Azathioprine. Chemical Name: 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. Structural Formula: Molecular Formula: C9H7N7O2S Molecular Weight: 277.3 CAS Registry Number: 446-86-6
A pale yellow powder which is stable under ordinary conditions. It is practically insoluble in water, in ethanol (96%), and in chloroform and is sparingly soluble in dilute mineral acids. It dissolves in dilute solutions of alkali hydroxides.
Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). Azathioprine is used for the suppression of the immune system.
Azathioprine is rapidly broken down in vivo into 6-MP and a methylnitroimidazole 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. The determination of azathioprine or 6-MP plasma concentrations has no prognostic value as regards effectiveness or toxicity of these compounds. While the precise mode of action remains to be elucidated, some suggested mechanisms include: The release of 6-MP which acts as a purine anti-metabolite; The possible blockade of -SH groups by alkylation; The inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of immune response; Damage to deoxyribonucleic acid (DNA) through incorporation of purine thioanalogues. Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment. Azathioprine is well absorbed from the gastrointestinal tract after oral administration. Studies in mice with 35S-azathioprine showed no unusually large concentration in any particular tissue although concentrations of 35S-azathioprine are very low in the brain.
Azathioprine is used as an immunosuppressant anti-metabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effects 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. Azathioprine, in combination with corticosteroids and/or other immunosuppressive agents and procedures, is indicated in the management of patients receiving organ transplants. Azathioprine, either alone or more usually in combination with corticosteroids and/or other procedures, has been used with clinical benefit which may include reduction of dosage or discontinuation of corticosteroids, in a proportion of patients suffering from the following:
severe rheumatoid arthritis;
systemic lupus erythematosus;
dermatomyositis / polymyositis;
autoimmune chronic active hepatitis;
pemphigus vulgaris;
polyarteritis nodosa;
autoimmune haemolytic anaemia;
chronic refractory idiopathic thrombocytopenic purpura.
The use of GenRx Azathioprine is contraindicated in patients with a previous history of hypersensitivity to azathioprine, or any of the excipients in this product (listed previously). Patients with hypersensitivity to 6- mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to azathioprine. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan or others) may have a prohibitive risk of neoplasia if treated with azathioprine. Therapy with GenRx Azathioprine should not be initiated in patients who may be pregnant, who are likely to become pregnant in the near future, or who are known to be pregnant (see PRECAUTIONS).
There are potential hazards associated with the use of azathioprine. Azathioprine should be prescribed only if the patient can be adequately monitored for toxic effects throughout the entire duration of treatment. During the first eight weeks of therapy, complete blood counts, including platelets, must be performed weekly or more frequently if high dosage is used or if a co-existent severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is recommended that complete blood counts be repeated at intervals of not longer than one month or more frequently if dosage alterations or other changes to therapy are made. Delayed haematological suppression may occur. A prompt reduction in dosage or the temporary withdrawal of the drug may be necessary if there is a rapid fall in, or a persistently low, leucocyte count or other evidence of bone marrow suppression. Patients receiving azathioprine should be instructed to report immediately if there is any evidence of infection, unexpected bruising or bleeding, black tarry stools and blood in the urine or stools, or other manifestations of bone marrow depression. 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 initial treatment with GenRx Azathioprine. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see ADVERSE EFFECTS). 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.
It is impossible to relate plasma levels of azathioprine or 6-mercaptopurine to therapeutic efficacy or toxicity. The conversion of 6-thioinosinic acid to 6-thiouric acid by xanthine oxidase is not dependent on intact hepatic and/or renal function. Nevertheless, it is recommended that the dosages used are at the lower end of the normal range and that haematological response is carefully monitored. Dosage should be further reduced if haematological toxicity occurs. Caution is necessary during the administration of azathioprine to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of azathioprine may be impaired, and the dosage of azathioprine should therefore be reduced to the lower end of the recommended range. Dosage should be further reduced if hepatic or haematological toxicity occurs. Limited evidence suggests that GenRx Azathioprine 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 GenRx Azathioprine. Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of azathioprine or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.
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 prescriber 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 immunisation 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.
The decision to maintain or discontinue azathioprine treatment during pregnancy, or to terminate the pregnancy, depends on the condition being treated, in which maternal wellbeing has to be weighed against the possible risks to the foetus. As a general rule therapy with azathioprine should not be initiated in patients known to be pregnant. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving azathioprine. There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure. Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid after the maternal administration of azathioprine. The rare possibility of neonatal leucopenia and/or thrombocytopenia which may not be clinically evident appears to be preventable by the reduction of maternal dose of azathioprine if, at 32 weeks' gestation, the maternal leucocyte count is at or below 8.6 x 109/L. The possibility of neonatal immunosuppression is a serious and potentially fatal complication. Extra care in haematological monitoring is advised during pregnancy. Relief of chronic progressive renal failure by renal transplantation involving the use of azathioprine has been accompanied by increased fertility in both male and female transplant recipients.
