Azathioprine

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• allopurinol (Zyloprim, Aloprim, Lopurin)
• aminosalicylates such as mesalamine (Apriso, Asacol, Pentasa), olsalazine (Dipentum), and sulfasalazine (Azulfidine)
• blood thinners such as warfarin (Coumadin, Jantoven)
• trimethoprim/sulfamethoxazole (Bactrim, Septra)
• ribavirin (Copegus, Rebetol, Ribasphere, Virazole)
• alkylating medications such as cyclophosphamide (Cytoxan), chlorambucil (Amboclorin), and melphalan (Alkeran)
• angiotensin-converting enzyme (ACE) inhibitors such as:
  • benazepril (Lotensin, Lotensin HCT)
  • captopril (Capoten, Capozide)
  • enalapril (Vasotec, Vaseretic)
  • fosinopril (Monopril, Monopril HCT)
  • lisinopril (Prinivil, Prinzide, Zestril, Zestoretic)
  • moexipril (Univasc, Uniretic)
  • quinapril (Accupril, Accuretic, Quinaretic)
  • ramipril (Altace)
  • trandolapril (Mavik, Tarka)

This is not a complete list of azathioprine drug interactions. Ask your doctor or pharmacist for more information.

Before taking azathioprine, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to azathioprine or to any of its ingredients
• have liver problems
• have kidney problems
• have an inflammatory bowel disease such as Crohn’s or ulcerative colitis
• have blood problems
• have any type of infection
• are scheduled to receive a vaccine
• are scheduled to receive surgery
• have a genetic deficiency with a specific enzyme called the TPMT enzyme
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Chronic immunosuppression with azathioprine, a purine antimetabolite increases risk of malignancy (cancer) 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.

Your doctor may perform blood tests to make sure you do not have conditions that would prevent you from safely using azathioprine.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take azathioprine with food to lessen stomach upset.

You may not be able to continue taking other arthritis medications together with azathioprine. Follow your doctor's dosing instructions very carefully.

Azathioprine can lower blood cells that help your body fight infections and help your blood to clot. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood will need to be tested often.

It may take up to 8 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve.

If you need surgery, tell the surgeon ahead of time that you are using azathioprine. You may need to stop using the medicine for a short time.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

Usual Adult Dose for Renal Transplant:

Initial dose: 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
Maintenance dose: 1 to 3 mg/kg orally or IV once a day

Comments:
-In a minority of cases, therapy has been started 1 to 3 days before transplantation
-The dose should not be increased to toxic levels because of threatened rejection

Use: Adjunctive therapy for prevention of rejection in renal homotransplantation.

Usual Adult Dose for Rheumatoid Arthritis:

Initial dose: 1 mg/kg (50 to 100 mg) orally or IV per day given in 1 to 2 divided doses
Maintenance dose: Lowest effective dose
Maximum dose: 2.5 mg/kg orally or IV per day
Duration: At least 12 weeks

Comments:
-Dose may be increased by 0.5 mg/kg/day (or approximately 25 mg/day), after 6 to 8 weeks of starting treatment and thereafter at 4 week intervals if necessary.
-Gradual dose reduction is recommended to reduce the risk of toxicities.
-Therapeutic response occurs after several weeks of therapy, usually 6 to 8 weeks. Patients not improved after 12 weeks can be considered refractory.
-Azathioprine may be continued long-term in patients with clinical response.

Usual Adult Dose for Crohn's Disease -- Acute:

Studies:
1.5 to 4 mg/kg per day for 10 days up to 52 weeks

Usual Adult Dose for Crohn's Disease -- Maintenance:

Studies:
1.5 to 4 mg/kg per day for 10 days up to 52 weeks

Usual Adult Dose for Chronic Inflammatory Demyelinating Polyradiculoneuropathy:

Study (n=14)
2 to 3 mg/kg orally once a day for 9 months

Usual Adult Dose for Atopic Dermatitis:

Study (n=37)
2.5 mg/kg orally once a day, in the morning, for 3 months

Usual Adult Dose for Sarcoidosis:

Study (n=11)
Initial dose: 2 mg/kg per day in combination with prednisolone 0.6 to 0.8 mg/kg per day, with prednisolone reduced to 0.1 mg/kg within 2 to 3 months
Maintenance dose: 2 mg/kg per day with prednisolone 0.1 mg/kg per day for 21 to 22 months

Usual Adult Dose for Ulcerative Colitis:

Study (n=9)
IV: 20 to 40 mg/kg via IV infusion over 36 hours or 40 mg/kg as three 8-hour infusions over 3 days followed by oral azathioprine
Oral: 2 mg/kg orally per day beginning the day after completion of the IV loading dose

Study (n=12)
50 mg per day for 2 weeks, then 2 to 2.5 mg/kg per day plus mesalamine 500 mg orally 3 times a day; these drugs were started immediately after signs of remission was achieved (mean: 14.5 days) with cyclosporine IV (4 mg/kg/day)

Usual Adult Dose for Uveitis:

Study (n=14)
Treatment of choroidal neovascularization: 1 to 1.5 mg/kg orally per day, in combination with prednisolone and cyclosporine

Usual Adult Dose for Multiple Sclerosis:

Study (n=6)
Patients refractory to interferon beta-1b:
Initial dose: Azathioprine should be titrated up to 1.5 mg/kg per day over 1 month, followed by 50 mg increments in 6-month intervals, concomitantly with 8 million international units subcutaneous interferon beta-1b on alternate days
Maintenance dose: 2 mg/kg per day

Usual Adult Dose for Systemic Lupus Erythematosus:

Studies:
1 to 3 mg/kg actual body weight (ABW)/day orally or IV once a day

Study (n=55)
Diffuse proliferative lupus glomerulonephritis: Sequential therapy starting with prednisone (1 mg/kg/day) for 8 to 10 weeks, gradually tapering to maintenance dosage of 5 to 10 mg/day, together with oral cyclophosphamide (1 to 2 mg/kg/day) for 6 to 9 months followed by azathioprine 50 to 100 mg/day

Usual Adult Dose for Chronic Active Hepatitis:

Study (n=72)
Autoimmune hepatitis: 1 to 2 mg/kg per day, concomitantly with prednisolone (5 to 15 mg/day) for a minimum of 1 year (average 5 years)

Usual Adult Dose for Takayasu's Arteritis:

Study (n=15)
2 mg/kg ABW/day for 1 year in combination with prednisolone taper

Usual Pediatric Dose for Atopic Dermatitis:

Study (n=37)
Greater than 17 years: 2.5 mg/kg orally once a day, in the morning, for 3 months

Usual Pediatric Dose for Organ Transplant -- Rejection Prophylaxis:

Initial dose: 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
Maintenance dose: 1 to 3 mg/kg orally or IV once a day

Usual Pediatric Dose for Eczema:

Study (n=91)
Greater than 6 years: 2.5 to 3.5 mg/kg per day in patients with normal levels of thiopurine methyltransferase

Usual Pediatric Dose for Systemic Lupus Erythematosus:

Case Study (n=67)
Lupus Nephritis:
Greater than 5 years: 2 to 3 mg/kg per day (maximum dose: 150 mg/day)
Dose should be titrated to maintain a total white blood cell count between 3 and 4 x 10(3) cells/mL.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with azathioprine, especially:

• allopurinol;

• a blood thinner (warfarin, Coumadin, Jantoven); or

• blood pressure medicine (benazepril, captopril, enalapril, lisinopril, quinapril, ramipril, trandolapril, and others).

This list is not complete. Other drugs may interact with azathioprine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• Imidazolyl derivative of 6-mercaptopurine; a purine antimetabolite.100 134 136

• Exact mechanism(s) of immunosuppression not fully elucidated; cytotoxicity due, in part, to incorporation of cytotoxic (6-thioguanine) nucleotides into DNA.100 134 136

• Inhibits graft rejection; little effect on established graft rejections or secondary responses.100 134 136

• Suppresses disease manifestations and underlying pathology in animal models of autoimmune disease.100 134 136

Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-Azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of Azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as Azathioprine. Usual doses produce blood levels of Azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable (see OVERDOSAGE).

