (TPMT2, TPMT3A and TPMT3C) account for about 95% of individuals with reduced levels of TPMT activity. Approximately 0.3% (1:300) of patients have nonfunctional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have 1 TPMT nonfunctional allele (heterozygous) leading to low intermediate TPMT activity and 90% of individuals have normal TPMT activity with 2 functional alleles. There may be also a group of approximately 2% who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can also be informative (see Precautions).
Elimination: After oral administration of ³⁵S-azathioprine 100 mg, 50% of the radioactivity was excreted in the urine and 12% in the feces after 24 hrs. In the urine, the major compound was the inactive oxidized metabolite, thiouric acid. Less than 2% was excreted in the urine as azathioprine or 6-MP. Azathioprine has a high extraction ratio with a total clearance >3 L/min in normal volunteers. There are no data on the renal clearance or t_½ of azathioprine. The renal clearance of 6-MP and the t_½ of 6-MP are 191 mL/min/m² and 0.9 hr, respectively.
Special Patient Populations: Elderly: No specific studies have been carried out in the elderly (see Dosage & Administration).
Overweight Children: In a US clinical study, 18 children (3-14 years) were evenly divided into 2 groups; either a weight to height ratio above or below the 75^th percentile. Each child was on maintenance treatment of 6-MP and the dosage was calculated based on their body surface area. The mean AUC (0-∞) of 6-MP in the group above the 75^th percentile was 2.4 times lower than that for the group below the 75^th percentile. Therefore, children considered to be overweight may require azathioprine doses at the higher end of the dose range and close monitoring of response to treatment is recommended (see Dosage & Administration).
Renal Impairment: Studies with azathioprine have shown no difference in 6-MP pharmacokinetics in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of azathioprine in renal impairment, consideration should be given to reducing the dosage in patients with impaired renal function (see Dosage & Administration).
Azathioprine and/or its metabolites are eliminated by hemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hrs.
Hepatic Impairment: A study with azathioprine was performed in 3 groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-MP exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease. Therefore, consideration should be given to reducing the dosage in patients with impaired hepatic function (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 mg/kg body weight/day over the period of organogenesis have shown varying degrees of fetal abnormalities.
Teratogenicity was evident in rabbits at 10 mg/kg body weight/day.

As an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids.
Imuran, in combination with corticosteroids and/or other immunosuppressive agents and procedures, is indicated to enhance the survival of organ transplants eg, renal, cardiac and hepatic transplants; and to reduce the corticosteroid requirements of renal transplant recipients.
Imuran is indicated for the treatment of moderate to severe inflammatory bowel disease (IBD) (Crohn's disease or ulcerative colitis) in patients in whom corticosteroid therapy is required, in patients who cannot tolerate corticosteroid therapy or in patients whose disease is refractory to other standard 1st-line therapy.
Imuran, either alone or more usually in combination with corticosteroids and/or other drugs and procedures, has been used with clinical benefit (which may include reduction of dosage or discontinuation of corticosteroids) in a proportion of patients suffering from severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune hemolytic anemia, chronic refractory idiopathic thrombocytopenic purpura and relapsing remittent multiple sclerosis.

