AZAMUN 50 mg Tablets
(and dosage form)
AZAMUN 50 mg Tablets
Each film-coated tablet contains 50 mg azathioprine.
A 26 Cytostatic agents.
AZAMUN is a purine antimetabolite and possesses immunosuppressive properties. It is a prodrug of 6-mercaptopurine.
Azathioprine is cleaved by nucleophiles such as glutathione, to 6-mercaptopurine, which in turn can be converted into 6-mercaptopurine nucleotides. These nucleotides lead to an inhibition of de novo purine synthesis.
AZAMUN is well absorbed by the gastro-intestinal tract. Mercaptopurine is metabolised either by methylation of the sulfhydryl group and subsequent oxidation of the methylated derivatives or by xanthine oxidase to 6-thiouric acid.
Azathioprine and its metabolites are excreted primarily in the urine.
AZAMUN is mainly used as an immunosuppressant in the management of patients receiving organ transplants. It is used in combination with corticosteroids and/or other immunosuppressive agents and procedures.
AZAMUN is used to treat diseases with an auto-immune component. In a proportion of patients suffering from severe rheumatoid arthritis, systemic lupus erythematosus, auto-immune active chronic hepatitis, pemphigus vulgaris, auto-immune haemolytic anaemia or idiopathic thrombocytopenic purpura, AZAMUN has a therapeutic effect when these conditions are:
(a) refractory to corticosteroids or,
(b) controlled by corticosteroids in dosages which are producing severe side effects.
The aim of azathioprine medication is to reduce the required maintenance dose of steroids and thus reducing adverse events. Therapeutic effect may be evident only after weeks or months.
Sensitivity to azathioprine. Sensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable sensitivity to AZAMUN.
AZAMUN can cause foetal harm when administered to pregnant women. AZAMUN should not be initiated during pregnancy. The fact that AZAMUN is potentially teratogenic must be considered when it is to be administered to males or females who may procreate while receiving therapy. There have been a few reports of congenital deformity when the father was receiving azathioprine at the time of conception.
Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid. Use during pregnancy is not recommended in patients being treated for auto-immune diseases.
Safety in lactation has not been established. Azathioprine and/or its metabolites have been found in low concentrations in colostrum and breast milk.
THE RISKS ASSOCIATED WITH AZAMUN THERAPY SHOULD BE CONSIDERED AGAINST THE SEVERITY OF THE PATIENT'S CONDITION AND THE EXPECTED BENEFICIAL CLINICAL EFFECT.
AZAMUN should not be prescribed unless the patient can be adequately monitored for toxic effects throughout the duration of the therapy.
The dosage of AZAMUN must be reduced for the treatment of active chronic hepatitis.
Azathioprine should be used with care in patients with renal or hepatic impairment. These patients may eliminate the drug and its metabolites at a reduced rate with a consequent cumulative effect. The dosage of AZAMUN should therefore be reduced in such cases, particularly in anuric patients.
The effects of AZAMUN are enhanced by allopurinol. The dose of azathioprine should be reduced to one-quarter of the usual dose when AZAMUN and allopurinol are given concomitantly.
DOSAGE AND DIRECTIONS FOR USE
Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.
Film-coated tablets should not be divided. Provided that the film-coat is intact, there is no risk in handling film-coated AZAMUN tablets.
Loading dose: Depending on the immunosuppressive regimen adopted, a loading dose of 1,0 to 5,0 mg/kg body-weight per day is usually given.
Maintenance dosage after transplantation: Usually 1,0 to 4,0 mg/kg body-weight per day after transplantation.
Corticosteroids are usually given concomitantly with AZAMUN in order to facilitate survival and function of the transplanted organ. It may be possible to slowly withdraw the steroids completely in some cases. Cessation of AZAMUN therapy, even after a period of years, carries a risk of rejection within a few weeks.
Dosage for the treatment of severe rheumatoid arthritis, systemic lupus erythematosus, auto-immune active chronic hepatitis, pemphigus vulgaris, auto-immune haemolytic anaemia, idiopathic thrombocytopenic purpura is usually 1,0 to 2,5 mg/kg body-weight per day, depending on patient response.
Dosage for the treatment of active chronic hepatitis is usually 1,0 to 2,0 mg/kg body-weight per day.
The dosage of AZAMUN and the duration of treatment may vary according to the condition, its severity and the clinical response obtained. A therapeutic response in auto-immune disease may not be evident for a few days or even weeks after initiation of AZAMUN therapy.
If no discernible improvement occurs in the patient's condition within three months, consideration should be given to the withdrawal of the drug.
Treatment is otherwise undertaken on a long-term basis unless the patient exhibits evidence of intolerance to azathioprine.
Use in the elderly
The dosage of AZAMUN in the elderly has not been established. It is recommended that the dosage used is at the lower end of the range given.
The maintenance dosage should be reduced to the minimum required for clinical response. Care should be taken to monitor haematological responses.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Bone Marrow Depression and Haematopoiesis
DURING THE FIRST EIGHT WEEKS OF AZAMUN THERAPY COMPLETE BLOOD COUNTS, INCLUDING PLATELET COUNTS MUST BE PERFORMED AT LEAST WEEKLY, OR MORE FREQUENTLY IF HIGH DOSAGE IS USED OR IF SEVERE RENAL AND/OR HEPATIC DISORDER IS PRESENT.
During the course of therapy, AZAMUN may have to be discontinued because of haematopoietic toxicity. The maximum effect of AZAMUN on the white cell count usually becomes manifest within the first two weeks of initiating treatment, but thereafter the risk of complications gradually declines as the duration of therapy increases.
The commonest complication is leucopenia which may be accompanied by thrombocytopenia.
Thrombocytopenia alone, anaemia, pancytopenia and bleeding have also been reported.
