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
IMURAN and are reversible upon discontinuation of the drug. The reaction can
recur within hours after re-challenge with a single dose of IMURAN.
Complete Blood Count (CBC) Monitoring
Patients on IMURAN 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.
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 nonfunctional 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 IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE
REACTIONS and DOSAGE AND ADMINISTRATION sections.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
See WARNINGS section.
Pregnancy Category D. See WARNINGS section.
The use of IMURAN 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.
Safety and efficacy of azathioprine in pediatric patients
have not been established.
2. Weinshilboum R. Thiopurine pharmacogenetics: clinical
and molecular studies of thiopurine methyltransferase. Drug Metab Dispos.
3. McLeod HL, Siva C. The thiopurine S-methyltransferase
gene locus --implications for clinical pharmacogenomics. Pharmacogenomics.
4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia
related to azathioprine – an enzyme deficiency caused by a common genetic
polymorphism: a review. JR Soc Med. 1992; 85:752-756.
5. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced
thiopurine methyltransferase activity and development of side effects of
azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum.
6. Data on file, Prometheus Laboratories Inc.
7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular
diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for
azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614.
8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine
methyltransferase genotype predicts therapy-limiting severe toxicity from
azathioprine. Ann Intern Med. 1998; 129:716-718.
9. Clunie GP, Lennard L. Relevance of thiopurine
methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology.
10. Clark JM. The mutagenicity of azathioprine in mice,
Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99.
11. Data on file, Prometheus Laboratories Inc.
12. Tagatz GE, Simmons RL. Pregnancy after renal
transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes.
13. Cote' CJ, Meuwissen HJ, Pickering RJ. Effects on the
neonate of prednisone and azathioprine administered to the mother during
pregnancy. J Pediatr. 1974; 85:324-328.
14. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal
pancytopenia and severe combined immunodeficiency associated with antenatal
administration of azathioprine and prednisone. J Pediatr. 1984; 105:625-628.
15. Williamson RA, Karp LE. Azathioprine teratogenicity:
review of the literature and case report. Obstet Gynecol. 1981; 58:247-250.
16. Tallent MB, Simmons RL, Najarian JS. Birth defects in
child of male recipient of kidney transplant. JAMA. 1970; 211: 1854-1855.
17. Data on file, Prometheus Laboratories Inc.
18. Saarikoski S, SeppÃ¤lÃ¤ M. Immunosuppression during
pregnancy: transmission of azathioprine and its metabolites from the mother to
the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106.
19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding
after renal transplantation. Transplant Proc. 1982; 14: 605-609.