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AZATHIOPRINE/MERCAPTOPURINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Azathioprine and mercaptopurine (the primary metabolite of azathioprine) are antimetabolites of the purine analog class.

Specific Substances

    A) AZATHIOPRINE
    1) 6-(1-methyl-4-nitroimidazol-5-ylthio)-purine
    2) BW 57-322
    3) NSC 39084
    4) CAS 446-86-6
    MERCAPTOPURINE
    1) 6-mercaptopurine monohydrate
    2) 6-MP
    3) Mercaptopur
    4) Mercaptopurinum
    5) NSC 755
    6) Purine-6-thiol monohydrate
    7) WR 2785
    8) CAS 50-44-2 (mercaptopurine anhydrous)
    9) CAS 6112-76-1 (mercaptopurine monohydrate)

    1.2.1) MOLECULAR FORMULA
    1) MERCAPTOPURINE MONOHYDRATE: C5H4N4S.H20

Available Forms Sources

    A) FORMS
    1) Azathioprine is available as 50 mg tablets and 100 mg/20 mL vial for intravenous injection (Prod Info IMURAN(R) oral tablets, IV injection, 2005).
    2) Mercaptopurine is available as 50 mg tablets (Prod Info PURINETHOL(R) oral tablets, 2011).
    B) USES
    1) Azathioprine is used as an immunosuppressive agent in renal transplantation, multiple myeloma, chronic inflammatory polyneuropathy, myasthenia gravis, polymyositis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and pemphigus vulgaris (Prod Info IMURAN(R) oral tablets, IV injection, 2005; Dorr & Von Hoff, 1994a; Kissel et al, 1986).
    2) Mercaptopurine is indicated in the treatment of acute leukemia (as induction and maintenance therapy) (Prod Info PURINETHOL(R) oral tablets, 2011; Dorr & Von Hoff, 1994a).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Bone marrow suppression is the dose-limiting toxicity following azathioprine therapy. Other adverse effects following therapeutic administration of either azathioprine or 6-mercaptopurine include fever, hepatitis, pancreatitis, skin rashes, and alopecia.
    B) WITH POISONING/EXPOSURE
    1) Oral overdose results in nausea, vomiting, delayed leukopenia, increased SGOT and bilirubin, and impaired renal function.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported following azathioprine or 6-mercaptopurine therapy.
    0.2.20) REPRODUCTIVE
    A) Azathioprine and mercaptopurine are classified as pregnancy category D. No cases of human malformations have been attributed to therapy with mercaptopurine or azathioprine. These drugs do induce teratogenic effects (limb, eye, digits, skeletal, CNS) in various animals (rat, mouse, rabbit, hamster).
    0.2.21) CARCINOGENICITY
    A) Hepatosplenic T-cell lymphoma has been reported with both azathioprine and mercaptopurine monotherapy and when used in combination with tumor necrosis factor blockers.

Laboratory Monitoring

    A) Determine baseline CBC and liver function tests.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) SYMPTOMATIC AND SUPPORTIVE MEASURES should be instituted.
    C) DIALYSIS - Has been reported to remove azathioprine and its metabolites.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. ADULT: An adult developed transient neutropenia after ingesting azathioprine 7500 mg. CHILD: Transient neutropenia occurred in a 22-month-old child following ingestion of 1 g of 6-mercaptopurine (86 mg/kg). A 30-month-old child developed elevated liver enzymes following ingestion of 400 mg (500 mg/m(2)) of 6-MP.
    B) THERAPEUTIC DOSE: ADULT: Azathioprine: 1 to 5 mg/kg/day orally. 6-mercaptopurine: 1.5 to 2.5 mg/kg/day orally as a single dose. PEDIATRIC: Azathioprine: Safety and efficacy not established. 6-mercaptopurine: 1.5 to 2.5 mg/kg/day as a single dose, usually in combination with methotrexate.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Bone marrow suppression is the dose-limiting toxicity following azathioprine therapy. Other adverse effects following therapeutic administration of either azathioprine or 6-mercaptopurine include fever, hepatitis, pancreatitis, skin rashes, and alopecia.
