AZATHIOPRINE MYLAN 50 mg is indicated, in combination with other drugs, immunosuppressants, in the prophylaxis of acute rejection of graft, allogeneic kidney, liver, heart, lung, pancreas. >

AZATHIOPRINE MYLAN 50 mg is usually indicated in diets, immunosuppressants as complement to agents, basic immunosuppressants

AZATHIOPRINE MYLAN 50 mg is indicated in the severe forms of the following diseases in patients intolerant to steroids or steroid-dependent or whose therapeutic response is insufficient despite treatment using high doses of steroids < Br>

· Severe rheumatoid arthritis can not be controlled by less toxic treatments

· Severe or moderately severe chronic inflammatory bowel disease (Crohn's disease and ulcerative colitis)

· Lupus erythematosus, acute disseminated

· Dermatomyositis

· Chronic active autoimmune hepatitis

· Periarteritis nodosa

· Autoimmune hemolytic anemia refractory to treatment with hot antibodies

· Chronic idiopathic thrombocytopenic purpura, refractory.

Oral use.

Azathioprine tablets should be swallowed with a glass of water (200 ml minimum). They can be eaten at mealtime.

Grafts

Depending on the plan, adopted immunosuppressant, a dosage that can attack; to 5 mg / kg body weight / day maximum, administered orally is usually given;. The maintenance dose can vary between 1 and 4 mg / kg Body weight / day and can be adjusted according to clinical requirements and hematological tolerance

Other conditions

In general, the dose; departure is between 1 and 3 mg / kg body weight; bw / day and should be adjusted; the clinical response (which may not occur; after several weeks or months ) And haematological tolerance. For the treatment of active chronic hepatitis, the dose is usually between 1.0 and 1.5 mg / kg body weight / day. When a therapeutic result is evident, consideration should be given to lowering the dose, maintaining it to the lowest dose that is compatible, and maintaining this result. If the condition of the patient does not improve within a period of three months, six months should be considered for discontinuation of administration of this drug. The maintenance dose required may vary from 1 mg / kg body weight / day to 3 mg / kg body weight / day, depending on the condition being treated and the patient's individual response, as well as the Hematologic tolerance

Use in patients with hepatic or renal impairment

In patients with renal and / or hepatic impairment (mild to moderate insufficiency), doses should be within the lower range of the normal limits .; Azathioprine is contraindicated in severe liver and kidney failure. , Section Contraindications).

Use in children and adolescents

There is a lack of data to recommend the use of azathioprine for the treatment of juvenile idiopathic arthritis, lupus, disseminated erythematosus, dermatomyositis and periarteritis nodosa (in children and adolescents aged Less than 18 years old.

For the other indications, the recommended dosage recommendations apply to children and adolescents and adults.
Use in the elderly

No specific information is available as to the safety of azathioprine by the elderly. It is advisable to use the lower limiting doses for adults and children (for controls, hematology, see Warnings, Specials and Precautions for Use) ..

If concomitant administration of allopurinol, or to oxipurinol thiopurinol with azathioprine, the dosage of the latter must be, reduced to a quarter of the original dose (see sections; Special warnings and precautions for Use and interactions with other medicines and other forms of interactions)

The appearance of the therapeutic effect may take several weeks or months.

The drug may be administered on a long-term basis unless the patient does not tolerate it.
In some diseases, such as rheumatoid arthritis or certain haematological disorders, for example, treatment can be stopped without a problem after a certain period of time.
Azathioprine should always be stopped gradually, under close surveillance.
< Br>

Film-coated tablet of light yellow color, biconvex, approximately 8 mm in diameter, marked "AE 50" on one side and one bar on the other. The tablet may be divided into two equal half-doses.

L04AX01: Other Immunosuppressants

(L: antineoplastic and immunomodulatory)

Azathioprine is used as; immunosuppressant antimetabolite either alone or, more, frequently in combination with other agents (usually corticosteroids) affecting;. Immune response
< Br>
Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is; rapidly decomposed in vivo into 6-MP, and; 1-methyl-4-nitro-5-thio-imidazole;. The 6-MP readily crosses cell membranes and is; intracellularly converted into a number of thioanalogues , Of which there is the principal active nucleotide, thioinosinic acid. The activity of the methylnitroimidazole fraction was not clearly defined. However, in several systems it modifies the activity of azathioprine compared to that of 6-MP.

Azathioprine exerts an effect both on the immunological response and on the tumor growth. It acts primarily as an agent, suppressor of the immune response, and although the exact mechanism by which it exerts this effect is not known, the following mechanisms of action have been advanced

1. The release of 6-MP acts as a purine antimetabolite.

2. SH groups could be blocked by alkylation.
3. Numerous pathways of the biosynthesis of nucleic acids could be inhibited, and thus prevent the proliferation of immune cells and cells involved in the amplification of the immune response.

