Azasan

Name: Azasan

What are the side effects of azathioprine?

The most common serious side effects of azathioprine involve the cells of the blood and gastrointestinal system. Azathioprine can cause serious lowering of the white blood cell count, resulting in an increased risk of infections. This effect is reversed when the dose of azathioprine is reduced or temporarily discontinued. Azathioprine can cause nausea, vomiting, and loss of appetite, which may resolve when the daily dose is reduced or divided and taken more than once a day. Azathioprine can cause liver toxicity (for example, in less than 1% of rheumatoid arthritis patients). All patients taking azathioprine require regular testing of blood for blood cell counts and liver tests to monitor for side effects of azathioprine. Other side effects encountered less frequently include fatigue, hair loss, joint pains, and diarrhea.

Description

AZASAN® (azathioprine) , an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 75 mg or 100 mg azathioprine and the inactive ingredients lactose monohydrate, pregelatinized starch, povidone, corn starch, magnesium stearate, and stearic acid.

Azathioprine is chemically 1H-purine, 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-. 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 is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. 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.

How supplied

AZASAN® (azathioprine) Tablets, USP are available in:

75 mg, triangle-shaped, yellow, scored tablets,

100 count bottles (NDC 65649-231-41)
15 count samples (NDC 65649-231-51)

100 mg, diamond-shaped, yellow, scored tablets,

100 count bottles (NDC 65649-241-41)
15 count samples (NDC 65649-241-51)

Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature]

Store in a dry place and protect from light.

Dispense in a tight, light-resistant container as defined in the USP.

REFERENCES

25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621.

26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590-1592.

27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428.

29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263.

30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049.

31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204.

Manufactured by: AAIPharma Inc., Wilmington, NC 28405. Manufactured for: Morrisville, NC 27560.

Side effects

The principal and potentially serious toxic effects of AZASAN® (azathioprine) are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of AZASAN® (azathioprine) as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing AZASAN® (azathioprine) for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

Toxicity Renal Homograft Rheumatoid Arthritis
Leukopenia
  Any Degree > 50% 28%
< 2500 cells/mm 316% 5.3%
Infections 20% < 1%
Neoplasia   *
  Lymphoma 0.5%  
  Others 2.8%  
*Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg/day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.

Hematologic

Leukopenia and/or thrombocytopenia are dose dependent and may occur late in the course of therapy with AZASAN® (azathioprine) . Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported.

TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for nonfunctional alleles) who are at increased risk for severe, life-threatening myelosuppression from AZASAN®. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS: Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. 6, 20

Gastrointestinal

Nausea and vomiting may occur within the first few months of therapy with AZASAN® (azathioprine) , and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in

divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of AZASAN® (azathioprine) . A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving azathioprine for panuveitis.21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, AZASAN® (azathioprine) should be permanently withdrawn.

Others

Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, and reversible interstitial pneumonitis.

REFERENCES

6. Data on file, Prometheus Laboratories Inc.

20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436.

21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic venoocclusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655.

22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454.

23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256.

Adverse Effects

>10%

Leukopenia (28-50%)

Infection (20%)

<1%

Lymphoma

Frequency Not Defined

Abdominal pain

Alopecia

Arthralgia

Bacterial, fungal, protozoal, viral infections

Bone marrow suppression

Diarrhea

Fever

Hepatotoxicity

Macrocytic anemia

Myalgia

Nausea or vomiting

Rash

Skin cancer

Steatorrhea

Sweet syndrome (acute febrile neutrophilic dermatosis)

Thrombocytopenia

Administration

Oral suspension of 50 mg/mL requires extemporaneous compounding by pharmacist

IV Incompatibilities

Stable in neutral or acid solutions; in alkaline solutions, hydrolyzed to 6-MP

IV Administration

Can be administered by IV push over 5 minutes at concentration not exceeding 10 mg/mL

Can be further diluted with NS or D5W and administered by intermittent infusion over 30-60 minutes (usual approach); however, infusions over periods ranging from 5 minutes to 8 hours have been done

Storage

Store powder at room temperature (25°C); reconstituted solution is stable for 2 weeks at room temperature but may be less stable under refrigeration

Protect from light

Because there are no preservatives, drug must be used within 24 hours

Uses of Azasan

Azasan is a prescription medication used in the following conditions:

  • to prevent transplant rejection, or to prevent an attack of the transplanted organ by the immune system
  • to treat severe rheumatoid arthritis, a condition in which the body attacks its own joints, causing pain, swelling, and loss of function

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Side Effects of Azasan

Serious side effects have been reported with Azasan. See the “Azasan Precautions” section.

Common side effects include the following:

  • nausea
  • vomiting
  • hair loss
  • rash
  • diarrhea
  • fever
  • muscle aches
  • hair loss

This is not a complete list of Azasan side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Inform MD

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

  • are allergic to Azasan 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.

Other Requirements

  • Store Azasan at room temperature.
  • Protect from light.
  • Keep this and all medicines out of the reach of children.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Azasan (azathioprine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using azathioprine and call your doctor right away if you have any of these symptoms of lymphoma:

  • fever, night sweats, weight loss, tiredness;

  • feeling full after eating only a small amount;

  • pain in your upper stomach that may spread to your shoulder; or

  • easy bruising or bleeding, pale skin, feeling light-headed or short of breath, rapid heart rate.