    B) WITH POISONING/EXPOSURE
    1) Oral overdose results in nausea, vomiting, delayed leukopenia, increased SGOT and bilirubin, and impaired renal function.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported following azathioprine or 6-mercaptopurine therapy.
    3.3.3) TEMPERATURE
    A) Fever has been reported following azathioprine or 6-mercaptopurine therapy (Prod Info IMURAN(R) oral tablets, IV injection, 2005; Dorr & Von Hoff, 1994a).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) CASE REPORT/PTOSIS: A 37-year-old woman experienced ptosis of her right eye 3 days after she began taking 6-mercaptopurine, 100 mg three times daily, instead of the prescribed propylthiouracil (Gupta et al, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) PULMONARY COMPLICATIONS: A single case of acute restrictive lung disease was reported at a dose of azathioprine of 100 mg/day which resolved after the drug was discontinued (Dorr & Von Hoff, 1994a).
    b) Pulmonary toxicity was reported in 3 patients who received azathioprine or 6-mercaptopurine therapy. All 3 patients developed a cough, shortness of breath, and fever within 4 weeks after beginning therapy with either azathioprine or 6-mercaptopurine for treatment of inflammatory bowel disease. Chest radiographs and CT scans showed diffuse interstitial infiltrates and ground glass opacities. Bronchoscopies and open-lung biopsies were negative for infectious etiologies. However, histopathologic examination of the biopsies indicated bronchiolitis obliterans with organizing pneumonia in one patient and interstitial pneumonitis in another patient. All 3 patients clinically improved following cessation of azathioprine/6-mercaptopurine therapy, although one patient continued to have residual pulmonary defects (Ananthakrishnan et al, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROLOGICAL FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHRONIC INGESTION: Fatigue, night sweats, and headaches were reported in a 37-year-old woman 3 days after she began taking 6-mercaptopurine, 100 mg three times daily, instead of the prescribed propylthiouracil (Gupta et al, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) GI disturbances such as nausea and vomiting are reported and appear to occur mainly at higher doses. Systemic illness (fever, nausea, vomiting, abdominal pain, anorexia, rash or urticaria) was reported in 12% of 64 patients treated therapeutically with azathioprine (Kissel et al, 1986).
    1) CASE REPORT: Two patients developed nausea, vomiting, fever, and diarrhea from a single dose of the drug. The authors classified this as a definite adverse reaction based on a positive rechallenge (Assini et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Nausea, vomiting, diarrhea, mild leukopenia, and liver function abnormalities were reported in a renal transplant patient who ingested 7500 mg azathioprine as a single dose. The patient's WBC count, and SGOT and bilirubin levels normalized 6 days following the overdose (Prod Info IMURAN(R) oral tablets, IV injection, 2005).
    b) A 22-month-old presented with vomiting after ingesting 1 gram 6-mercaptopurine (86 mg/kg, 2600 mg/m(2)) (Chow et al, 2004).
    c) CASE REPORT/CHRONIC INGESTION: Nausea and one episode of vomiting were reported in a 37-year-old woman 3 days after she began taking 6-mercaptopurine, 100 mg three times daily, instead of the prescribed propylthiouracil (Gupta et al, 2009).
    B) ULCERATIVE STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Oral ulceration occurs rarely with therapeutic doses, but may occur with large doses (Dorr & Von Hoff, 1994a).
    C) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Azathioprine has caused severe vomiting in association with drug-induced pancreatitis (Sturdevant et al, 1979).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Hepatic dysfunction (hepatocellular and cholestatic) manifested by elevation of liver function test and onset of jaundice have also been reported (Dorr & Von Hoff, 1994a).