Category D:
Drugs which have caused, are suspected to have caused or may be expected to cause,
an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
6-Mercaptopurine has been identified in the colostrum and breast-milk of the women receiving azathioprine treatment. Nursing mothers should be advised to consult their physician, since use by nursing mothers is not recommended because of possible adverse effects on the infant.
The rapid in vivo cleavage of the azathioprine molecule followed by tissue fixation makes it impossible to relate plasma levels to drug toxicity. There are no specific data as to the tolerance of azathioprine in elderly patient. It is recommended that the dosages used be at the lower end of the range given for adults and children. Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
Carcinogenicity (see ADVERSE EFFECTS)
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. 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 and photosensitivity, exposure to sunlight and UV light should be limited and patients should wear protective clothing and use a sunscreen with a high protection factor. Renal transplant recipients in some geographical areas are at greater risk of skin cancers than those in other areas. Other neoplasms reportedly associated with azathioprine include carcinoma of the urinary bladder and adenocarcinoma of the lung.
Chromosomal abnormalities, which may occur independently of the influence of azathioprine, have been demonstrated in both male and female transplant recipients. Chromosomal abnormalities, which disappear in time, have been demonstrated in offspring of transplant recipients. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in these offspring. 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.
Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 mg/kg bodyweight/day over the period of organogenesis have shown varying degrees of foetal abnormalities. Teratogenicity was evident in rabbits at 10 mg/kg bodyweight/day. Epidemiological evidence in humans indicates that the frequency of occurrence of congenital abnormalities in the offspring of maternal transplant recipients is similar to that in the general population, but the issue remains unresolved.. As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving GenRx Azathioprine.
Allopurinol / Oxypurinol / Thiopurinol
Xanthine oxidase is inhibited by allopurinol, oxypurinol and thiopurinol, which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxypurinol and/or thiopurinol are given concomitantly with 6-mercaptopurine (6-MP) or azathioprine, the dose of 6-MP and azathioprine should be reduced to one-quarter of the original dose.
Neuromuscular Blocking Agents
Azathioprine can potentiate the neuromuscular blockade produced by depolarising agents such as succinylcholine and reduce the blockade produced by non-depolarising agents such as tubocurarine.
Cytostatic / Myelosuppressive Agents
Azathioprine should be used with caution in patients receiving, or who have recently received, other bone marrow suppressive agents. Where possible, concomitant administration of cytostatic drugs, or drugs which may have a myelosuppressive effect, such as penicillamine, should be avoided. There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and co- trimoxazole. It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of azathioprine.
W arfarin
Inhibition of the anticoagulant effect of warfarin, when administered with azathioprine, has been reported.
Aminosalicylates
As there is in vitro evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent azathioprine therapy (see PRECAUTIONS).
Vaccines
The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines and so the administration of live vaccines to patients receiving 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.
Miscellaneous
Frusemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown. Drugs known to either induce (phenytoin, phenobarbital, rifampicin) or inhibit (ketoconazole, erythromycin) hepatic microsomal enzymes may alter the hepatic clearance of azathioprine. Co-administration of azathioprine and captopril may result in increased susceptibility to leucopenia.
Azathioprine should be used with caution in hypersplenism. The withdrawal of azathioprine should be gradual and performed under close supervision. Dental work, whenever possible, should be completed prior to initiation of azathioprine therapy or deferred until blood counts are normal.
Hypersensitivity Reactions
Several different clinical syndromes, which appear to be of an idiosyncratic hypersensitivity nature, have been described occasionally. They include general malaise, headache, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, vasculitis, myalgia, muscular pain, arthralgia, hypotension, disturbed liver function, cholestatic jaundice, pancreatitis, cardiac dysrhythmia and renal dysfunction. In many cases, rechallenge has confirmed an association with azathioprine. Additional adverse reactions of low frequency have been reported. These include skin rashes (approximately 2%), steatorrhoea, negative nitrogen balance, Stevens-Johnson syndrome and toxic epidermal necrolysis (all less than 1%). It has been suggested that the imidazole side chain gives rise to hypersensitivity, whereas the 6-mercaptopurine (6-MP) molecule gives rise to cholestasis. Immediate withdrawal of azathioprine and initiation of supportive circulatory measures have led to recovery in the majority of cases. Other marked underlying pathology has contributed to the very rare deaths reported. Azathioprine use should be PERMANENTLY withdrawn after any such clinical syndrome.
Neoplasms Benign and Malignant (including Cysts and Polyps)
The 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, 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 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 leukaemia and myelodysplasia (some in association with chromosomal abnormalities).
Haematopoiesis
Azathioprine may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leucopenia, but also sometimes as anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anaemia. These occur particularly in patients predisposed to myelotoxicity, such as those with TPMT deficiency and renal or hepatic insufficiency and in patients failing to reduce the dose of azathioprine when receiving concurrent allopurinol therapy. The therapeutic use of azathioprine is associated with reversible, dose-related reduction in numbers of circulating total white cells, granulocytes and lymphocytes together with increases in mean corpuscular volume and red cell haemoglobin content. Megaloblastic bone marrow changes have been observed, but severe megaloblastic anaemia and erythroid hypoplasia are rare. Azathioprine may produce thrombocytopenia that is dose-related and may be delayed.
