Aspen Pharmacare


DCH Auriga
Full Prescribing Info
Each tablet contains 50 mg of the active ingredient azathioprine.
Pharmacology: Pharmacodynamics: Mechanism of Action: IMURAN is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and 1-methyl-4-nitro-5-thiomidazole. 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. IMURAN has an effect on both immunological reaction and tumour growth. Its major role has been as an agent for suppressing the immune response, and although the precise mechanism by which this effect is achieved is not known, the following mechanisms of action have been suggested: The action of the released 6-MP as a purine antimetabolite.
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 the immune response.
Damage to deoxyribonucleic acid (DNA) through incorporation of purine thioanalogues.
Because of these mechanisms, the therapeutic effect of IMURAN may be evident only after several weeks or months of treatment.
The activity of the methylnitroimidazole moiety, a metabolite of IMURAN 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 IMURAN, 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 the presence of xanthine oxidase (30% degradation within 30 minutes) (see Metabolism as follows). Azathioprine should be administered at least 1 hour before or 3 hours after food or milk (see Dosage & Administration).
Distribution: The volume of distribution at steady state (Vdss) of azathioprine is unknown. The mean (± SD) apparent Vdss 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).
Concentrations 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 into 6-MP by glutathione-S-transferase 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 one enzyme predominating. Because of the complex metabolism, inhibition of one enzyme does not explain all cases of lack of efficacy and/or pronounced myelosuppression. The predominant enzymes responsible for the metabolism of 6-MP or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT) (see Monitoring and Interactions: Aminosalicylates under Precautions), xanthine oxidase (see previously mentioned text under Absorption and Allopurinol/oxipurinol/thiopurinol under Interactions), inosine monophosphate dehydrogenase (IMPDH) (see Ribavirin under Interactions), and hypoxanthine guanine phosphoribosyltransferase (HPGRT). Additional enzymes involved in the formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which form 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 Methyl Transferase (TPMT): TPMT activity is inversely related to red blood cell 6-MP derived Elimination 7329166-8726 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.
It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT*2, TPMT*3A and TPMT*3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one nonfunctional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT testing cannot substitute for complete blood count (CBC) monitoring in patients receiving IMURAN (see Precautions).
Elimination: After oral administration of 100mg 35S-azathioprine, 50% of the radioactivity was excreted in the urine and 12% in the faeces after 24 hours. In the urine, the major compound was the inactive oxidised 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 greater than 3L/min in normal volunteers. There are no data on the renal clearance or half-life of azathioprine. The renal clearance of 6-MP and the half-life 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 (aged 3 to 14 years) were evenly divided into two groups; either a weight to height ratio above or below the 75th 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 75th percentile was 2.4 times lower than that for the group below the 75th 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, dosages should be given at the lower end of the normal range in patients with impaired renal function (see Dosage & Administration).
Azathioprine and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hours.
Hepatic impairment A study with azathioprine was performed in three 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-mercaptopurine 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, dosages should be given at the lower end of the normal range in patients with impaired hepatic function (see Dosage & Administration).
Toxicology: Pre-clinical Safety Data: Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5 to 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.
IMURAN is used 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, such as renal transplants, cardiac transplants and hepatic transplants. It also reduces the corticosteroid requirements of renal transplant recipients.
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 the following: severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, auto-immune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, auto-immune haemolytic anaemia, chronic refractory idiopathic thrombocytopenic purpura.
Dosage/Direction for Use
IMURAN tablets should be administered at least 1 hour before or 3 hours after food or milk (see Pharmacology: Pharmacokinetics: Absorption under Actions).
Adults: Transplants: Depending on the immunosuppressive regimen employed, a dosage of up to 5 mg/kg bodyweight/day may be given orally or intravenously on the first day of therapy.
Maintenance dosage should range from 1 to 4 mg/kg bodyweight/day and must be adjusted according to clinical requirements and haematological tolerance.
Evidence indicates that IMURAN therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.
Other Indications: In general, starting dosage is from 1 to 3 mg/kg bodyweight/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 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 IMURAN. 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.
Children: 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 (see Pharmacology: Pharmacokinetics: Special Patient Populations: Overweight children under Actions).
Transplants And Other Indications: See previously mentioned text under Adults.
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 recommended that the dosages used should be at the lower end of the range.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
Renal impairment: In patients with renal insufficiency, dosages should be given at the lower end of the normal range (see Precautions and Pharmacology: Pharmacokinetics: Special Patient Populations: Renal impairment under Actions).
Hepatic impairment: In patients with hepatic insufficiency, dosages should be given at the lower end of the normal range (see Precautions and Pharmacology: Pharmacokinetics: Special Patient Populations: Hepatic Impairment under Actions).
Drug interactions: The principal pathway for detoxification of IMURAN is inhibited by allopurinol. In patients receiving IMURAN, the concomitant administration of allopurinol will require a reduction in dose to approximately 1/3 to 1/4 of the usual dose of IMURAN. Subsequent adjustment of doses of IMURAN should be made on the basis of therapeutic response and any toxic effects (see Interactions).
TPMT-deficient patients: Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe IMURAN toxicity from conventional doses of IMURAN and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see Monitoring under Precautions and Pharmacology: Pharmacokinetics under Actions).
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 Monitoring under Precautions and Pharmacology: Pharmacokinetics under Actions).
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 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 IMURAN. 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.
As 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 (such as the use of activated charcoal) may not be effective in the event of IMURAN overdose unless the procedure can be undertaken within 60 minutes of ingestion. Gastric lavage has been used. Subsequent monitoring, including haematological monitoring, is necessary to allow prompt treatment of any adverse effects which may develop. 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 IMURAN is not known, though IMURAN is partially dialysable.
