Azatioprina Generis

Azatioprina Generis 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.

Azatioprina Generis 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 Generis 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

Azatioprina Generis 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 Generis, 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 Generis, 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.

Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.

General

When the oral route is impractical, Azatioprina Generis injection may be administered by the i.v. route only, however, this route should be discontinued as soon as oral therapy can be tolerated once more.

Posology

Azatioprina Generis should be administered at least 1 hour before or 3 hours after food or milk.

Dosage in transplantation - adults:

Depending on the immunosuppressive regime employed, a dosage of up to 5 mg/kg bodyweight/day may be given on the first day of therapy, either orally or intravenously.

Maintenance dosage should range from 1-4 mg/kg/bodyweight/day and must be adjusted according to clinical requirements and haematological tolerance.

Evidence indicates that Azatioprina Generis therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.

Dosage in other conditions - adults:

In general, starting dosage is from 1-3 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 3 months, consideration should be given to withdrawing the medicinal product.

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.

Paediatric population

Transplants: See above Dosage in transplantation - adults.

Other Indications:

Overweight children

Use in older people:

There is limited experience of the administration of Azatioprina Generis to elderly patients./or hepatic impairment).

Patients with renal and/ or hepatic impairment

In patients with renal and/or hepatic insufficiency, consideration should be given to reducing the dosage.

Drug interactions

When xanthine oxidase inhibitors, such as allopurinol, and Azatioprina Generis are administered concomitantly it is essential that only 25% of the usual dose of Azatioprina Generis is given since allopurinol decreases the rate of catabolism of Azatioprina Generis.

TPMT-deficient patients

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine 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 6-mercaptopurine therapy. In any case, close monitoring of blood counts is necessary.

Method of administration

For oral use.

The tablet should be taken with at least a glass of liquid (200 ml).

Precautions to be taken before handling or administering the medicinal product

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 Generis 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 Generis.

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 Generis 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 Generis, 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.

Azatioprina Generis 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 Generis.

Azatioprina Generis 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).

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Co-administration of ribavirin and Azatioprina Generis is not advised. Ribavirin may reduce efficacy and increase toxicity of Azatioprina Generis.

Monitoring

There are potential hazards in the use of Azatioprina Generis. 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 3 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 Azatioprina Generis 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 Azatioprina Generis is withdrawn early enough.

Azatioprina Generis 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 Azatioprina Generis 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 myelosuppression effect of Azatioprina Generis and prone to developing rapid bone marrow depression following the initiation of treatment with Azatioprina Generis. This problem could be exacerbated by co-administration 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 Azatioprina Generis) in combination with other cytotoxics. 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.

Patients with renal and/or hepatic impairment

Caution is advised during the administration of Azatioprina Generis in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored.

Lesch-Nyhan syndrome

Limited evidence suggests that Azatioprina Generis 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 Generis.

Effects on fertility

Relief of chronic renal insufficiency by renal transplantation involving the administration of Azatioprina Generis has been accompanied by increased fertility in both male and female transplant recipients.

Mutagenicity and Carcinogenicity

Chromosomal abnormalities have been demonstrated in both male and female patients treated with Azatioprina Generis. It is difficult to assess the role of Azatioprina Generis 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 Azatioprina Generis. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with Azatioprina Generis. Azatioprina Generis and long-wave ultraviolet light have been shown to have a synergistic clastogenic effect in patients treated with Azatioprina Generis for a range of disorders.

Patients receiving immunosuppressive therapy 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.

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.

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 Azatioprina Generis. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with Azatioprina Generis should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

Varicella Zoster Virus Infection (see also 4.8)

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.

Infections

Patients treated with 6-mercaptopurine alone or in combination with other immunosuppressive agents, including corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection, and viral reactivation. The infectious disease and complications may be more severe in these patients than in non-treated patients.

Prior exposure to or infection with varicella zoster virus should be taken into consideration prior to starting treatment. Local guidelines may be considered, including prophylactic therapy if necessary.