    1) Toxicity can be aggravated by combined administration of allopurinol, a xanthine oxidase inhibitor, unless dosage of each drug is reduced.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Elevated SGOT and bilirubin levels developed in a renal transplant patient following an overdose ingestion of 7500 mg azathioprine (Prod Info IMURAN(R) oral tablets, IV injection, 2005).
    b) CASE REPORT/CHRONIC INGESTION: A 37-year-old woman, with hyperthyroidism, developed elevated liver enzyme levels (AST 86, ALT 141, Alkaline phosphatase 127) after inadvertent chronic ingestion of 6-mercaptopurine, 100 mg three times daily for 6 days (total dose 1800 mg) instead of the prescribed propylthiouracil. With supportive care, the patient's liver enzyme levels normalized 21 days post-ingestion (Gupta et al, 2009).
    c) CASE REPORT/CHILD: A 30-month-old child unintentionally ingested 8 6-mercaptopurine tablets (total ingestion: 400 mg (500 mg/m2)) prescribed for his sister. Liver cytolysis on days 1 and 3 revealed a peak AST concentration of greater than 3 times normal and a peak ALT concentration of greater than 5 times normal, respectively. There was no evidence of cholestasis or cytopenia during this time, and his liver enzymes normalized within 12 days. Crystals in the urine confirmed 6-mercaptopurine ingestion (Fernandez et al, 2015).
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Hepatitis and hepatic veno-occlusive disease have been reported (Katzka et al, 1986; Read, 1986; Barrowman et al, 1986; Cooper et al, 1986; Farge et al, 1986). During therapeutic administration of azathioprine to 64 patients, hepatotoxicity was reported in 9% (Kissel et al, 1986).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Transient hematuria and crystalluria have been documented following high dose intravenous bolus therapy with 6-mercaptopurine (Duttera et al, 1972).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Toxicity following the therapeutic use of these drugs primarily involves depression of the bone marrow, with leukopenia, anemia, thrombocytopenia and bleeding reported (Dorr & Von Hoff, 1994a).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia is the primary hematologic effect (Dorr & Von Hoff, 1994a). During therapeutic administration of azathioprine to 64 patients reversible leukopenia was reported in 22%, and macrocystosis in 20% (Kissel et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Mild leukopenia occurred in a renal transplant patient following an overdose ingestion of 7500 mg azathioprine. The patient's WBC count normalized 6 days after the overdose. (Prod Info IMURAN(R) oral tablets, IV injection, 2005).
    b) CASE REPORT: A 22-month-old ingested 1 gram 6-mercaptopurine (86 mg/kg, 2600 mg/m(2)) and developed vomiting. She developed neutropenia with a nadir neutrophil count of 0.49x10(9)/L 11 days after ingestion which gradually returned to normal without therapy on day 46 following ingestion (Chow et al, 2004).
    C) COAG./BLEEDING TESTS ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHRONIC INGESTION: A 37-year-old woman, with hyperthyroidism, developed a prothrombin (PT) time of 18.1 with an INR of 1.7 after inadvertent chronic ingestion of 6-mercaptopurine, 100 mg three times daily for 6 days (total dose 1800 mg) instead of the prescribed propylthiouracil. Following overnight observation and administration of 5 mg vitamin K, the patient showed improvement with a decrease in her PT and INR (16.8 and 1.6, respectively) (Gupta et al, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rash has occurred following therapeutic administration of azathioprine and 6-mercaptopurine (Dorr & Von Hoff, 1994a; Kissel et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHRONIC INGESTION: An erythematous, diffuse rash and darkening of the malar area were reported in a 37-year-old woman following inadvertent ingestion of 6-mercaptopurine, 100 mg three times daily for 6 days (total dose 1800 mg), instead of the prescribed propylthiouracil (Gupta et al, 2009).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia may occur (Dorr & Von Hoff, 1994a).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHRONIC INGESTION: Hair loss was reported in a 37-year-old woman 3 days after she began taking 6-mercaptopurine, 100 mg three times daily, instead of the prescribed propylthiouracil (Gupta et al, 2009).
