Azathioprine

Azathioprine is an immunosuppressive antimetabolite, chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound.

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and amethylnitroimidazole moiety. The 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The rate of conversion varies from one person to another. Nucleotides do not traverse cell membranes and therefore do not circulate in body fluids. Irrespective of whether it is given directly or is derived in vivo from azathioprine, 6-MP is eliminated mainly as the inactive oxidised metabolite thiouric acid. This oxidation is brought about by xanthine oxidase, an enzyme that is inhibited by allopurinol. The activity of the methylnitroimidazole moiety has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP. Determination of plasma concentrations of azathioprine or 6-MP have no prognostic value as regards effectiveness or toxicity of these compounds.

Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment. Azathioprine appears to be well absorbed from the upper gastro-intestinal tract. Plasma levels of azathioprine and 6-mercaptopurine do not correlate well with the therapeutic efficacy or toxicity of azathioprine.

Absorption: Azathioprine is well absorbed following oral administration. Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-mercaptopurine have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-mercaptopurine was approximately 27% lower following administration with food and milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes). Azathioprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. The dose should not be taken with milk or dairy products.

After oral administration of [35S]-azathioprine, the maximum plasma radioactivity occurs at 1-2 hours and decays with a half-life of 4-6 hours. This is not an estimate of the half-life of azathioprine itself, but reflects the elimination from plasma of azathioprine and the [35S]-containing metabolites of the drug.

Azathioprine is principally excreted as 6-thiouric uric acid in the urine. 1-methyl-4-nitro-5-thioimidazole has also been detected in urine as a minor excretory product. A small proportion of the drug may be cleaved between the S atom and the purine ring. Only a small amount of the dose of azathioprine administered is excreted unmetabolised in the urine.

Biotransformation: Thiopurine S-Methyl Transferase (TPMT): TPMT activity is inversely related to red blood cell 6-mercaptopurine 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.

Transplants:

• Depending on the immunosuppressive regimen employed, a dosage of up to 5mg/kg body weight/day may be given orally or intravenously on the first day of therapy.
• Maintenance dosage should range from 1 to 4mg/kg body weight/day and must be adjusted according to clinical requirements and haematological tolerance.
• Evidence indicates that azathioprine therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.

Dosage in Other indications:

• In general, the starting dosage is 1 to 3mg/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 haematological tolerance.
• When the 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 three months, consideration should be given to withdrawing azathioprine. However, for patients with IBD, a treatment duration of at least twelve months should be considered and a response to treatment may not be clinically apparent until after three to four months of treatment.
• The maintenance dosage required may range from less than 1mg/kg body weight/day to 3mg/kg body weight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Overweight children: Children considered to be overweight may require doses at the higher end of the dose range and therefore close monitoring of response to treatment is recommended.

Elderly: There is limited experience of the administration of azathioprine 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 azathioprine, it is recommended that the dosages used should be at the lower end of the range.

Renal impairment: In patients with renal insufficiency, consideration should be given to reducing the dosage.

Hepatic impairment: In patients with hepatic insufficiency, consideration should be given to reducing the dosage.

For oral use. Azathioprine should be taken at least 1 hour before or 2 hours after milk or dairy products

Allopurinol/oxipurinol/thiopurinol: When allopurinol, oxipurinol and/or thiopurinol are given concomitantly with 6-mercaptopurine or azathioprine, the dose of 6-mercaptopurine and azathioprine should be reduced to 25% of the original dose.

Neuromuscular blocking agents: There is considerable variation in the potency of interaction of Succinylcholine & tubocurarine with Azathioprine.

Anticoagulants: Inhibits the effect of the anticoagulant of warfarin, when administered with azathioprine, has been reported.

Cytostatic/myelosuppressive agents: Where possible, concomitant administration of cytostatic drugs, or drugs which may have a myelosuppressive effect, such as penicillamine, should be avoided.

Methotrexate: When azathioprine is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.

Vaccines: The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines and azathioprine therapy is contraindicated on theoretical grounds. 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.

Ribavirin: Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore co-administration is not advised.

Other interactions: There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulphasalazine) inhibit the TPMT enzyme. Therefore, lower doses of azathioprine may need to be considered.

Hypersensitivity to azathioprine or to any of the excipients of this preparation. Hypersensitivity to 6-mercaptopurine should alert the prescriber to probable hypersensitivity to azathioprine.