Imuran should be administered at least 1 hr before or 3 hrs after food or milk (see Pharmacokinetics: Absorption under Pharmacology under Actions).
Adults: Transplants: Depending on the immunosuppressive regimen employed, a dosage of up to 5 mg/kg body weight/day may be given orally on the 1st day of therapy.
Maintenance dosage should range from 1-4 mg/kg body weight/day and must be adjusted according to clinical requirements and hematological tolerance.
Evidence indicates that Imuran therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.
Multiple Sclerosis: The dose recommended for the treatment of relapsing remittent multiple sclerosis is 2-3 mg/kg body weight/day. Treatment duration in excess of 1 year may be required to establish efficacy. Control of disease progression may not be apparent until after 2 years of therapy.
Other Indications: In general, starting dosage is from 1-3 mg/kg body weight/day and should be adjusted, within these limits, depending on the clinical response (which may not be evident for weeks or months) and hematological tolerance.
When therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with the maintenance of that response. If no improvement occurs in the patient's condition within 3 months, consideration should be given to withdrawing Imuran. However, for patients with IBD, a treatment duration of at least 12 months should be considered and a response to treatment may not be clinically apparent until after 3-4 months of treatment.
The maintenance dosage required may range from <1-3 mg/kg body weight/day, depending on the clinical condition being treated and the individual patient response, including hematological tolerance.
Children: Multiple Sclerosis: Multiple sclerosis is not a commonly diagnosed disease in children. The use of Imuran is not recommended.
Overweight Children: May require doses at the higher end of the dose range and therefore close monitoring of response to treatment is recommended (see Pharmacokinetics: Special Patient Populations: Overweight Children under Pharmacology under Actions).
Elderly: There is limited experience of the administration of Imuran to elderly patients.
Although the available data do not provide evidence that the incidence of side effects among elderly patients is higher than that among other patients treated with Imuran, it is advisable to monitor renal and hepatic function, and to consider dose reduction if there is impairment (see Renal Impairment and Hepatic Impairment as follows).
Renal Impairment: In patients with renal insufficiency, consideration should be given to reducing the dose (see Pharmacokinetics: Special Patient Populations: Renal Impairment under Pharmacology under Actions and Precautions).
Hepatic Impairment: In patients with hepatic insufficiency, consideration should be given in reducing the dosage (see Pharmacokinetics: Special Patient Populations: Hepatic Impairment under Pharmacology under Actions and Precautions).
Drug Interactions: When xanthine oxidase inhibitors eg, allopurinol and Imuran are administered concomitantly, it is essential that only 25% of the usual dose of Imuran is given since allopurinol decreases the rate of catabolism of Imuran (see Interactions).
Patients with Thiopurine S-Methyltransferase (TPMT) Deficiency: Patients with inherited little or no TPMT activity is at increased risk for severe Imuran toxicity from conventional doses Imuran and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see Pharmacokinetics: Monitoring under Pharmacology under Actions and Precautions).
Most patients with heterozygous TPMT deficiency can tolerate recommended Imuran doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see Pharmacokinetics: Monitoring under Pharmacology under Actions and Precautions).

Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with Imuran, and result from bone marrow depression which may be maximal after 9-14 days. These signs are more likely to be manifested following chronic overdosage, rather than after a single acute overdose. There has been a report of a patient who ingested a single overdose of Imuran 7.5 g. The immediate toxic effects of this overdose were nausea, vomiting and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. Recovery was uneventful.
There is no specific antidote. Blood counts should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (eg, use of activated charcoal) may not be effective in the event of azathioprine overdose unless the procedure can be undertaken within 60 min of ingestion.

Hypersensitivity to azathioprine or to any of the excipients of Imuran. Hypersensitivity to 6-MP should alert the physician to probable hypersensitivity to Imuran.