    C) GENERALIZED EXFOLIATIVE DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A severe palmar-plantar erythema with desquamation and pain was reported in a 32 year old man receiving mercaptopurine 400 mg/day (high dose) and allopurinol 200 mg/day.
    1) The authors concluded that such combination therapy results in toxic mercaptopurine levels due to allopurinol's ability to block xanthine oxidase, an enzyme necessary for metabolism of mercaptopurine (Cox & Robertson, 1986).
    2) This was successfully treated with discontinuation of mercaptopurine and initiation of topical steroid therapy (Cox & Robertson, 1986).
    D) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria has been reported (Kissel et al, 1986).
    E) INJECTION SITE REACTION
    1) EXTRAVASATION: Azathioprine is not a vesicant and will not cause skin damage if the intravenous solution is accidentally administered interstitially.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Immunosuppressed patients are at risk for opportunistic infectious complications with azathioprine therapy (Dorr & Von Hoff, 1994a).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 49-year-old man developed nausea, vomiting, hypotension, cardiomyopathy, shock, acute renal failure, and elevated liver enzyme levels following therapy with azathioprine, 50 mg/day for 2 weeks. The patient completely recovered following aggressive symptomatic and supportive treatment (Brown et al, 1997). The authors attributed the patient's multi-organ effects to a hypersensitivity reaction to the azathioprine.

Reproductive

    3.20.1) SUMMARY
    A) Azathioprine and mercaptopurine are classified as pregnancy category D. No cases of human malformations have been attributed to therapy with mercaptopurine or azathioprine. These drugs do induce teratogenic effects (limb, eye, digits, skeletal, CNS) in various animals (rat, mouse, rabbit, hamster).
    3.20.2) TERATOGENICITY
    A) IMMUNOLOGIC ABNORMALITIES
    1) Lymphopenia, reduced IgG and IgM levels, and cytomegalovirus infection together with reduced thymic shadow occurred in 1 infant exposed to azathioprine 150 mg/day and prednisone 30 mg/day to prevent renal allograft rejection throughout pregnancy. Most features had normalized by 10 weeks (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    2) Pancytopenia and severe immune deficiency were noted in 1 preterm infant with prenatal exposure to azathioprine 125 mg/day and prednisone 12.5 mg/day to prevent renal allograft rejection (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    B) CONGENITAL ABNORMALITIES
    1) Preaxial polydactyly occurred in 1 infant exposed to azathioprine 200 mg/day and prednisone 20 mg every other day during pregnancy. Another infant conceived with long-term paternal azathioprine exposure was born with a large myelomeningocele in the upper lumbar region, bilateral hip dislocation, and bilateral talipes equinovarus (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    C) PERINATAL DISORDER
    1) Aniridia was reported in a six-week old infant. Karyotyping of the infant showed an abnormal chromosomal constitute with a deletion, consistent with a diagnosis of WAGR syndrome (Wilms tumor, aniridia, genital anomalies, retardation), although an abdominal ultrasound of the infant showed normal-size kidneys and no Wilms tumor. Because both parents showed normal karyotypes following chromosomal analysis, it is believed that the infant's chromosomal aberration may have been due to paternal ingestion of azathioprine prior to conception (Ben-Neriah & Ackerman, 2001).
