Symptoms and signs
Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with Azatioprina Mylan 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
There is no specific antidote. Gastric lavage has been used. Subsequent monitoring, including haematological monitoring, is necessary to allow prompt treatment of any adverse effects which may develop. The value of dialysis in patients who have taken an overdose of Azatioprina Mylan is not known, though azathioprine is partially dialysable.
Azatioprina Mylan is contra-indicated in patients known to be hypersensitive to azathioprine. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to Azatioprina Mylan.
Azatioprina Mylan therapy should not be initiated in patients who may be pregnant, or who are likely to become pregnant without careful assessment of risk versus benefit (see Special Warnings and Precautions for Use and Pregnancy and Lactation).
None known.
For this product there is no modern clinical documentation that 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 and < 1/10; uncommon, > 1/1000 and < 1/100; rare, > 1/10000 and < 1/1000; very rare, < 1/10000.
Infection and infestations
Transplant patients receiving Azatioprina Mylan in combination with other immunosuppressants.
| Very common: | Viral, fungal and bacterial infections. |
Other indications.
| Uncommon: | Viral, fungal and bacterial infections. |
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 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 chromasomal abnormalities)
Blood and lymphatic system disorders
| Very common: | Depression of bone marrow function; leucopenia. |
| Common: | Thrombocytopenia. |
| Uncommon: | Anaemia. |
| Rare: | Agranulocytosis, pancytopenia, aplastic anaemia, megaloblastic anaemia, erythriod hypoplasia. |
Azatioprina Mylan 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 Azatioprina Mylan when receiving concurrent allopurinol therapy.
Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with Azatioprina Mylan therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia is rare.
Respiratory, thorasic and mediastinal disorders
| Very rare: | Reversible pneumonitis. |
Reversible pneumonitis has been described very rarely.
Gastrointestinal disorders
| Uncommon: | Pancreatitis. |
| Rare: | Colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population. |
A minority of patients experience nausea when first given Azatioprina Mylan. 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 re-challenge, has been reported in patients treated with Azatioprina Mylan 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 Azatioprina Mylan 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 re-challenge has confirmed an association with Azatioprina Mylan on occasions.
Hepato-biliary disorders
| Uncommon: | Cholestasis and degeneration of liver function tests. |
| Rare: | Life-threatening hepatic damage. |
Cholestasis and deterioration of liver function have occasionally been reported in association with Azatioprina Mylan therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Hypersensitivity reactions).
Rare, but life-threatening hepatic damage associated with chronic administration of azathioprine 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 azathioprine has resulted in either a temporary or permanent improvement in liver histology and symptoms.
Skin and subcutaneous tissue disorders
| Rare: | Alopecia, photosensitivity. |
Hair loss has been described on a number of occasions in patients receiving azathioprine and other immunosuppressive agents. In many instances the condition resolved spontaneously despite continuing therapy. The relationship between alopecia and azathioprine treatment is uncertain.
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 Azatioprina Mylan. 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).
In many cases, re-challenge has confirmed an association with Azatioprina Mylan.
Immediate withdrawal of azathioprine and institution of 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 Azatioprina Mylan, the necessity for continued administration of Azatioprina Mylan should be carefully considered on an individual basis.
No additional data of clinical relevance to the prescriber.
Azatioprina Mylan tablets are 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.
Azatioprina Mylan, 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; and to reduce the corticosteroid requirements of renal transplant recipients.
Azatioprina Mylan, 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.
Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It 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. Determination of plasma concentrations of azathioprine or 6-MP have no prognostic values as regards effectiveness or toxicity of these compounds.
While the precise modes of action remain to be elucidated, some suggested mechanisms include:
1. the release of 6-MP which acts as a purine antimetabolite.
2. the possible blockade of -SH groups by alkylation.
3. the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.
4. damage to deoxyribonucleic acid (DNA) through incorporation of purine thio-analogues.
Because of these mechanisms, the therapeutic effect of Azatioprina Mylan may be evident only after several weeks or months of treatment.
Azatioprina Mylan appears to be well absorbed from the upper gastro-intestinal tract.
Studies in mice with [35S]-azathioprine showed no unusually large concentration in any particular tissue, and there was very little [35S]-label found in brain.
Plasma levels of azathioprine and 6-MP do not correlate well with the therapeutic efficacy or toxicity of Azatioprina Mylan.