4. Deoxyribonucleic acid (DNA) could be altered due to the incorporation of thio-analogues, puric.
· Hypersensitivity to azathioprine, 6-mercaptopurine (azathioprine metabolite), or to any of the excipients of the medication

· Severe infections.

· Severe renal, hepatic or severe bone marrow disease.

· Pancreatitis.

· Any live vaccine is contraindicated in combination with azathioprine, especially BCG, yellow fever vaccine, smallpox vaccine

Pregnancy, unless the expected benefits are greater than the risks involved (see section Pregnancy and lactation)

· Breastfeeding (see section Pregnancy and lactation).

· The use of azathioprine tablets involves risks and, as such, should be prescribed only if the patient can be adequately monitored throughout the course of treatment to detect the onset of , Any toxic effects

During the first eight weeks of treatment, blood count and leukocyte count, as well as platelet count, should be determined at least once a week Controls should be more frequent
< Br>

O when using high doses

O in elderly patients

O in case of renal insufficiency

In patients with mild to moderate hepatic impairment (see also sections Posology and method of administration and Pharmacokinetic properties)

O in case of mild to moderate functional deficiency of bone marrow (see also section Posology and method of administration)

O in patients with hypersplenism

The frequency of haematological checks may be decreased after 8 weeks. It is recommended to repeat each month a complete blood count or at least at intervals not exceeding 3 months.
Patients should be advised to immediately inform their physician if they have throat ulcers, fever, infection, hematomas, bleeding, or other signs of bone marrow depression

· Hepatic function should be monitored regularly, especially in patients with hepatic dysfunction

· Close monitoring of hematological parameters is required when azathioprine is administered concurrently with

O, allopurinol, oxipurinol or thiopurinol (see sections Posology and method of administration and Interactions with other medicinal products and other forms of interactions)
< Br>

O aminosalicylic acid derivatives such as mesalazine, olsalazine or sulfasalazine (see section Interactions with other medicinal products and other forms of interactions)

O ACE inhibitors, trimethoprim-sulfamethoxazole, cimetidine, or indomethacin (see section Interactions with other medicinal products and other forms of interactions)
< Br>

O agents with cytotoxic or myelosuppressive properties (see section Interactions with other medicinal products and other forms of interactions)

· A high percentage of patients (10%) have partial deficit, secondary thiopurine methyltransferase (TPMT), and genetic polymorphism. This is why they can metabolize azathioprine in an incomplete manner and are therefore exposed to a higher myelotoxic effect. Particular attention is recommended when administered simultaneously with aminosalicylic acid derivatives (including sulphasalazine) which are inhibitors of the TPMT enzyme. It is desirable to establish the phenotype and genotype of the patient where possible and appropriate prior to the administration of azathioprine for possible deficiency thiopurine methyltransferase Br>

· Few data indicate that azathioprine is not beneficial in patients with hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, and considering that the metabolism in these patients is abnormal, the use of azathioprine can not be recommended in these patients.
· When concomitant treatment with allopurinol, oxipurinol or thiopurinol is initiated, the dose of azathioprine should be reduced to one quarter of the initial dose. >

Special precautions should be taken when azathioprine is co-administered with neuromuscular medicinal products such as tubocurarine or succinylcholine (see section 4.4.2 Interactions with other medicinal products and other forms of interaction). It may also potentiate the neuromuscular block induced by depolarizing substances such as succinylcholine (see section Interactions with other drugs and other forms of interactions). Patients should be instructed to inform their anesthesiologist of their treatment with azathioprine before any surgery

Coagulation should be closely monitored and should be administered concomitantly with coumarin and azathioprine anticoagulants (see section Interactions with other medicinal products and other forms of interaction). >

· Discontinuation of azathioprine may lead to severe worsening of the disease, eg systemic lupus erythematosus with impairment, nephritis, Crohn's disease, recto-colitis, ulcerative hemorrhage, Hepatitis, autoimmune.

· The cessation of azathioprine should always be carried out gradually and under close supervision.


· An increased number of skin tumors was observed in patients receiving azathioprine. They were mainly localized in areas of skin exposed to the sun. Patients should be warned, unnecessary exposure to the sun or UV rays should be avoided, and their skin should be examined regularly (see also Undesirable effects).
< Br>

· Particular caution should be exercised in patients with acute untreated infection (see also Contraindications).

Azathioprine should be administered to patients who undergo simultaneous cytotoxic therapy only under medical supervision.