    D) LACK OF EFFECT
    1) AZATHIOPRINE: An retrospective case control study of 10 years of Australian birth records found that women with chronic inflammatory bowel disease (IBD) exposed to either azathioprine (AZA) mercaptopurine (MP) throughout pregnancy did not have a higher risk of preterm birth, low birth weight, neonatal adverse effects, or congenital anomalies when compared with unexposed controls. A total of 93 births from 63 women were eligible for the study, with 19 births in the exposed group (exposure to AZA (n=18; mean dose 100 mg) or MP (n=1; 100 mg dose) during first trimester) and 74 births in the control group (IBD patients with no exposure to AZA or MP during pregnancy). Concurrent therapies in both the exposed and control groups included 5-aminosalicylic acid (68.4% and 45.9%, respectively) and corticosteroids (57.9% and 12.2%, respectively). A nonsignificant increase in preterm births occurred in the exposed group compared with controls (26.3% vs 13.5%; odds ratio (OR) 2.28 (95% confidence interval (CI), 0.67 to 7.73)); comparisons of neonatal adverse outcomes requiring intensive care (5.3% vs 5.4%, respectively; OR 0.97 (95% CI, 0.1 to 9.23)) and congenital anomalies (5.3% vs 1.4%, respectively; OR 4.05 (95% CI, 0.24 to 67.99)) were also nonsignificant . Two infants were born with congenital abnormalities (congenital hyperplastic heart in the exposed group and congenital reflux nephropathy in the control group). No low-birth-weight infants were born in either group. Researchers did note a significantly increased risk of adverse birth outcomes with corticosteroid use (adjusted OR 8.8 (95% CI, 2.73 to 28.3) among exposed women compared with controls (Shim et al, 2011).
    2) There are no bona fide cases of human malformations attributed to maternal treatment with azathioprine. There are 77 cases of normal infants born under treatment with this drug (Schardein, 1985).
    3) MERCAPTOPURINE: Many studies (24 cases) report normal offspring following maternal therapy during early pregnancy (Schardein, 1985). A retrospective case control study of 10 years of Australian birth records found that women with chronic inflammatory bowel disease (IBD) exposed to either azathioprine (AZA) mercaptopurine (MP) throughout pregnancy did not have a higher risk of preterm birth, low birth weight, neonatal adverse effects, or congenital anomalies when compared with unexposed controls (Shim et al, 2011).
    4) In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, there were no cases of macroscopically abnormal fetuses (Prod Info mercaptopurine oral tablets, 2013). Numerous cases of mercaptopurine use in combination chemotherapy have not resulted in fetal abnormalities (Prod Info PURIXAN(TM) oral suspension, 2014).
    5) Mercaptopurine was given throughout the third trimester to a 34-year-old pregnant woman being treated for acute lymphoblastic leukemia. Other cytotoxic agents used during therapy were daunorubicin, vincristine, asparaginase, and prednisone. A healthy infant was born after 18 weeks of chemotherapy. The infant had a normal karyotype, but with several gaps and a ring chromosome. Chromosomal abnormalities may persist for several years and may increase the risk of cancer and genetic damage in the next generation (Schleuning & Clemm, 1987).
    6) A case report described an infant born without congenital abnormalities to a 25-year-old woman treated for left-sided ulcerative colitis throughout her entire pregnancy with combination therapy of allopurinol 100 mg and low-dose mercaptopurine 25 mg. During routine gestational follow-ups, no fetal abnormalities or growth restrictions were seen, and an uncomplicated cesarean section was performed at 39 weeks gestational age. The infant had a birth weight of 3550 g and had an Apgar score of 9/10/10 at 1, 5, and 10 minutes. At the time of delivery, the level of 6-thioguanine nucleotides (6-TGN) in the umbilical cord vein was 88 picomoles (pmol)/8 x 10(8) and the level of 6-methylmercaptopurine (6-MMP) was undetectable, while the maternal level of 6-TGN was 112 pmol/8 x 10(8) and 6-MMP was 160 pmol/8 x 10(8) (Seinen et al, 2013).
