Azasan

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Azathioprine is an immunosuppressant, that is, a drug that is used to suppress the immune system. It is used to treat patients who have undergone kidney transplantation and for diseases in which modifying the activity of the immune system is important. Azathioprine is a prodrug (a precursor of a drug) which is converted in the body to its active form called mercaptopurine (Purinethol). The exact mechanism of action of azathioprine is not known.

Like other immunosuppressants, it suppresses the proliferation of T and B lymphocytes, types of white blood cells that are part of the immune system and defend the body against both infectious diseases and foreign materials. For example, in the case of organ transplantation, immunosuppressants prevent the body from immunologically rejecting the new organ. In the case of autoimmune diseases (diseases caused by an abnormal immune reaction against the body's own tissues) such as rheumatoid arthritis, suppressing the immune system reduces the inflammation that accompanies immune reactions and slows damage to the joints caused by the inflammation. The FDA approved azathioprine in March 1968.

Dosage Forms & Strengths

tablet

• 50mg
• 75mg
• 100mg

powder for injection

• 100mg/vial

Kidney Transplantation

Prevention of transplant rejection

3-5 mg/kg/day IV/PO initially on day of transplant or 3 days before transplant (rare) 

Maintenance: 1-3 mg/kg/day IV/PO 

Rheumatoid Arthritis

1 mg/kg/day IV/PO initially in single daily dose or divided q12hr; may be increased by 0.5 mg/kg/day after 6-8 weeks, then by 0.5 mg/kg/day every 4 weeks; not to exceed 2.5 mg/kg/day  

Maintenance: Reduce daily dose by 0.5 mg/kg every 4 weeks until lowest effective dosage is reached

Lupus Nephritis (Off-label)

Induction and maintenance therapy for lupus nephritis (2012 American College of Rheumatology guidelines)

2 mg/kg/day PO with or without low-dose corticosteroids  

Crohn Disease (Off-label)

Maintenance, remission, or reduction of steroid

2-3 mg/kg PO once daily  

Ulcerative Colitis (Off-label)

Maintenance, remission, or reduction of steroid

1.5-2.5 mg/kg PO once daily  

Chronic Refractory Thrombocytopenic Purpura (Off-label)

1-2 mg/kg PO once daily to maximum daily dose of 150 mg for at least 3-6 months before typical response is observed

Dosing considerations

• Lower dosage (100 mg/day) is reported effective in some patients
• Longer treatment duration (up to 84 months) is reported in some patients

Dosage Forms & Strengths

tablet

• 50mg
• 75mg
• 100mg

powder for injection

• 100mg/vial

Juvenile Idiopathic Arthritis

1 mg/kg/day IV/PO initially in single daily dose or divided q12hr; may be increased by 0.5 mg/kg/day after 6-8 weeks, then by 0.5 mg/kg/day every 4 weeks; not to exceed 2.5 mg/kg/day  

Maintenance: Reduce daily dose by 0.5 mg/kg every 4 weeks until lowest effective dosage is reached

Transplantation (Off-label)

Prevention of transplant rejection

3-5 mg/kg/day IV/PO initially on day of transplant or 3 days before transplant (rare)  

Maintenance: 1-3 mg/kg/day IV/PO

Lupus Nephritis (Off-label)

Induction and maintenance therapy for lupus nephritis (2012 American College of Rheumatology guidelines)

<12 years: Safety and efficacy not established

>12 years: 2 mg/kg/day PO with or without low-dose corticosteroids

Black Box Warnings

Chronic immunosuppression with this purine antimetabolite increases neoplasia risk, mutagenic risk, and hematologic toxicities

Reported malignancies include posttransplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease

Prescribing physicians should be familiar with mutagenic potential and with possible hematologic toxicities

Contraindications

Documented hypersensitivity

Pregnancy, lactation

Rheumatoid arthritis: Patients previously treated with alkylating agents

Cautions

Long-term use increases risk of neoplasia

Increased risk of infection and hepatotoxicity

Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, reported in patients treated with immunosuppressants, including azathioprine

Hepatosplenic T-cell lymphoma

• Rare postmarketing cases of HSTCL reported primarily in adolescent and young adult patients with Crohn disease and ulcerative colitis treated with tumor necrosis factor (TNF) blockers
• Reports have also included 1 patient being treated for psoriasis and 2 patients being treated for rheumatoid arthritis
• HSTCL is an aggressive, rare type of T-cell lymphoma that is usually fatal
• Most reported cases with TNF blockers have occurred in context of concomitant treatment with azathioprine or 6-mercaptopurine (6-MP), though cases have been reported with azathioprine or 6-MP alone
• In the FDA Adverse Event Reporting System (AERS) database, the literature, and the HSTCL Cancer Survivors' Network, HSTCL cases have been identified in association with the following drugs: infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), 6-MP (3)

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Azasan falls into category D. It has been shown that use of Azasan in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Whenever possible, use of Azasan in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.