Immunization using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunizations with organism vaccines are not recommended (see Interactions).
Co-administration of ribavirin and Imuran are not advised. Ribavirin may reduce efficacy and increase toxicity of Imuran (see Interactions).
Monitoring: There are potential hazards in the use of Imuran. It should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of therapy.
Particular care should be taken to monitor hematological response and to reduce the maintenance dosage to the minimum required for clinical response.
It is suggested that during the first 8 weeks of therapy, complete blood count should be performed weekly or more frequently if high dosage is used or if severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is suggested that complete blood counts are repeated monthly, or at least at intervals of not longer than 3 months.
At the 1st signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leukocytes and platelets may continue to fall after treatment is stopped.
Patients receiving Imuran should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding, or other manifestations of bone marrow depression. Bone marrow suppression is reversible if Imuran is withdrawn early enough.
Imuran is hepatotoxic and liver function tests should be routinely monitored during treatment. More frequent monitoring may be advisable in those with preexisting liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue Imuran immediately if jaundice becomes apparent.
There are rare individuals with an inherited deficiency of the TPMT who may be unusually sensitive to the myelosuppressive effect of Imuran and prone to developing rapid bone marrow depression following the initiation of treatment with Imuran. This problem could be exacerbated by co-administration with drugs that inhibit TPMT eg, olsalazine, mesalazine or sulfasalazine. Also a possible association between decreased TPMT activity and secondary leukemias and myelodysplasia has been reported in individuals receiving 6-MP (the active metabolite of azathioprine) in combination with other cytotoxics (see Adverse Reactions). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore, close monitoring of blood counts is still necessary.
The dosage of Imuran may be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression (see Cytostatic/Myelosuppressive Agents under Interactions).
Renal and/or Hepatic Impairment: Caution is advised during the administration of Imuran in patients with renal and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored (see Special Patient Populations under Pharmacokinetics and Dosage & Administration).
Lesch-Nyhan Syndrome: Limited evidence suggests that Imuran is not beneficial to patients with hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive Imuran.
Varicella Zoster Virus Infection (see Adverse Reactions): Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised especially with respect to the following.
Before starting the administration of immunosuppressants, the physician should check to see if the patient has a history of VZV. Serologic testing may be useful in determining previous exposure. Patients who have no history of exposure should avoid contact with individuals with chickenpox or herpes zoster. If the patient is exposed to VZV, special care must be taken to avoid patients developing chickenpox or herpes zoster, and passive immunization with varicella-zoster immunoglobulin (VZIG) may be considered.
If the patient is infected with VZV, appropriate measures should be taken, which may include antiviral therapy and supportive care.
Progressive Multifocal Encephalopathy (PML): PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving Imuran with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the 1st sign or symptom suggestive of PML and appropriate evaluation undertaken to establish a diagnosis (see Adverse Reactions).
Hepatitis B (see Adverse Reactions): Hepatitis B carriers [defined as patients positive for hepatitis B surface antigen (HBsAg) for >6 months], or patients with documented past HBV infection, who receive immunosuppressive drugs are at risk of reactivation of HBV replication, with asymptomatic increases in serum HBV, DNA and ALT levels. Local guidelines may be considered including prophylactic therapy with oral anti-HBV agents.
Effects on the Ability to Drive or Operate Machinery: There are no data on the effect of Imuran on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of Imuran.
Carcinogenicity: (See Adverse Reactions.) Patients receiving immunosuppressive therapy are at an increased risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. It has been reported that reduction or discontinuation of immunosuppression may be associated with partial or complete regression of non-Hodgkin's lymphomas and Kaposi's sarcomas.
Reports of hepatosplenic T-cell lymphoma in the IBD population have been received when Imuran is used in combination with anti-TNF agents.
Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level. As is usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited and patients should wear protective clothing and use a sunscreen with a high protection factor.
Mutagenicity: Chromosomal abnormalities have been demonstrated in both male and female patients treated with Imuran. It is difficult to assess the role of Imuran in the development of these abnormalities. Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the offspring of patients treated with Imuran. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with Imuran.
Imuran and long-wave ultraviolet (UV) light have been shown to have a synergistic clastogenic effect in patients treated with Imuran for a range of disorders.
Use in Pregnancy & Lactation: Relief of chronic renal insufficiency by renal transplantation involving the administration of Imuran has been accompanied by increased fertility in both male and female transplant recipients.
Substantial transplacental and transamniotic transmission of azathioprine and its metabolites from the mother to the fetus have shown to occur.
Imuran should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefit.
Evidence of teratogenicity of Imuran in man is equivocal. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Imuran. There have been reports of premature birth and low birth weight following maternal exposure to Imuran, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure.
Leukopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took Imuran throughout their pregnancies. Extra care in hematological monitoring is advised during pregnancy.
6-Mercaptopurine has been identified in the colostrum and breast milk of women receiving Imuran treatment. It is recommended that mothers receiving Imuran should not breastfeed.

