Azatioprina 50 MG Comprimido Oral

WARNINGS

Malignancy Patients receiving immunosuppressants, including azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin.

Physicians should inform patients of the risk of malignancy with azathioprine.

As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors.

The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including azathioprine.

Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.

Rheumatoid Arthritis Information is available on the risk of malignancy with the use of azathioprine in rheumatoid arthritis (see ADVERSE REACTIONS ).

It has not been possible to define the precise risk of malignancy due to azathioprine.

The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients.

However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine.

Inflammatory Bowel Disease Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with azathioprine.

These cases have had a very aggressive disease course and have been fatal.

The majority of reported cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males.

Some of the patients were treated with azathioprine as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis.

The safety and efficacy of azathioprine for the treatment of Crohn’s disease and ulcerative colitis have not been established.

Cytopenias Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with azathioprine.

Severe bone marrow suppression may also occur.

Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of azathioprine.

Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of azathioprine.

TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing azathioprine toxicity.

2-9 (See PRECAUTIONS : Laboratory Tests ).

Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection.

It is suggested that patients on azathioprine have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary.

Delayed hematologic suppression may occur.

Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression.

Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count.

Serious infections Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients.

Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously.

Reduction of azathioprine dosage and/or use of other drugs should be considered.

Effect on Sperm in Animals Azathioprine has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; 10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

11 Pregnancy Pregnancy Category D .

Azathioprine tablets can cause fetal harm when administered to a pregnant woman.

Azathioprine tablets should not be given during pregnancy without careful weighing of risk versus benefit.

Whenever possible, use of azathioprine tablets in pregnant patients should be avoided.

This drug should not be used for treating rheumatoid arthritis in pregnant women.

12 Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily).

Abnormalities included skeletal malformations and visceral anomalies.

11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine tablets.

In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy.

At 10 weeks most features were normalized.

DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily.

14 There have been two published reports of abnormal physical findings.

Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy.

15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus.

The father was on long-term azathioprine therapy.

16 Benefit versus risk must be weighed carefully before use of azathioprine tablets in patients of reproductive potential.

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing age should be advised to avoid becoming pregnant.

DRUG INTERACTIONS

Drug Interactions Use with Allopurinol One of the pathways for inactivation of azathioprine is inhibited by allopurinol.

Patients receiving azathioprine tablets and allopurinol concomitantly should have a dose reduction of azathioprine tablets, to approximately ⅓ to ¼ the usual dose.

It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving azathioprine tablets and allopurinol because both TPMT and XO inactivation pathways are affected (see CLINICAL PHARMACOLOGY , WARNINGS , PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections).

Use with Aminosalicylates There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme.

Concomitant use of these agents with azathioprine tablets should be done with caution.

Use with Other Agents Affecting Myelopoesis Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

Use with Angiotensin-Converting Enzyme Inhibitors The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.

Use with Warfarin Azathioprine tablets may inhibit the anticoagulant effect of warfarin.

Use with ribavirin The use of ribavirin for hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity.

Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine.

Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioionosine monophosphate (6MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia).

Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary.

Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section.

OVERDOSAGE

The oral LD 50 s for single doses of azathioprine tablets in mice and rats are 2500 mg/kg and 400 mg/kg, respectively.

Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death.

About 30% of azathioprine is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.

24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg azathioprine.

The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function.

The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.

DESCRIPTION

Azathioprine is an immunosuppressive antimetabolite.

Each uncoated azathioprine tablet intended for oral administration contains 50 mg of azathioprine.

In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and starch.

Azathioprine is chemically 6-[(1-methyl-4-nitro- 1H -imidazol-5-yl)thio]- 1H -purine.

The structural formula of azathioprine is: It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound.

Azathioprine, USP is a pale yellow, odorless powder.

It is insoluble in water, soluble in dilute solutions of alkali hydroxides, sparingly soluble in dilute mineral acids, very slightly soluble in alcohol and in chloroform.

The sodium salt of azathioprine is sufficiently soluble to make a 10 mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C).

Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming.

Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide.

structure formula for Azathioprine

HOW SUPPLIED

Azathioprine Tablets USP, 50 mg are yellow, round, flat, beveled edge tablets with bisect on one side; one side of the bisect is debossed with logo of “ZC” and other side is debossed with “59” and other side is plain and are supplied as follows: Bottles of 30 NDC 54868-5310-0 Bottles of 60 NDC 54868-5310-3 Bottles of 90 NDC 54868-5310-4 Bottles of 180 Bottles of 270 NDC 54868-5310-6 NDC 54868-5310-5 STORAGE Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature] in a dry place and protect from light.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

INDICATIONS AND USAGE

Azathioprine tablets are indicated as an adjunct for the prevention of rejection in renal homotransplantation.

It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.

Renal Homotransplantation Azathioprine tablets are indicated as an adjunct for the prevention of rejection in renal homotransplantation.

Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables.

The effect of azathioprine tablets on these variables has not been tested in controlled trials.

Rheumatoid Arthritis Azathioprine tablets are indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms.

Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with azathioprine tablets.

The combined use of azathioprine tablets with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects.

The use of azathioprine tablets with these agents cannot be recommended.

PEDIATRIC USE

Pediatric Use Safety and efficacy of azathioprine in pediatric patients have not been established.

PREGNANCY

Pregnancy Pregnancy Category D .

Azathioprine tablets can cause fetal harm when administered to a pregnant woman.

Azathioprine tablets should not be given during pregnancy without careful weighing of risk versus benefit.

Whenever possible, use of azathioprine tablets in pregnant patients should be avoided.

This drug should not be used for treating rheumatoid arthritis in pregnant women.

12 Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily).

Abnormalities included skeletal malformations and visceral anomalies.

11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine tablets.

In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy.

At 10 weeks most features were normalized.

DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily.

14 There have been two published reports of abnormal physical findings.

Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy.

15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus.

The father was on long-term azathioprine therapy.

16 Benefit versus risk must be weighed carefully before use of azathioprine tablets in patients of reproductive potential.

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing age should be advised to avoid becoming pregnant.

NUSRING MOTHERS

Nursing Mothers The use of azathioprine tablets in nursing mothers is not recommended.

Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk.

17, 18, 19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING – MALIGNANCY Chronic immunosuppression with azathioprine, a purine antimetabolite increases risk of malignancy in humans.

Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease.

Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities.

Physicians should inform patients of the risk of malignancy with azathioprine.

See WARNINGS .

INFORMATION FOR PATIENTS

Information for Patients Patients being started on azathioprine tablets should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician.

They should be informed of the danger of infection while receiving azathioprine tablets and asked to report signs and symptoms of infection to their physician.

Careful dosage instructions should be given to the patient, especially when azathioprine tablets are being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION ).

Patients should be advised of the potential risks of the use of azathioprine tablets during pregnancy and during the nursing period.

The increased risk of malignancy following therapy with azathioprine tablets should be explained to the patient.

DOSAGE AND ADMINISTRATION

TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZATHIOPRINE TABLETS.

TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity.

Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from azathioprine tablets if conventional doses are given.

Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles).

Azathioprine tablets should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given.

Dosage reduction is recommended in patients with reduced TPMT activity.

Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction.

Renal Homotransplantation The dose of azathioprine tablets required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management.

The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant.

Azathioprine tablets are usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation.

Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible.

The dose of azathioprine tablets should not be increased to toxic levels because of threatened rejection.

Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.

Rheumatoid Arthritis Azathioprine tablets are usually given on a daily basis.

The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule.

The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory.

Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day.

Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks.

Patients not improved after 12 weeks can be considered refractory.

Azathioprine tablets may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.

Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant.

The optimum duration of maintenance azathioprine tablets has not been determined.

Azathioprine tablets can be discontinued abruptly, but delayed effects are possible.

Use in Renal Dysfunction Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of azathioprine tablets or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered.

Several guidelines on this subject have been published.

25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.