    E) ANIMAL STUDIES
    1) RABBITS, MICE: Skeletal malformations and visceral abnormalities have been reported with exposures equivalent to the human dose during rabbit and mouse gestation (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    2) These drugs do induce teratogenic effects (limb, eye, digits, skeletal, CNS) in various animals (rat, mouse, rabbit, hamster) (Schardein, 1985; Prod Info PURIXAN(TM) oral suspension, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Azathioprine is classified as pregnancy category D (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014). Azathioprine has been used during pregnancy in organ transplant recipients. During over 40 years of experience with azathioprine as an immunosuppressant in organ transplant patients, no predominant or specific malformation pattern has been identified which is attributable to this drug. Retrospective review of pregnancy outcomes revealed that infants exposed to azathioprine may develop the following adverse effects: thymic atrophy, leukopenia, anemia, thrombocytopenia, chromosome aberrations, reduced immunoglobulin levels, and infections. Adjustment of azathioprine dosage to maintain normal maternal leukocyte counts may decrease or prevent neonatal leukopenia and thrombocytopenia (Armenti et al, 1998). Current guidelines regarding pregnant renal transplant patients state that immunosuppressive therapy with or without steroids and azathioprine may be continued during pregnancy (EBPG Expert Group on Renal Transplantation, 2002). The manufacturer warns that azathioprine should not be used for treating rheumatoid arthritis in pregnant women, and that benefit versus risk must be weighed thoroughly before use in any patient of reproductive potential. Additionally, women of childbearing potential should avoid becoming pregnant while undergoing treatment with azathioprine (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    2) Mercaptopurine is classified as pregnancy category D (Prod Info PURIXAN(TM) oral suspension, 2014; Prod Info mercaptopurine oral tablets, 2013).
    3) Mercaptopurine can cause fetal harm when administered during pregnancy. Women of reproductive potential should be advised to avoid pregnancy while receiving the drug. Women using mercaptopurine during pregnancy should be advised of potential hazard to the fetus. Women treated with mercaptopurine in the first trimester of pregnancy have an increased incidence of abortion and stillbirth; the risk of malformation in surviving offspring is not known (Prod Info PURIXAN(TM) oral suspension, 2014; Prod Info mercaptopurine oral tablets, 2013).
    B) ADVERSE BIRTH OUTCOME
    1) Mercaptopurine can cause fetal harm when administered during pregnancy. Women treated with mercaptopurine in the first trimester of pregnancy have an increased incidence of abortion and stillbirth. The risk of malformation in surviving offspring is not known (Prod Info PURIXAN(TM) oral suspension, 2014; Prod Info mercaptopurine oral tablets, 2013).
    2) In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died undelivered, 1 delivered a stillborn child, and 1 aborted (Prod Info PURIXAN(TM) oral suspension, 2014; Prod Info mercaptopurine oral tablets, 2013).
    3) A Danish cohort study found that women exposed to either mercaptopurine (MP) or azathioprine (AZA) during pregnancy had a higher risk of adverse birth outcomes than unexposed controls; however, induced preterm birth was the only higher adverse birth outcome when the comparison was limited to women with similar underlying diseases. The Fertility Database, Statistics Denmark was used to compare birth outcomes of women who filled prescriptions for MP or AZA during pregnancy to birth outcomes of women who did not. The drug-exposed group was divided into the early pregnancy group (filled prescriptions from 30 days before conception to the end of the first trimester; n=64), used to estimate the risk of congenital abnormalities (CA), and the entire pregnancy group (filled prescriptions during the first through the third trimesters; n=65), used to estimate the risk of preterm birth and low birth weight (LBW) at term. There were 6/64 CA in the early pregnancy group vs 49/1243 in the control group (relative risk (RR), 2.3; 95% confidence interval (CI), 1-5.2). In the entire pregnancy group, 8/65 had spontaneous preterm birth vs 51/1274 in the control group (RR, 3; 95% CI, 1.5-6.2), and 9/65 had induced preterm birth vs 8/1274 in the control group (RR, 22.9; 95% CI, 9.3-56.3). No difference was found for LBW at term. A comparison with another cohort (n=174), with similar underlying diseases and drug exposure prior to pregnancy but not during or in the prior 3 months, showed no differences for LBW at term or CA. This group had 19/174 spontaneous preterm births (RR, 1.1; 95% CI, 0.5-2.6), and 6/174 induced preterm births (RR, 4.6; 95% CI, 1.7-12). The study lacked knowledge of patient compliance, treatment dose/length, data on smoking/alcohol use, and data on miscarriages/induced abortions (Langagergaard et al, 2007).