Azathioprine is well absorbed following oral administration. 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. As a consequence of the rapid and extensive metabolism of azathioprine, only a fraction of the radioactivity measured in plasma is comprised of unmetabolised drug. Studies in which the plasma concentration of azathioprine and 6-MP have been determined following intravenous administration of azathioprine have estimated the mean plasma T1/2 for azathioprine to be in the range of 6-28 minutes and the mean plasma T1/2 for 6-MP to be in the range 38-114 minutes after i.v. administration 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. This would indicate that, rather than azathioprine being exclusive cleaved by nucleophilic attack at the 5-position of the nitroimidazole ring to generate 6-MP and 1-methyl-4-nitro-5-(S-glutathionyl)imidazole. 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.
Use in the elderly (see Renal and/or hepatic insufficiency)
There is limited experience of the administration of Azatioprina Mylan 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 Azatioprina Mylan, 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.
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity (see 4.4).These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUDT15 variants may be considered before initiating azathioprine therapy. In any case, close monitoring of blood counts is necessary.
4.3 ContraindicationsAzatioprina Mylan is contra-indicated in patients known to be hypersensitive to azathioprine. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to Azatioprina Mylan.
Azatioprina Mylan therapy should not be initiated in patients who may be pregnant, or who are likely to become pregnant without careful assessment of risk versus benefit (see Special Warnings and Precautions for Use and Pregnancy and Lactation).
4.4 Special warnings and precautions for useMonitoring
There are potential hazards in the use of Azatioprina Mylan. 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.
Patients receiving Azatioprina Mylan should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding 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 initiation of treatment with Azatioprina Mylan. 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.
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being NUDT15 variant homozygotes (see 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10 % in East Asians, 4 % in Hispanics, 0.2 % in Europeans and 0 % in Africans. In any case, close monitoring of blood counts is necessary.
Renal and/or hepatic insufficiency
It has been suggested that the toxicity of Azatioprina Mylan may be enhanced in the presence of renal insufficiency, but controlled studies have not supported this suggestion. 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 Azatioprina Mylan to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of Azatioprina Mylan may be impaired, and the dosage of Azatioprina Mylan should therefore be reduced if hepatic or haematological toxicity occurs.
Limited evidence suggests that Azatioprina Mylan 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 Azatioprina Mylan.
Mutagenicity
Chromosomal abnormalities have been demonstrated in both male and female patients treated with Azatioprina Mylan. It is difficult to assess the role of Azatioprina Mylan in the development of these abnormalities.
Effects on fertility
Relief of chronic renal insufficiency by renal transplantation involving the administration of Azatioprina Mylan has been accompanied by increased fertility in both male and female transplant recipients.
)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.
Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level.
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. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
)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.
None known.
Transplantation - adults and children
Depending on the immunosuppressive regimen employed, a dosage of up to 5 mg/kg body weight/day may be given on the first day of therapy, either orally or intravenously.
Maintenance dosage should range from 1 to 4 mg/kg body weight/day and must be adjusted according to clinical requirements and haematological tolerance.
Evidence indicates that Azatioprina Mylan therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.
Dosage in other conditions - adults and children
In general, starting dosage is from 1 to 3 mg/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 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 Azatioprina Mylan.
The maintenance dosage required may range from less than 1 mg/kg body weight/day to 3 mg/kg body weight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.
In patients with renal and/or hepatic insufficiency, dosages should be given at the lower end of the normal range (see Special Warnings and Precautions for Use for further details).
Use in the elderly (see Renal and/or hepatic insufficiency)
There is limited experience of the administration of Azatioprina Mylan 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 Azatioprina Mylan, 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.
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity (see 4.4).These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUDT15 variants may be considered before initiating azathioprine therapy. In any case, close monitoring of blood counts is necessary.
Health professionals who handle Azatioprina Mylan Injection should follow guidelines for the handling of cytotoxic drugs (for example, the Royal Pharmaceutical Society of Great Britain Working Party Report on the Handling of Cytotoxic Drugs, 1983).
Provided that the film-coating is intact, there is no risk in handling film-coated Azatioprina Mylan Tablets. Azatioprina Mylan Tablets should not be divided and, provided the coating is intact, no additional precautions are required when handling them.