Relief of chronic renal insufficiency by renal transplantation involving the administration of Imuran has been accompanied by increased fertility in both male and female transplant recipients.
Substantial transplacental and transamniotic transmission of azathioprine and its metabolites from the mother to the fetus have shown to occur.
Imuran should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefit.
Evidence of teratogenicity of Imuran in man is equivocal. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Imuran. There have been reports of premature birth and low birth weight following maternal exposure to Imuran, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure.
Leukopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took Imuran throughout their pregnancies. Extra care in hematological monitoring is advised during pregnancy.
6-Mercaptopurine has been identified in the colostrum and breast milk of women receiving Imuran treatment. It is recommended that mothers receiving Imuran should not breastfeed.

For Imuran, there is no modern clinical documentation which can be used as support for determining the frequency of adverse effects. Adverse effects may vary in their incidence depending on the indication. The following convention has been utilized for the classification of frequency: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000).
Infections and Infestations: Very Common: Viral, fungal and bacterial infections in transplant patients receiving Imuran in combination with other immunosuppressants.
Uncommon: Viral, fungal and bacterial infections in other patient populations.
Patients receiving Imuran alone or in combination with other immunosuppressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection and reactivation with VZV hepatitis B and other infectious agents. Very Rare: Cases of JC virus associated PML have been reported following the use of azathioprine in combination with other immunosuppressants (see Precautions).
Benign and Malignant Neoplasms (Including Cysts and Polyps): Rare: Neoplasms including non-Hodgkin's lymphomas, skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's), uterine cervical cancer in situ, acute myeloid leukemia and myelodysplasia (see Precautions).
The risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcoma (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ, is increased in patients who receive immunosuppressive drugs, particularly in transplant recipients receiving aggressive treatment and such therapy should be maintained at the lowest effective levels. The increased risk of developing non-Hodgkin's lymphomas in immunosuppressed rheumatoid arthritis patients compared with the general population appears to be related at least in part to the disease itself.
There have been rare reports of acute myeloid leukemia and myelodysplasia (some in association with chromosomal abnormalities). Very Rare: Hepatosplenic T-cell lymphoma in patients with IBD when used in combination with anti-TNF agents.
Blood and Lymphatic System Disorders: Very Common: Depression of bone marrow function, leukopenia. Common: Thrombocytopenia. Uncommon: Anemia. Rare: Agranulocytosis, pancytopenia, aplastic and megaloblastic anemia, erythroid hypoplasia.
Imuran may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leukopenia, but also sometimes as anemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anemia. These occur particularly in patients predisposed to myelotoxicity eg, those with TPMT deficiency and renal or hepatic insufficiency and in patients failing to reduce the dose of Imuran when receiving concurrent allopurinol therapy.
Reversible, dose-related increases in mean corpuscular volume and red cell hemoglobin content have occurred in association with Imuran therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anemia and erythroid hypoplasia are rare.
Immune System Disorders: Uncommon: Hypersensitivity reactions. Very Rare: Stevens-Johnson syndrome and toxic epidermal necrolysis.
Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of Imuran. Clinical features include general malaise, dizziness, nausea, vomiting, diarrhea, fever, rigors, exanthema, rash, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and cholestasis (see Hepatobiliary Disorders under Adverse Reactions).
In many cases, rechallenge has confirmed an association with Imuran.
Immediate withdrawal of Imuran and institution of circulatory support where appropriate have led to recovery in the majority of cases. Other marked underlying pathology has contributed to the very rare deaths reported. Following a hypersensitivity reaction to azathioprine, the necessity for continued administration of azathioprine should be carefully considered on an individual basis.
Respiratory, Thoracic and Mediastinal Disorders: Very Rare: Reversible pneumonitis.
Gastrointestinal Disorders: Common: Nausea. Uncommon: Pancreatitis. Very Rare: Colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhea in inflammatory bowel disease population.
A minority of patients experience nausea when 1st given oral azathioprine. This appears to be relieved by administering the tablets after meals.
Serious complications, including colitis, diverticulitis and bowel perforation, have been described in transplant recipients receiving immunosuppressive therapy. However, the etiology is not clearly established and high-dose corticosteroids may be implicated. Severe diarrhea, recurring on rechallenge, has been reported in patients treated with Imuran for inflammatory bowel disease. The possibility that exacerbation of symptoms might be drug-related should be borne in mind when treating such patients.
Pancreatitis has been reported in a small percentage of patients on Imuran therapy, particularly in renal transplant patients and those diagnosed as having inflammatory bowel disease. There are difficulties in relating the pancreatitis to the administration of 1 particular drug, although rechallenge has confirmed an association with azathioprine on occasions.
Hepatobiliary Disorders: Uncommon: Cholestasis and deterioration of liver function tests.
Rare: Life-threatening hepatic damage.
Cholestasis and deterioration of liver function have occasionally been reported in association with Imuran therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Immune System Disorders as previously mentioned).
Rare, but life-threatening hepatic damage associated with chronic administration of Imuran has been described primarily in transplant patients. Histological findings include sinusoidal dilatation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. In some cases withdrawal of Imuran has resulted in either a temporary or permanent improvement in liver histology and symptoms.
Skin and Subcutaneous Tissue Disorders: Rare: Alopecia.
Hair loss has been described on a number of occasions in patients receiving Imuran and other immunosuppressive agents. In many instances the condition resolved spontaneously despite continuing therapy. The relationship between alopecia and Imuran treatment is uncertain.