Azathioprine may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

Also call your doctor at once if you have:

  • signs of infection (fever, chills, sore throat, body aches, weakness, muscle pain, flu symptoms);

  • severe nausea, vomiting, or diarrhea;

  • pain or burning with urination;

  • white patches or sores inside your mouth or on your lips; or

  • liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

  • mild upset stomach, nausea, diarrhea, loss of appetite;

  • hair loss; or

  • skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Azasan (azathioprine)?

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.

Uses For Azasan

Azathioprine is used to prevent rejection of a transplanted kidney. It belongs to the group of medicines known as immunosuppressive agents. Azathioprine will lower the body's natural immunity in patients who receive transplants to prevent rejection of the new kidney. It is also used to relieve joint pain and swelling for patients with rheumatoid arthritis.

This medicine is available only with your doctor's prescription.

Proper Use of azathioprine

This section provides information on the proper use of a number of products that contain azathioprine. It may not be specific to Azasan. Please read with care.

Use this medicine exactly as directed by your doctor. Do not take more of it, or less of it, than your doctor ordered. Taking too much may increase the chance of unwanted effects, and taking too little will not help your condition.

This medicine is sometimes given together with other medicines. If you are using several medicines together, make sure you understand how to take them during the day. Ask your doctor to help you plan a way to remember to take your medicines at the right times.

Do not stop taking this medicine without first checking with your doctor.

Azathioprine sometimes causes nausea or vomiting. Taking this medicine after meals or at bedtime may lessen stomach upset. Talk to your doctor if you have questions or continue to have problems with nausea or vomiting.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For kidney transplant rejection:
      • Adults—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 3 to 5 milligrams (mg) per kilogram (kg) of body weight per day given as a single dose once a day. The first dose is started either 1 to 3 days before the transplant or on the day of the transplant. Your doctor may adjust your dose as needed.
      • Children—Use and dose must be determined by your doctor.
    • For rheumatoid arthritis:
      • Adults—Dose is based on body weight and must be determined by your doctor. The starting dose is usually 1 milligram (mg) per kilogram (kg) of body weight per day given as a single dose once a day or divided into two doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 2.5 mg per kg of body weight per day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Azasan Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • chest pain
  • cough or hoarseness
  • fever or chills
  • lower back or side pain
  • painful or difficult urination
  • pinpoint red spots on the skin
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Rare
  • Abdominal or stomach pain or tenderness
  • clay-colored stools
  • dark urine
  • decreased appetite
  • fast heartbeat
  • fever (sudden)
  • headaches
  • itching
  • loss of appetite
  • muscle or joint pain
  • nausea, vomiting, and diarrhea (severe)
  • redness or blisters on the skin
  • swelling of the feet or lower legs
  • unusual feeling of discomfort or illness (sudden)
  • yellow eyes or skin
Incidence not known
  • Abdominal or stomach cramps
  • diarrhea
  • difficulty with breathing
  • difficulty with moving
  • fat in the stool
  • general feeling of illness
  • pale skin
  • sores on the skin
  • sudden loss of weight
  • troubled breathing with movement
  • weight loss

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Nausea or vomiting (mild)
  • swollen joints
Incidence not known
  • Hair loss or thinning of the hair

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How is this medicine (Azasan) best taken?

Use Azasan (azathioprine tablets) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take after meals unless your doctor says otherwise.
  • To gain the most benefit, do not miss doses.
  • Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Azasan Description

Azasan ®, an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 75 mg or 100 mg azathioprine and the inactive ingredients lactose monohydrate, pregelatinized starch, povidone, corn starch, magnesium stearate, and stearic acid.

Azathioprine is chemically 1 H-purine, 6-[(1-methyl-4-nitro-1 H-imidazol5-yl)thio]-. 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 is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. 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.

Adverse Reactions

The principal and potentially serious toxic effects of Azasan ® are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of Azasan ® as well as on the patient's underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing Azasan ® for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

Toxicity Renal Homograft Rheumatoid Arthritis
Lekopenia
Any Degree >50% 28%
<2500 cell/mm 3 16% 5.3%
Infections 20% <1%
Neoplasia *
Lymphoma 0.5%
Others 2.8%

Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg/day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.


Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with Azasan ®. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Anemias, including macrocytic anemia and/or bleeding have been reported.

TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for nonfunctional alleles) who are at increased risk for severe, life-threatening myelosuppression from Azasan ®. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS: Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving

azathioprine. 6, 20


Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with Azasan ®, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/ or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/ or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of Azasan ®. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving azathioprine for panuveitis. 21, 22, 23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, Azasan ® should be permanently withdrawn.


Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma (see Warnings - Malignancy), and Sweet's Syndrome (acute febrile neutrophilic dermatosis).

Overdosage

The oral LD 50s for single doses of Azasan ® 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 Azasan ® 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.

Azathioprine Identification

Substance Name

Azathioprine

CAS Registry Number

446-86-6

Drug Class

Immunosuppressants

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