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no Azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites (see Metabolism Scheme in Figure 1). The cytotoxicity of Azathioprine is due, in part, to the incorporation of 6-TGN into DNA.

6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism.1, 2, 3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of Azathioprine tablets. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of Azathioprine tablets.4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing Azathioprine tablets toxicity.2, 3, 7, 8, 9 Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions (see WARNINGS, PRECAUTIONS: Drug Interactions, PRECAUTIONS: Laboratory Testsand ADVERSE REACTIONSsections).

Figure 1. Metabolism pathway of Azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA.

GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU: Thiouric acid; XO: Xanthine oxidase) (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.)

Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the Azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function.

Homograft Survival

The use of Azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses.

Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by Azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal.

Immunoinflammatory Response

Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by Azathioprine.

The mechanisms whereby Azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, Azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued.

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

Patients receiving immunosuppressants, including Azathioprine, are at increased risk for bacterial, viral, fungal,protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal outcomes.

Progressive Multifocal Leukoencephalopathy

Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Azathioprine. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft.

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.

General

A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with Azathioprine tablets and are reversible upon discontinuation of the drug. The reaction can recur within hours after rechallenge with a single dose of Azathioprine tablets.

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 Interactionssubsection 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.

Laboratory Tests

Complete Blood Count (CBC) Monitoring

Patients on Azathioprine tablets should 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.

TPMT Testing

It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT*2, TPMT*3A and TPMT*3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING Azathioprine TABLETS (see CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONSand DOSAGE AND ADMINISTRATIONsections).

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 Testsand ADVERSE REACTIONSsections).

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.

Pregnancy:

Teratogenic Effects

Pregnancy Category D. See WARNINGSsection.

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.

Pediatric Use

Safety and efficacy of Azathioprine in pediatric patients have not been established.

Uveitis (off- label use): Oral: 1 to 3.2 mg/kg/day either alone or in conjunction with corticosteroids and/or immunosuppressants (Goebel 2011)

Rapid WBC count decrease, persistently low WBC count, or serious infection: Reduce dose or temporarily withhold treatment.

Severe toxicity (hematologic or other) in renal transplantation: May require discontinuation.

Hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease): Permanently discontinue.

Do not use azathioprine if you are pregnant. It could harm the unborn baby.

Some people using azathioprine have developed a rare fast-growing type of lymphoma (cancer). This condition affects the liver, spleen, and bone marrow, and it can be fatal. This has occurred mainly in teenagers and young adults using azathioprine or similar medicines to treat Crohn's disease or ulcerative colitis.

Call your doctor at once if you have any of the following symptoms: fever, night sweats, itching, loss of appetite, weight loss, tiredness, feeling full after eating only a small amount, pain in your upper stomach that may spread to your shoulder, nausea, easy bruising or bleeding, pale skin, feeling light-headed or short of breath, rapid heart rate, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Azathioprine can lower blood cells that help your body fight infections. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection.

If you need to have surgery, tell the surgeon ahead of time that you are using azathioprine. You may need to stop using the medicine for a short time.

This medication can affect fertility (your ability to have children), whether you are a man or a woman. Talk with your doctor if you have concerns about this.

Do not receive a "live" vaccine while you are being treated with azathioprine and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Study (n=14)
2 to 3 mg/kg orally once a day for 9 months

Study (n=9)
IV: 20 to 40 mg/kg via IV infusion over 36 hours or 40 mg/kg as three 8-hour infusions over 3 days followed by oral azathioprine
Oral: 2 mg/kg orally per day beginning the day after completion of the IV loading dose

Study (n=12)
50 mg per day for 2 weeks, then 2 to 2.5 mg/kg per day plus mesalamine 500 mg orally 3 times a day; these drugs were started immediately after signs of remission was achieved (mean: 14.5 days) with cyclosporine IV (4 mg/kg/day)

Study (n=72)
Autoimmune hepatitis: 1 to 2 mg/kg per day, concomitantly with prednisolone (5 to 15 mg/day) for a minimum of 1 year (average 5 years)