IMURAN is contraindicated in patients known to be hypersensitive to azathioprine or any other component of the preparation.
Hypersensitivity to 6 mercaptopurine should alert the prescriber to probable hypersensitivity to IMURAN.
Special Precautions
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended (see Interactions).
Co-administration of ribavirin and IMURAN is 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 haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
It is suggested that during the first eight 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 three 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 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 pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue IMURAN immediately if jaundice becomes apparent.
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (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 coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. 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 IMURAN) 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 need to 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: It is impossible to relate plasma levels of IMURAN or 6-mercaptopurine to therapeutic efficacy or toxicity. Conversion of 6-thioinosinic acid to 6-thiouric acid by xanthine oxidase is not dependent on intact hepatic and/ or renal function (see Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations under Actions).
Nevertheless, it is recommended that the dosages used should be at the lower end of the normal range and that haematological response should be carefully monitored. Dosage should be further reduced if haematological toxicity occurs. Caution is necessary during the administration of IMURAN to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of IMURAN may be impaired, and the dosage of IMURAN should therefore be reduced to the lower end of the recommended range. Dosage should be further reduced if hepatic or haematological toxicity occurs.
Lesch-Nyhan syndrome:
Limited evidence suggests that IMURAN is not beneficial to patients with hypoxanthine-guaninephosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive IMURAN.
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 off-spring 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 light (UV) have been shown to have a synergistic clastogenic effect in patients treated with IMURAN for a range of disorders.
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 have been received when IMURAN is used alone or in combination with anti-TNF agents or other immunosuppressants. Although most reported cases occurred in the IBD population (un-licensed indication), 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. 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.
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 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.
Progressive Multifocal Leukoencephalopathy (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 first sign or symptoms 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 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.
Effects on Ability to Drive and Use Machines: 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 the drug.
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 foetus have been 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 the 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.
Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took IMURAN throughout their pregnancies. Extra care in haematological 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.
Adverse Reactions
For IMURAN, there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication. The following convention has been utilised for the classification of frequency: Very common ≥1/10; common ≥1/100, <1/10; uncommon ≥1/1000 and <1/100; rare ≥1/10,000 and <1/100 ; 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. Reactivation of varicella zoster virus, hepatitis B and other infectious agents are also uncommon. (See Precautions).
Very rare: cases of JC virus associated PML have been reported following the use of azathioprine in combination with other immunosuppressants (see Precautions).
Neoplasms benign and malignant (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 leukaemia and myelodysplasia (see Precautions).
The risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and nonmelanoma), 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 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 leukaemia and myelodysplasia (some in association with chromosomal abnormalities).
Very rare: Hepatosplenic T-cell lymphoma (see Precautions).
Blood and lymphatic system disorders: Very common: depression of bone marrow function; leucopenia. Common: thrombocytopenia. Uncommon: anaemia. Rare: agranulocytosis, pancytopenia, aplastic anaemia, megaloblastic anaemia, erythroid hypoplasia.
IMURAN 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 IMURAN when receiving concurrent allopurinol therapy. Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with IMURAN therapy.
Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia 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, diarrhoea, fever, rigors, exanthema, rash, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and cholestasis (see Hepato biliary disorders as follows).
In many cases, rechallenge has confirmed an association with IMURAN.
Immediate withdrawal of IMURAN and institution 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 IMURAN, the necessity for continued administration of IMURAN should be carefully considered on an individual basis.
Respiratory, thoracic and mediastinal disorders: Very rare: reversible pneumonitis.
Gastrointestinal disorders: Common: nausea (with IMURAN tablets only). Uncommon: pancreatitis. Very rare: colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population (un-licensed indication).
A minority of patients experience nausea when first given oral IMURAN. 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 aetiology is not clearly established and high-dose corticosteroids may be implicated. Severe diarrhoea, recurring on rechallenge, has been reported in patients treated with IMURAN for inflammatory bowel disease (un-licensed indication). The possibility that exacerbation of symptoms might be drugrelated 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 (un-licensed indication). There are difficulties in relating the pancreatitis to the administration of one particular drug, although rechallenge has confirmed an association with IMURAN on occasions.
Hepato-biliary 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 under Adverse Reactions).
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.
Drug Interactions
Vaccines: The immunosuppressive activity of IMURAN could result in an atypical and potentially deleterious response to live vaccines and so 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 IMURAN 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.
Effect of concomitant drugs on 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 Precautions and Pharmacology: Pharmacokinetics: Metabolism under Actions).
Cytostatic/myelosuppressive agents (see Precautions): 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 IMURAN and co-trimoxazole.
There have been case reports suggesting that haematological abnormalities may develop due to the concomitant administration of IMURAN and ACE Inhibitors. 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-mercaptopurine or IMURAN, the dose of 6-mercaptopurine and IMURAN should be reduced to 25% of the original dose (see Drug Interactions under Dosage & Administration).
Aminosalicylates: 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 IMURAN may need to be considered when administered concomitantly with aminosalicylate derivatives (see Precautions).
Methotrexate: Methotrexate (20 mg/m2 orally) increased 6-mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased 6-mercaptopurine 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.
Effect 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.
Caution For Usage
Instructions for Use/Handling: Safe handling: Health professionals who handle uncoated IMURAN 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.
Incompatibilities: None reported for IMURAN tablets.
Store below 25°C.
Protect from light.
ATC Classification
L04AX01 - azathioprine ; Belongs to the class of other immunosuppressants.
FC tab 50 mg x 100's.
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