    4) In a review of 140 pregnancies, the incidence of pregnancy-related complications was significantly increased when fathers with inflammatory bowel disease had taken mercaptopurine within 3 months of conception. Among the 57 men identified, 23 were taking mercaptopurine before fertilization and fathered 50 pregnancies. This group was further subdivided into pregnancies fathered by men who had taken mercaptopurine within 3 months of conception (n of 13) and those fathered by men who had discontinued mercaptopurine at least 3 months before conception (n of 37). The remaining 34 men (control group) did not take mercaptopurine before fertilization (19 had never taken it and 15 had taken it after conception) and fathered 90 pregnancies. The mercaptopurine group received a mean daily dose of 100 milligrams (mg) for a range from a few weeks to 19 years. Among the 13 pregnancies occurring within 3 months of mercaptopurine administration, four (30.7%) were associated with complications, including two spontaneous abortions in the first trimester, and two congenital anomalies (15.3%). The congenital anomalies included a missing thumb in a male child and acrania combined with digital and limb abnormalities in one fetus. No congenital anomalies and two spontaneous abortions occurring in the first trimester were reported in the control group. The risk of pregnancy-related complications was significantly increased in the group of men taking mercaptopurine within 3 months of conception compared with men discontinuing mercaptopurine therapy at least 3 months prior to conception (p less than 0.013) and compared with the control group (p less than 0.002). No maternal illnesses or exposures to medications, infections, radiation, and toxins during pregnancy were observed in either study group (Rajapakse et al, 2000).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) MERCAPTOPURINE
    a) At the time of this of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans. Therefore, a decision should be made to discontinue the drug or discontinue breastfeeding (Prod Info PURIXAN(TM) oral suspension, 2014; Prod Info mercaptopurine oral tablets, 2013).
    B) AZATHIOPRINE
    1) SUMMARY: Low concentrations of azathioprine and its metabolites are found in breast milk (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014; Coulam et al, 1982). While low 6-mercaptopurine (MP-6 levels) were detected in 2 of 31 breast milk samples in one prospective observational study (n=10), researchers concluded from the absence of detectable infant serum MP-6 or 6 thioguanine nucleotide (6-TGN) levels that azathioprine-treated women with normal thiopurine methyltransferase activity may breastfeed (Sau et al, 2007), a recommendation echoed in another 8-subject prospective study that extrapolated a maximum infant exposure of less than 0.008 mg 6-MP/kg/body weight/day (less than 1% of the maternal dose) (Christensen et al, 2008). In 2 other cases, there was negligible infant exposure, with no adverse events in infants breastfed by mothers receiving azathioprine (Moretti et al, 2006). However, breastfeeding while undergoing treatment with azathioprine is not recommended by the manufacturer. In light of the tumorigenic potential demonstrated by azathioprine, a decision to either discontinue nursing or discontinue the drug should be made (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    2) Levels of 6-mercaptopurine (6-MP) in the breast milk of 8 lactating women administered azathioprine 75 to 200 mg maintenance therapy once daily (duration, 0.3 to 7 years) for inflammatory bowel disease peaked within 4 hours of intake (range, 2 to 50 mcg/L), then dropped after 6 hours to an average of 10% of peak values, extrapolating to a maximum infant exposure of less than 1% of the daily maternal dose (less than 0.008 mg 6-MP/kg/body weight/day). Baseline plasma 6-MP values were measured 24 hours after the last azathioprine dose; milk and plasma measurements were then recorded from samples obtained 30 and 60 minutes after azathioprine administration, then hourly for the next 5 hours. Thiopurine methyltransferase activity was normal in all subjects. No measurements of serum 6-thioguanine nucleotide or N-methylolpentamethylmelamine levels were recorded in the subjects or their infants. The researchers deemed breastfeeding generally safe with azathioprine therapy given the low maximum infant exposure to 6-MP (Christensen et al, 2008).