Azathioprine is mutagenic and potentially carcinogenic. Appropriate precautions are necessary to handle this substance, especially by pregnant nurses (see section Precautions, Special Disposal and Handling).
If a film-coated tablet is to be split, skin contact should be avoided with tablet dust or the broken part (see Dosage and Mode of Administration and Special Precautions, Disposal and Manipulation).

· Allopurinol, oxipurinol and thiopurinol exert an inhibitory effect on the metabolism of azathioprine by blocking an enzyme, xanthine oxidase. In the case of coadministration of allopurinol, oxipurinol and / or thiopurinol with azathioprine, the dose of azathioprine should be reduced to one-fourth of the original dose (see sections Posology and method of administration) Administration and Warnings, special and precautions for use).

There is clinical evidence that azathioprine antagonizes the effect of non-depolarizing muscle relaxants such as curare, d-tubocurarin and pancuronium. The experimental results confirm that azathioprine reverses neuromuscular blockade caused by d-tubocurarine and show that azathioprine potentiates neuromuscular blockade caused by succinylcholine (see Special warnings and precautions for use) .

· If azathioprine is combined with other immunosuppressants, such as ciclosporin and tacrolimus, the increased risk of excessive immunosuppression should be considered.

There is a risk of an increase in the myelosuppressive effect of azathioprine due to the inhibition of its hepatic metabolism when administered simultaneously with aminosalicylic acid derivatives such as Olsalazine, mesalazine, sulfasalazine, (see Warnings).
· An inhibition of the anticoagulant effect of warfarin and phenprocoumone has been reported when administered with azathioprine (see Special warnings and precautions for use).

Concomitant administration of azathioprine with ACE inhibitors, trimethoprim, sulfamethoxazole, cimetidine or indomethacin increases the risk of aplasia, medulla (see section 4.4), and special precautions Job description.

· Concomitant administration of azathioprine with agents with myelosuppressive or cytotoxic properties may increase myelotoxic effects. This also applies to myelosuppressive treatments completed shortly before the initiation of treatment with azathioprine (see section 4.4 Special warnings and precautions for use).

· In vitro, furosemide has been shown to disrupt the metabolism of azathioprine by human hepatic tissue. The clinical significance of this observation is not known.
The immunosuppressive activity of azathioprine may generate an atypical and potentially harmful response to live virus vaccines and on this theoretical basis the administration of live virus vaccines to azathioprine-treated patients is Contraindicated (see section Contraindications).

An attenuated response to dead vaccines is likely and such a response to the hepatitis B vaccine has been observed in patients receiving a combination of azathioprine and corticosteroids.

· A small clinical study has indicated that the standard therapeutic doses of azathioprine do not adversely affect the response to the pneumococcal, versatile vaccine given the average titer of anti-capsular antibodies specific (see section 4.4). Specials and precautions for use).

Not applicable.

The most probable side effect of an overdose is a depression of the spinal cord, which in some cases will only reach a maximum between the 9th and 19th day after dose administration. The main signs of bone marrow aplasia are throat ulcers, fever and infections. Hematomas, bleeding and fatigue are also possible. A single high dose of azathioprine is less likely to have a toxic effect than a minor chronic overdose compared to the prescribed dose. Although the effects of an overdose may be delayed, it is not Unusual as an improvement, occurs after the 12th day, provided that the patient has not received high doses during the intervention period.
There is no antidote specific to overdosage. If an overdose occurs, it will be necessary to control the hematological parameters and, in particular, the liver function. It is known that azathioprine is dialysable and dialysis can be performed in severe cases.

Pregnancy

Azathioprine should not be used during pregnancy unless the risks and benefits have been carefully evaluated.




Breastfeeding

Mercaptopurine could be detected in colostrum and milk of women treated with azathioprine. Lactation is contraindicated in women treated with azathioprine (see section Contraindications).

Fifteen percent of patients are likely to experience adverse effects. The nature, frequency and severity of adverse reactions may depend on the dose of azathioprine and the duration of treatment, as well as the underlying disease of the patient and its associated treatments.

The main adverse effect attributed to azathioprine is depression, bone marrow function, dose-dependent and generally reversible, which manifests as leukopenia, thrombocytopenia and, in rare cases, d 'anemia. Leukopenia may occur in more than 50% of patients receiving conventional doses of azathioprine. Other manifestations of bone marrow depression, namely thrombocytopenia, anemia, macrocytosis and abnormalities, megaloblastic bone marrow, are less frequent.

The nature and frequency of the undesirable effects of azathioprine are summarized in the table below.
Very common

Common

Uncommon

Rare

Very rare

(≥1 / 10)

(≥1 / 100;