It is essential that blood counts be taken monthly throughout the period of therapy. If AZAMUN is used in conjunction with or soon after withdrawal of another drug known to have a depressive effect on the bone marrow, it is particularly important that frequent blood counts be taken.
Since this drug may have a delayed action, it is important to reduce dosage or withdraw the medication temporarily at the first sign of an abnormally large fall in leucocyte count and/or other evidence of persistent depression of the bone marrow. Such bone marrow depression is usually reversible at the doses recommended for auto-immune disease.
The effect on white cell count is not closely correlated with the immunosuppressive effect of AZAMUN; a good immunosuppressive effect can often be obtained without change in the white cell count, but sometimes the count may be greatly reduced without any apparent immunosuppression.
Therapeutic use of AZAMUN is associated with reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content. Megaloblastic bone marrow changes have been observed and severe megaloblastic anaemia and erythroid hypoplasia have occurred occasionally.
Failure to reduce the dosage of AZAMUN in the presence of allopurinol can result in severe bone marrow depression (see Warnings and Interactions).
AZAMUN has an immunosuppressant effect involving both antibody and cell mediated immunity. Infection, which is always a hazard of immunosuppressive therapy, particularly when corticosteroids are given, may require the dosage of immunosuppressive agents to be reduced temporarily.
Fungal, protozoal, viral and uncommon bacterial infections in patients on immunosuppressive therapy have occurred and should be treated vigorously. Some of these have proved fatal.
Patients receiving AZAMUN should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression.
Reversible alopecia, rashes, muscle and joint pains, fever, rigors, pneumonitis, pancreatitis, meningitis, arrhythmias, renal dysfunction, and hypotension may occur, some or all of which may represent hypersensitivity reactions.
Pruritus and erythema, often of an area previously irradiated, may occur. Anaphylaxis may occur. Headache, malaise, weakness, dizziness, vomiting, arthralgia, disturbed liver functions and cholestatic jaundice have also been reported.
It has been suggested that the imidazole side chain gives rise to sensitivity, whereas the 6-mercaptopurine (6-MP) molecule gives rise to cholestasis.
Consideration must be given to withholding AZAMUN if there is evidence of toxic hepatitis or biliary stasis. Elevated serum bilirubin levels have been observed in some patients after initiation of azathioprine therapy.
AZAMUN therapy may have to be adjusted if anorexia, nausea, vomiting or diarrhoea occur. Stomatitis, mouth ulceration, oesophagitis, abdominal pain, intestinal haemorrhage, ulceration and perforation have been reported.
Persistent negative nitrogen balance has been observed in some patients on continuous azathioprine and corticosteroid therapy. If this occurs, the dosage should be reduced. Other reported complications include drug fever, serum sickness, pulmonary oedema, reversible pneumonitis, peritoneal haemorrhage, retinopathy, alopecia, arthralgia, and Raynaud's phenomenon.
Hyperuricaemia and acute renal failure due to uric acid nephropathy and hyperphosphataemia may occur. Pigmentation of the skin and nails may also occur.
Chromosomal abnormalities, which can occur independently of the influence of AZAMUN, have been demonstrated in both male and female transplant recipients.
Chromosomal abnormalities, which disappear in time, have been demonstrated in offspring of transplant recipients.
Azathioprine has long term effects on the gonads and may suppress ovarian and testicular function with amenorrhoea and inhibition of spermatogenesis.
Immunosuppression and Cancer
Some homograft recipients, whose immune responses have been suppressed, appear to be vulnerable to neoplasia either in the transplanted organ or at some other unrelated site, during the first few weeks or months after transplantation. This is a recognised hazard after transplantation and it could conceivably occur also when immunosuppressive therapy is used in the treatment of auto-immune disease.
Allopurinol, oxipurinol and 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. The dose of 6-mercaptopurine (6-MP) or AZAMUN should be reduced to one-quarter of the usual dose when allopurinol, oxipurinol and/or thiopurinol are given concomitantly.
Neuromuscular blockade: AZAMUN 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 drugs/drugs with myelosuppressive effects: Where possible, concomitant or recent administration of cytostatic drugs, or drugs which may have a myelosuppressive effect, such as penicillamine, should be avoided.
Furosemide: Furosemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown.
Cimetidine: It has been suggested that cimetidine may have myelosuppresive effects, which may be enhanced by the concomitant administration of AZAMUN.
Leukocyte production: Medicines which may affect leukocyte production, including cotrimoxazole, may lead to exaggerated leucopenia, especially in renal transplant recipients.
Angiotensin converting enzyme inhibitors: The use of angiotensin converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce severe leucopenia.
Warfarin: Mercaptopurine decreases warfarin activity and severe bleeding occurred in a patient on long-term warfarin treatment after discontinuation of azathioprine.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdose with AZAMUN and result from bone marrow depression, which may be maximal after 9 - 14 days. These signs are more likely to be manifest following chronic overdosage, rather than after a single acute overdose.
Treatment is symptomatic and supportive.
A light yellow, film-coated, circular, biconvex tablet. Engraved AZA breakline 50 on one side and plain on the other side.
AZAMUN 50 mg tablets are provided in clear transparent PVC/PVDC/Aluminium blister packs containing 100 tablets.
Store below 25°C. Protect from light and moisture. Keep blisters in outer carton until required for use.
KEEP OUT OF REACH OF CHILDREN.
NAME AND BUSINESS ADDRESS OF APPLICANT
Pharmaplan (Pty) Ltd
106 16 thRoad
DATE OF PUBLICATION OF THIS PACKAGE INSERT
3 February 2003
Version: 11 February 2003
Updated on this site: May 2014
Source: Pharmaceutical Industry
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