For this product there is no modern clinical documentation that can be used as support for determining the frequency of undesirable effects

Infections and infestations: Very common: viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants

Neoplasms benign, malignant and unspecified (incl cysts and polyps): Rare: neoplasms including lymphoproliferative disorders, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ, acute myloid leukaemia and myelodysplasia

Blood and lymphatic system disorders: Very common: depression of bone marrow function; leucopenia. Common: thrombocytopenia

Immune system disorders:Uncommon: hypersensitivity reactions

Respiratory, thoracic and mediastinal disorders: Very rare

Gastrointestinal disorders: Common: nausea

Teratogenicity: Evidence of the teratogenicity of azathioprine in man is equivocal. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving azathioprine.

Mutagenicity: Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the offspring of patients treated with azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with azathioprine. Azathioprine and long-wave ultraviolet light have been shown to have a synergistic clastogenic effect in patients treated with azathioprine for a range of disorders

Fertility: The specific effect of azathioprine therapy on human fertility is unknown.

Pregnancy: Substantial transplacental and trans amniotic transmission of azathioprine and its metabolites from the mother to the fetus has been shown to occur. Pregnancy Category D. Azathioprine should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefits. Evidence of the teratogenicity of azathioprine in man is equivocal. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving azathioprine.

Women of childbearing potential/contraception in men and women: Due to the genotoxic potential of azathioprine, women of childbearing potential should use effective contraceptive measures while being treated with azathioprine and for one month following completion of treatment. Men are recommended to use effective contraceptive measures and to not father a child while receiving azathioprine and for three months following the completion of treatment.

Lactation: It is recommended that mothers receiving azathioprine should not breastfeed. 6-Mercaptopurine has been identified in the colostrum and breast milk of women receiving azathioprine treatment

Monitoring: There are potential hazards in the use of azathioprine. It should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of therapy. It is suggested that during the first 8 weeks of therapy, complete blood counts, including platelets, 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 first signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leucocytes and platelets may continue to fall after treatment is stopped. Patients receiving azathioprine 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 azathioprine is withdrawn early enough. There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also it has been reported that decreased TPMT activity increases the risk of secondary leukaemias and myelodysplasia in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics. 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 azathioprine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.

Hepatotoxicity: Azathioprine is hepatotoxic and liver function tests should be routinely monitored during treatment.

Renal and/or hepatic insufficiency: Caution is advised during the administration of azathioprine in patients with renal impairment and/or hepatic impairment.

Lesch-Nyhan syndrome: Mutagenicity: Chromosomal abnormalities have been demonstrated in both male and female patients treated with azathioprine.

Effects on fertility: Relief of chronic renal insufficiency by renal transplantation involving the administration of azathioprine has been accompanied by increased fertility in both male and female transplant recipients.

Carcinogenicity: Patients receiving immunosuppressive therapy, including azathioprine are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. Reports of hepatosplenic T-cell lymphoma have been received when azathioprine is used alone or in combination with anti-TNF agents or other immunosuppressants. Although most reported cases occurred in the IBD population, there have also been cases reported outside of this population.Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level.

Photosensitivity and risk of 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, to minimize the risk of skin cancer and photosensitivity

Varicella Zoster Virus Infection: Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised.

Progressive Multifocal Leukoencephalopathy (PML): PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving azathioprine with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first sign or symptoms suggestive of PML and appropriate evaluation undertaken to establish a diagnosis.

Hepatitis B: Hepatitis B carriers (defined as patients positive for hepatitis B surface antigen [HBsAg] for more than six 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.

Macrophage activation syndrome: Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of azathioprine.

Symptoms and signs: Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with azathioprine and result from bone marrow depression which may be maximal after 9 to 14 days. These signs are more likely to be manifest following chronic overdosage, rather than after a single acute overdose. There has been a report of a patient who ingested a single overdose of 7.5 g of azathioprine. The immediate toxic effects of this overdose were nausea, vomiting and diarrhoea, followed by mild leucopenia and mild abnormalities in liver function. Recovery was uneventful.

Treatment: As there is no specific antidote, blood counts should be closely monitored and general supportive measures instituted if necessary. Active measures (such as the use of activated charcoal) may not be effective in the event of azathioprine overdose unless the procedure can be undertaken within 60 minutes of ingestion. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. The value of dialysis in patients who have taken an overdose of azathioprine is not known, though azathioprine is partially dialysable.

Cytotoxic immunosuppressants

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