Serologic testing prior to starting treatment should be considered with respect to hepatitis B. Local guidelines may be considered, including prophylactic therapy for cases which have been confirmed positive by serologic testing. Cases of neutropenic sepsis have been reported in patients receiving 6- mercaptopurine for ALL.

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine 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.

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving Azatioprina Generis 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.

Excipients(s) with known effect

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in the elderly (see Renal and/or hepatic insufficiency)

There is limited experience of the administration of Azatioprina Generis 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 Generis, 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.

Azatioprina Generis 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 Generis.

Azatioprina Generis 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).

Monitoring

There are potential hazards in the use of Azatioprina Generis. 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 Generis 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 Generis. 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 Generis 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 Generis to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of Azatioprina Generis may be impaired, and the dosage of Azatioprina Generis should therefore be reduced if hepatic or haematological toxicity occurs.

Limited evidence suggests that Azatioprina Generis 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 Generis.

Mutagenicity

Chromosomal abnormalities have been demonstrated in both male and female patients treated with Azatioprina Generis. It is difficult to assess the role of Azatioprina Generis in the development of these abnormalities.

Effects on fertility

Relief of chronic renal insufficiency by renal transplantation involving the administration of Azatioprina Generis 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.

There are no data on the effect of Azatioprina Generis on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.

None known.

For this product 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 to < 1/10)

Uncommon (> 1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data)

Infection and infestations

Very common: viral, fungal and bacterial infections in transplant patients receiving Azatioprina Generis in combination with other immunosuppressants

Uncommon: viral, fungal and bacterial infections in other patient populations, bacterial and viral infections, infections associated with neutropenia

Very rare: cases of JC virus associated PML have been reported following the use of Azatioprina Generis in combination with other immunosuppressants.

Neoplasms benign and malignant (including cysts and polyps)

The risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanomas and non-melanomas), 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).

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

Azatioprina Generis 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 Generis when receiving concurrent allopurinol therapy.

Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with Azatioprina Generis 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 Azatioprina Generis. 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, rechallenge has confirmed an association with Azatioprina Generis.

Immediate withdrawal of Azatioprina Generis 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 Generis, the necessity for continued administration of Azatioprina Generis should be carefully considered on an individual basis.

Respiratory, thoracic and mediastinal disorders

Very rare: reversible pneumonitis

Gastrointestinal disorders

Common: nausea

A minority of patients experience nausea when first given Azatioprina Generis. This appears to be relieved by administering the tablets after meals.

Uncommon: pancreatitis

Very rare: colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population

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 Azatioprina Generis 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 Generis 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 Azatioprina Generis 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 Azatioprina Generis therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Immune system disorders).

Rare, but life-threatening hepatic damage associated with chronic administration of Azatioprina Generis 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 Azatioprina Generis 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 Azatioprina Generis and other immunosuppressive agents. In many instances the condition resolved spontaneously despite continuing therapy. The relationship between alopecia and Azatioprina Generis treatment is uncertain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

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 Generis in combination with other immunosuppressants.

Other indications.

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

Azatioprina Generis 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 Generis when receiving concurrent allopurinol therapy.

Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with Azatioprina Generis therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia is rare.

Respiratory, thorasic and mediastinal disorders

Reversible pneumonitis has been described very rarely.

Gastrointestinal disorders

A minority of patients experience nausea when first given Azatioprina Generis. 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 Generis 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 Generis 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 Generis on occasions.

Hepato-biliary disorders

Cholestasis and deterioration of liver function have occasionally been reported in association with Azatioprina Generis 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

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

Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of Azatioprina Generis. 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 Generis.

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 Generis, the necessity for continued administration of Azatioprina Generis should be carefully considered on an individual basis.

Symptoms and signs

Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with Azatioprina Generis 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 Azatioprina Generis.

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

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 Azatioprina Generis overdose unless the procedure can be undertaken within 60 minutes of ingestion.

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 Azatioprina Generis is not known, though Azatioprina Generis is partially dialysable.

Symptoms and signs

Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with Azatioprina Generis 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 Generis is not known, though azathioprine is partially dialysable.