Avoiding pregnancy while taking Azasan is recommended in women of childbearing potential.

Take Azasan exactly as prescribed.

Oral:

• This medication comes in tablet form and is taken once or twice a day, with or without food.
• If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Azasan at the same time.

Injectable:

• This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends will be individulized for each patient. 

The dose may be based on the following:

• the condition being treated
• how you respond to this medication
• other medications you are taking
• your weight
• your renal function

Rheumatoid arthritis

The initial dose of Azasan (azathioprine) should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice daily schedule. The dose can be titrated up if needed and if there are no serious toxicities to a maximum 2.5 mg/kg/day.

Kidney transplant

The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible.

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.

You should not take this medicine if you are allergic to azathioprine, or if you are pregnant (unless the benefits of treating you outweigh any risks posed by taking azathioprine).

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.

However, people with autoimmune disorders (including rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, and psoriasis) may have a higher risk of lymphoma. Talk to your doctor about your individual risk.

While taking azathioprine, you may have a higher risk of developing skin cancer. Talk to your doctor about this risk and what skin symptoms to watch for.

To make sure azathioprine is safe for you, tell your doctor if you have:

• liver disease;

• any type of viral, bacterial, or fungal infection;

• if you have received a kidney transplant; or

• if you have recently received chemotherapy treatments with medications such as cyclophosphamide (Cytoxan), chlorambucil (Leukeran), melphalan (Alkeran).

FDA pregnancy category D. Do not use azathioprine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Azathioprine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using azathioprine.

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.

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.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Chest pain or pressure.
• Very upset stomach or throwing up.
• Feeling very tired or weak.
• Very bad dizziness or passing out.
• Loose stools (diarrhea).
• Muscle pain or weakness.
• Night sweats.
• A big weight loss.
• Fever that does not go away.
• Change in color or size of a mole.
• A skin lump or growth.
• A very bad brain problem called progressive multifocal leukoencephalopathy (PML) has happened with Azasan. It may cause disability or can be deadly. Tell your doctor right away if you have signs like confusion, memory problems, low mood (depression), change in the way you act, change in strength on 1 side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Azasan ® should not be given to patients who have shown hypersensitivity to the drug.

Azasan ® should not be used for treating rheumatoid arthritis in pregnant women.

Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with Azasan ®.

Malignancy
Patients receiving immunosuppressants, including Azasan ®, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with Azasan ®. 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 Azasan ®. 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 Azasan ® for the treatment of Crohn's disease and ulcerative colitis have not been established.

Cytopenias:
Severe leukopenia, thrombocytopenia, anemias including macrocytic and/or pancytopenia may occur in patients being treated with Azasan ®. 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 Azasan ®. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of Azasan®. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing Azasan ® 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 Azasan ® 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. Azasan ® can cause fetal harm when administered to a pregnant woman. Azasan ® should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of Azasan ® in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12

Azasan ® is 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 Azasan ®. 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 Azasan ® in patients of reproductive potential. There are no adequate and wellcontrolled 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.

Animal studies have revealed evidence of teratogenicity. There are no controlled data in human pregnancy. Congenital anomalies, including polydactyly, plagiocephaly, congenital heart disease, hypospadias, and bilateral talipes equinovarus have occurred. Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies. There have been reports of premature birth and low birth weight (especially in combination with corticosteroids), and spontaneous abortion after either maternal or paternal exposure; some data suggest an increased risk of intrauterine growth retardation and prematurity. Chromosomal aberrations have also been reported. Azathioprine has been reported to cause temporary depression of spermatogenesis in mice. Benefit versus risk must be weighed carefully before using azathioprine in patients of reproductive potential. The patient should be apprised of the potential hazard to the fetus if azathioprine is used during pregnancy or if the patient becomes pregnant while taking this drug. Extra hematologic monitoring should be considered during pregnancy. A National Transplantation Pregnancy Registry (NTPR) has been established to monitor maternal-fetal outcomes of pregnant women exposed to immunosuppressant drugs, including azathioprine. Physicians are encouraged to register patients by calling 1-215-955-4820 (USA). AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Use is considered contraindicated unless the benefits outweigh the risks. Rheumatoid arthritis: Contraindicated (US) AU TGA pregnancy category: D US FDA pregnancy category: D Comments: Adequate methods of contraception should be encouraged in both male and female patients of reproductive age during, and for at least 3 months after treatment cessation.

LactMed Record Number

20

Last Revision Date

20170808

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