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Product information

PRODUCT INFORMATION
IMURAN (azathioprine)
50-mg Scored Tablets
Rx only
WARNING: Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans.
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. See WARNINGS.
DESCRIPTION:
IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration.
Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato
starch, povidone, and stearic acid.
Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the 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.
CLINICAL PHARMACOLOGY:

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 IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN.4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN 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 Tests and ADVERSE REACTIONS sections.
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. INDICATIONS AND USAGE:
IMURAN is 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: IMURAN is 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 IMURAN on these variables has not been tested in controlled trials.
Rheumatoid Arthritis: IMURAN is 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 IMURAN. The combined use of IMURAN with disease modifying anti-rheumatic drugs
(DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with
these agents cannot be recommended.
CONTRAINDICATIONS:
IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN 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 neoplasia
if treated with IMURAN.
WARNINGS:
Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated
with IMURAN. 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
IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening
myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify
patients who are at an increased risk for developing IMURAN 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 IMURAN 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 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. IMURAN is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient’s risk of neoplasia. 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. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to IMURAN. 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. Data on neoplasia in patients receiving IMURAN can be found under ADVERSE REACTIONS. IMURAN 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. IMURAN can cause fetal harm when administered to a pregnant woman.
IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible,
use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid
IMURAN 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 IMURAN. 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 IMURAN 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. PRECAUTIONS:
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 IMURAN and are reversible upon discontinuation of the drug. The reaction can recur
within hours after re-challenge with a single dose of IMURAN.
Information for Patients: Patients being started on IMURAN 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 IMURAN and asked to report
signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient,
especially when IMURAN is 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 IMURAN during pregnancy and during the nursing period. The increased risk of
neoplasia following therapy with IMURAN should be explained to the patient.
Laboratory Tests: 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.
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 IMURAN.
See CLINICAL PHARMACOLOGY, WARNINGS,
ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections.
Drug Interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by
allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN,
to approximately 1/3 to 1/4 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 IMURAN 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 IMURAN 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: IMURAN may inhibit the anticoagulant effect of warfarin.
Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section.
Pregnancy: Teratogenic Effects: Pregnancy Category D. See WARNINGS section.
Nursing Mothers: 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.
Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established.
ADVERSE REACTIONS:
The principal and potentially serious toxic effects of IMURAN 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 IMURAN 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 IMURAN for rheumatoid arthritis. The relative incidences in
clinical studies are summarized below:
Toxicity Renal
Homograft
Rheumatoid
Arthritis
* 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 per 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 IMURAN. 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
non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. 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 IMURAN, 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 IMURAN. 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 IMURAN 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, IMURAN 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 and hepatosplenic T-
cell lymphoma.

OVERDOSAGE:

The oral LD50s for single doses of IMURAN 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
IMURAN 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 IMURAN. 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. DOSAGE AND ADMINISTRATION:
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN
PATIENTS RECEIVING IMURAN.
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 IMURAN if conventional doses are given. Physicians may consider
alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles).
IMURAN 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 IMURAN 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. IMURAN is 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 IMURAN 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: IMURAN is 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. IMURAN 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 IMURAN has not been determined. IMURAN 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 IMURAN 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.
HOW SUPPLIED: 50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with
“IMURAN” and “50” on each tablet; bottle of 100 (NDC 65483-590-10).
Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light.

REFERENCES:
1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329-339.
2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase.
Drug Metab Dispos. 2001;29:601-605. 3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89-98. 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. 1998; 41:1858-1866. 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. 2004; 43:13-18. 10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat 11. Data on file, Prometheus Laboratories Inc. 12. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial 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. 16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 17. Data on file, Prometheus Laboratories Inc. 18. Saarikoski S, Seppälä 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: 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 veno-occlusive 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. 24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302. 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- 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. PROMETHEUS LABORATORIES INC.
Manufactured by Pharmaceutics International, Inc.
Hunt Valley, MD 21031
for Prometheus Laboratories Inc.
San Diego, CA 92121

Source: http://www.prometheuspatients.com/PDF/Imuran.pdf

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