Vaccines: The immunosuppressive activity of Imuran could result in an atypical and potentially deleterious response to live vaccines, the administration of live vaccines to patients receiving Imuran therapy is not recommended (see Precautions).
A diminished response to killed vaccines is likely and such a response to hepatitis B vaccine has been observed among patients treated with a combination of azathioprine and corticosteroids.
A small clinical study has indicated that standard therapeutic doses of Imuran do not deleteriously affect the response to polyvalent pneumococcal vaccine, as assessed on the basis of mean anti-capsular specific antibody concentration.
Cytostatic/Myelosuppressive Agents: (See Precautions.) Where possible, concomitant administration of cytostatic drugs or drugs which may have a myelosuppressive effect eg, penicillamine, should be avoided. There are conflicting clinical reports of interactions, resulting in serious hematological abnormalities, between Imuran and co-trimoxazole.
There has been a case report suggesting that hematological abnormalities may develop due to the concomitant administration of Imuran and captopril. It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of Imuran.
Allopurinol/Oxipurinol/Thiopurinol: Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol are given concomitantly with 6-MP or azathioprine, the dose of 6-MP and azathioprine should be reduced to ¼ of the original dose (see Drug Interactions under Dosage & Administration).
Aminosalicylates: As there is in vitro and in vivo evidence that aminosalicylate derivatives (eg, olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme. Therefore, lower doses of Imuran may need to be considered when administered concomitantly with aminosalicylate derivatives (see Precautions).
Methotrexate: Methotrexate (20 mg/m² orally) increased 6-MP AUC by approximately 31% and methotrexate (2 or 5 g/m² IV) increased 6-MP AUC by 69% and 93%, respectively. Therefore, when Imuran is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.
Effects of Azathioprine on Other Drugs: Anticoagulants: Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with Imuran; therefore, higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with Imuran.
Ribavirin: Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of Imuran and ribavirin; therefore, co-administration is not advised (see Pharmacokinetics: Metabolism under Pharmacology under Actions and Precautions).

Instructions for Use and Handling: Safe Handling: Health professionals who handle Imuran uncoated tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations.
Provided that the film-coating is intact, there is no risk in handling film-coated Imuran tablets. Film-coated Imuran tablets should not be divided and provided the coating is intact, no additional precautions are required when handling them.
Disposal: Imuran tablets should be disposed of in a manner appropriate to the prevailing local regulatory requirements for the destruction of dangerous substances.

Store at temperatures not exceeding 25°C. Protect from light.

Immunosuppressants

L04AX01 - azathioprine ; Belongs to the class of other immunosuppressants.

Rx