Alopecia
Hair loss has been described in 50% of renal transplant recipients receiving azathioprine and corticosteroids, but does not appear to be a major problem when azathioprine is used for other indications. It is reversible in over 80% of cases despite continuing immunosuppression.
Susceptibility to Infection
Patients receiving azathioprine alone or in combination with other immunosuppressants, particularly corticosteroids have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection with varicella, herpes zoster and other infectious agents (see PRECAUTIONS). Viral, fungal and bacterial infections are very common in transplant patients receiving azathioprine in combination with other immunosuppressants.
Gastrointestinal Reactions
Nausea, vomiting and gastrointestinal discomfort may occur during the first few months of therapy with azathioprine. These effects may be minimised by dosage adjustment, by administering the tablets in divided doses and/or after food. Serious complications, including colitis, diverticulitis and bowel perforation, have been described in transplant recipients and appear to relate to high dosage of corticosteroids rather than to azathioprine per se. Severe diarrhoea, recurring on rechallenge, has been reported in patients treated with azathioprine 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 azathioprine 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 one particular drug, although rechallenge has confirmed an association with azathioprine on occasions. Cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see ADVERSE EFFECTS, Hypersensitivity Reactions).
Pulmonary Reactions
Reversible pneumonitis has been described very rarely.
Hepatotoxicity
Hepatotoxicity may manifest by the elevation of serum alkaline phosphatase, bilirubin and/or serum transaminases and is generally reversible after interruption of azathioprine. The periodic measurement of serum transaminases, alkaline phosphatase and bilirubin is indicated for the early detection of hepatotoxicity. Hepatotoxicity has been uncommon (less than1%) in patients with rheumatoid arthritis. Rare, but life threatening hepatic damage associated with chronic administration of azathioprine has been described, primarily in transplant patients. Histological findings include sinusoidal dilation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. In some cases withdrawal of azathioprine has resulted in either a temporary or permanent improvement in liver histology and symptoms. Azathioprine should be permanently withdrawn in patients with hepatic veno-occlusive disease.
Other
Other adverse reactions include sores in the mouth and on the lips, meningitis, formication, exacerbation of myasthenia gravis and dermatomyositis and alterations in the senses of smell and taste.
GenRx Azathioprine tablets are intended for oral administration only. Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.
Depending on the immunosuppressive regimen adopted, a loading dose of up to 5 mg/kg bodyweight/day may be given orally on the first day of therapy. The maintenance dosage should range from 1 to 4 mg/kg/day orally, 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.
In general, the starting dose is from 1 mg/kg/day, gradually increasing in increments of 0.5 mg/kg/day over several weeks, if necessary up to a maximum of 2.5 mg/kg/day. 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 azathioprine. The maintenance dosage required may range from less than 1 mg/kg bodyweight/day, to 3 mg/kg bodyweight/day depending on the clinical condition being treated and the individual patient response, including haematological tolerance.
The rapid in vivo cleavage of the azathioprine molecule followed by tissue fixation makes it impossible to relate plasma levels to drug toxicity. There are no specific data as to the tolerance of azathioprine in elderly patient. It is recommended that the dosages used be at the lower end of the range given for adults and children. Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
The oral LD50 for single doses of azathioprine in mice and rats is 2500 mg/kg and 400 mg/kg respectively.
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. Occasional reports describe ingestion of azathioprine from 0.5 to 7.5 g on a single occasion with apparent uneventful recovery.
Treatment is symptomatic and has included gastric lavage. If overdosage occurs the blood picture and hepatic function in particular should be monitored. Azathioprine is dialysable but the procedure is of doubtful value since azathioprine is rapidly metabolised with entry of metabolites into tissue cells.
Blister packs of 100 tablets. Pale yellow, round, film-coated, biconvex, tablets engraved with "AZA", breakline & "50" on one face. The other face is plain. AUST R number 80923 GenRx Azathioprine 50 mg tablets are intended for oral administration. Each tablet contains 50 mg of azathioprine, as the active ingredient. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, mannitol, maize starch, povidone, croscarmellose sodium, and sodium stearylfumarate in the tablet core. The 50 mg tablet coating contains Opadry(tm) Clear OY-7240 (macrogol 400 and hypromellose). Store below 30degC. Protect from light and moisture.
Azathioprine tablets should not be divided, crushed or broken. Provided that the film coating is intact, there is no risk in handling film coated tablets.
Apotex Pty Ltd 16 Giffnock Avenue Macquarie Park NSW 2113 Australia GenRx is a registered trade mark of Apotex Pty Ltd.
S4 - Prescription Only Medicine.
12 November 2001