INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ZAPRINE 50 (film coated tablets)

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

ZAPRINE 50 (film coated tablets)

COMPOSITION:
ZAPRINE 50 mg tablets: Each tablet contains 50 mg
azathioprine.

PHARMACOLOGICAL CLASSIFICATION:
A26 Cytostatic agents

PHARMACOLOGICAL ACTION:
Azathioprine is a derivative of mercaptopurine and is an antimetabolite of the purine class possessing immunosuppressive properties.
Azathioprine is well absorbed by the gastro intestinal tract. The prodrug azathioprine is cleaved by nucleophiles such as glutathione, to mercaptopurine, which is subsequently converted into mercaptopurine - containing nucleotides. Mercaptopurine is metabolised by either methylation of the sulfhydryl group and subsequent oxidation of the methylated derivatives or by xanthine oxidase to 6 thiouric acid.

INDICATIONS
Transplantation:
Azathioprine, in combination with corticosteroids and/or other immunosuppressive agents and procedures, is indicated in the management of patients receiving organ transplants.
Auto immune Diseases:
Azathioprine has a therapeutic effect in a proportion of patients suffering from:
severe rheumatoid arthritis, systemic lupus erythematosus, auto-immune active chronic hepatitis, pemphigus vulgaris, auto-immune haemolytic anaemia, idiopathic thrombocytopenic purpura, 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. Therapeutic effect may be evident only after weeks or months.

CONTRA-INDICATIONS:
Hypersensitivity to azathioprine. Hypersensitivity to 6 mercaptopurine (6 MP) should alert the prescriber to probable hypersensitivity to azathioprine.
Azathioprine can cause harm to the foetus when administered to pregnant women. Azathioprine should not be initiated during pregnancy. The fact that azathioprine is potentially teratogenic must be considered when it is 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.

WARNINGS
THE RISKS ASSOCIATED WITH AZATHIOPRINE THERAPY SHOULD BE CONSIDERED AGAINST THE SEVERITY OF THE PATIENTS CONDITION AND THE EXPECTED BENEFICIAL CLINICAL EFFECT.
Azathioprine should not be prescribed unless adequate monitoring of the patient for toxic effects throughout the duration of the therapy is possible.
The dosage of azathioprine must be reduced for the treatment of active chronic hepatitis.
Patients with impaired renal and/or hepatic function may eliminate the medicine and its metabolites at a reduced rate with a consequent cumulative effect.
The dosage of azathioprine should therefore be reduced in such cases, particulary in anuric patients.
When azathioprine and allopurinol are given concomitantly, only one quarter of the usual dosage of azathioprine should be given.

DOSAGE AND DIRECTIONS FOR USE:
Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.
Azathioprine tablets are given by mouth.
Film-coated tablets should not be divided. Provided that the film-coat is intact, there is no risk in handling film-coated azathioprine tablets.
Transplantation:
Depending on the immunosuppressive regimen adopted, a loading dose of 1,0 to 5,0 mg/kg body mass/day is usually given.
Maintenance dosage after transplantation is usually 1,0 to 4,0 mg/kg body mass per day after transplantation.
Corticosteroids are usually given concomitantly with azathioprine 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 azathioprine therapy, even after a period of years, carries a risk of rejection within a few weeks.
Auto-immune Diseases:
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 mass per day, depending on patient response. Dosage for the treatment of active chronic hepatitis is usually 1,0 to 2,0 mg/kg body mass per day.
Directions:
The dosage of azathioprine as well as 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 azathioprine therapy. If no discernible improvement occurs in the patient’s condition within three months, consideration should be given to the withdrawl 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 azathioprine in the elderly has not been established. It is recommended that the dosages used are at the lower end of the range given.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Bone Marrow Depression and haematopoiesis
DURING THE FIRST EIGHT WEEKS OF AZATHIOPRINE 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, azathioprine may have to be discontinued because of haematopoietic toxicity. The maximum effect of azathioprine on the white cell count usually becomes evident within the first two weeks of initiating treatment, but thereafter the risk of complications gradually declines as the duration of therapy increases. The most common 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 at monthly intervals throughout the period of therapy. If azathioprine is used in conjunction with or soon after withdrawl 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 medicine 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 immunosuppresive effect of azathioprine; 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 azathioprine 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 azathioprine in the presence of allopurinol can result in severe bone marrow depression. (see Warnings and Interactions).
Infection:
Azathioprine 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 azathioprine should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression.
Sensitivity reactions:
Allergic reactions including skin rashes, pruritus and erythema, often of an area previously irradiated, may occur. Anaphylaxis may occur. Headache, hypotension, cardiac dysrrhythmia, malaise, weakness, dizziness, vomiting, fever, rigours, muscular pains, arthralgia, disturbed liver function tests, cholestatic jaundice and pancreatitis have been reported. In many cases, re-challenge has confirmed an association with azathioprine.
It has been suggested that the imidazole side-chain gives rise to sensitivity, whereas the 6-mercaptopurine (6-MP) molecule gives rise to cholestasis.
Liver toxicity:
If there is evidence of toxic hepatitis or biliary stasis, consideration must be given to withholding azathioprine. Elevated serum bilirubin levels have been observed in some patients after initiation of azathioprine therapy.
Gastro-intestinal Intolerance
Azathioprine may cause anorexia, nausea, vomiting or diarrhoea. In such cases azathioprine therapy may have to be adjusted.
Stomatitis, mouth ulceration, oesophagitis, abdominal pain, intestinal haemorrhage, ulceration and perforation may occur.
Other:
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.
Azathioprine has vesicant or irritant effects on the skin and mucous membranes and intravenous injections may cause thrombophlebitis.
Hyperuricaemia and acute renal failure due to uric acid nephropathy, hyperphosphataemia and pigmentation of the skin and nails may occur.
Mutagenicity:
Chromosomal abnormalities, which can 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.
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.
INTERACTIONS:
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 (6-MP) or azathioprine, the dose of 6 MP and azathioprine should be reduced to one quarter of the original dose.
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.
Where possible, concomitant or recent administration of cytostatic agents, or medicines which may have a myelosuppressive effect, such as penicillamine, should be avoided. Furosemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown.
It has been suggested that cimetidine may have myelosuppressive effects which may be enhanced by the concomitant administration of azathioprine.
Medicines which may affect leucocyte production, including co-trimoxazole, may lead to exaggerated leucopenia, especially in renal transplant recipients.
The use of angiotensin converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce severe leucopenia.

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 azathioprine 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.

IDENTIFICATION:
ZAPRINE 50 :        White to yellowish-white film coated tablets, almost rectangular, biconvex, with a one sided breaking notch.
8.9 (+0.1) mm x 6.0 (+0.1) mm height: 3.6 - 4.2 mm

PRESENTATION:
ZAPRINE 50 film coated tablets:        White, opaque polypropylene / aluminium blisters.
10 tablets per blister strip
10 blister strips per carton

STORAGE INSTRUCTIONS:
Keep out of reach of children.
Store below 25°C.
Protect from light.

REGISTRATION NUMBERS:
ZAPRINE 50        34/26/0444

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Hexal Pharma (SA) (PTY) Ltd
10 Fangio Road
Mahogany Ridge
Westmead
Pinetown

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
18/12/2001

                AZRBP1

Updated on this site: January 2003
Source: Pharmaceutical Industry

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