Therapeutic Group and ATC code: Antineoplastic and Immunosuppressive agents: L04AX01

Mode of action

Azatioprina Generis is a pro-drug of 6-mercaptopurine (6-MP). 6-MP is inactive but acts as a purine antagonist and requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGNs) for immunosuppression. The TGNs and other metabolites (e.g. 6-methyl-mecaptopurine ribonucleotides) inhibit de novo purine synthesis and purine nucleotide interconversions. The TGNs are also incorporated into nucleic acids and this contributes to the immunosuppressive effects of the drug. Other potential mechanisms of Azatioprina Generis include the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.

Because of these mechanisms, the therapeutic effect of Azatioprina Generis may be evident only after several weeks or months of treatment.

The activity of the methylnitroimidazole moiety, a metabolite of Azatioprina Generis but not 6-MP, has not been defined clearly. However, in several systems it appears to modify the activity of Azatioprina Generis as compared with that of 6-MP.

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 Generis may be evident only after several weeks or months of treatment.

Azatioprina Generis 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 Generis.

Plasma levels of Azatioprina Generis and 6-mecaptopurine do not correlate well with the therapeutic efficacy or toxicity of Azatioprina Generis.

Absorption

The absorption of Azatioprina Generis is incomplete and variable. The median (range) absolute bioavailability of 6- MP after administration of Azatioprina Generis 50 mg is 47% (27 - 80%). The extent of absorption of Azatioprina Generis is similar across the gastrointestinal tract, including the stomach, jejunum, and cecum. However, the extent of 6-MP absorption, after Azatioprina Generis 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 Azatioprina Generis, pharmacokinetic studies with 6-MP have been conducted that are relevant to Azatioprina Generis. 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). Azatioprina Generis should be administered at least 1 hour before or 3 hours after food or milk.

Distribution

The volume of distribution at steady state (Vdss) of Azatioprina Generis 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.

Biotransformation

guanosine monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase(ITPase).

Azatioprina Generis itself is also metabolized by aldehyde oxidase to form 8-hydroxy Azatioprina Generis, 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 Azatioprina Generis may predict adverse drug reactions to Azatioprina Generis therapy.

Thiopurine S-Methyl Transferase (TPMT)

TPMT activity is inversely related to red blood cell 6-MP derived 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.

Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT*2, TPMT*3A and TPMT*3C—account for about 95% of individuals with reduced levels of TPMT activity. Approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of individuals have normal TPMT activity with two functional alleles. There may also be a group of approximately 2% who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can also be informative.

Elimination

After oral administration of 100mg ³⁵S-Azatioprina Generis, 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 Azatioprina Generis or 6-MP. Azatioprina Generis 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 Azatioprina Generis. 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

Older people

No specific studies have been carried out in the elderly.

Paediatric population - 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 Azatioprina Generis doses at the higher end of the dose range and close monitoring of response to treatment is recommended.

Patients with renal impairment

Studies with Azatioprina Generis 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 Azatioprina Generis in renal impairment, consideration should be given to reducing the dosage in patients with impaired renal function.

Azatioprina Generis and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hours.

Patients with hepatic impairment

A study with Azatioprina Generis 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, consideration should be given to reducing the dosage in patients with impaired hepatic function.

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.

Teratogenicity

Studies in pregnant rats, mice and rabbits using Azatioprina Generis 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.

No additional data of clinical relevance to the prescriber.

Not applicable.

None known.

There are no risks associated with handling tablets with intact coating. In that case no special safety precautions are necessary.

However, cytotoxic agents should be handled in strict accordance with the instructions when nursing staff have divided or crushed the tablets.

Surplus medical products as well as contaminated appliances should be temporarily stored in clearly labelled containers. Any unused product or waste material should be disposed of in accordance with local requirements.

Health professionals who handle Azatioprina Generis 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 Generis Tablets. Azatioprina Generis Tablets should not be divided and, provided the coating is intact, no additional precautions are required when handling them.