    3) A prospective observational cohort study (n=10) of breastfeeding women administered azathioprine 75 mg to 150 mg once daily for treatment of lupus, renal transplant or Crohn's disease found low concentrations of 6-mercaptopurine (6-MP) in 2 of 31 breast milk samples, but no detectable active metabolites in the serum levels of their infants nor any clinical or hematological signs of immunosuppression. After delivery, each woman contributed one to 6 samples of breast milk between days 3 and 28, with 16 samples collected within 6 hours of azathioprine administration. Full blood counts and serum 6-MP and 6-thioguanine nucleotide (6-TGN) levels were measured in 7 of the 10 infants. One woman contributed 2 samples containing 1.2 and 7.7 nanogram/mL concentrations of 6-MP (therapeutic immunosuppressant serum level, 50 nanogram/mL) collected 3 and 6 hours, respectively, after azathioprine administration on day 28 (MP-6 levels are measurable within 7 hours of azathioprine initiation). Thiopurine methyltransferase (TPMT) metabolism status was unknown prior to azathioprine initiation. No signs of immunosuppression nor serum 6-MP and 6-TGN were found in the infants in up to 28 days of follow-up (Sau et al, 2007).
    4) CASE SERIES: The clinical outcome of infants of 4 women, who were breastfeeding while taking azathioprine (50 to 100 mg/day), were evaluated. Breast milk samples were obtained from 2 of the 4 women and analyzed, via high performance liquid chromatography (HPLC), to determine the amount of 6-mercaptopurine (6-MP- azathioprine's active metabolite) that is transferred into breast milk. In both samples, the levels of 6-MP were undetectable (HPLC limit of detection was 5 ng/mL). Even if the drug had reached the limit of detection, infant exposure would have been less than 0.09% of the maternal weight-adjusted azathioprine dose. All 4 infants continued to develop normally with no adverse effects reported (Moretti et al, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) AZATHIOPRINE
    a) MICE: Temporary reductions in sperm production and viability and count occurred in mice administered 10 times the human therapeutic dose. Fewer fertile matings occurred with doses of 5 mg/kg (Prod Info IMURAN(R) intravenous injection, 2014; Prod Info IMURAN(R) oral tablets, 2014).
    2) MERCAPTOPURINE
    a) Mercaptopurine may impair fertility. Offspring of female mice that were given chronic low doses during pregnancy were sterile, or if they became pregnant, had reduced litter sizes and increased fetal deaths (Prod Info PURIXAN(TM) oral suspension, 2014; Prod Info mercaptopurine oral tablets, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Hepatosplenic T-cell lymphoma has been reported with both azathioprine and mercaptopurine monotherapy and when used in combination with tumor necrosis factor blockers.
    3.21.3) HUMAN STUDIES
    A) HEPATOSPLENIC T-CELL LYMPHOMA
    1) As of December 31, 2010, the US Food and Drug Administration has documented 28 cases worldwide of hepatosplenic T-cell lymphoma (HSTCL) in patients who received tumor necrosis factor (TNF) blockers since the initiation of TNF blockers to the market, mostly occurring in patients who received combination therapy with azathioprine or mercaptopurine. Most cases were fatal and patients were primarily adolescents and young adults who were being treated for Crohn's disease or ulcerative colitis. Twelve additional cases of HSTCL were reported in patients receiving azathioprine alone, which resulted in 10 deaths. Among the 12 cases, 5 patients also received either a concomitant steroid (n=4) or mesalamine (n=1). The median patient age was 21 years (range, 15 to 45 years), patients were predominantly male (n=8), and the duration of use was 4 to 17 years for either Crohn's disease (n=6), ulcerative colitis (n=5), or hepatitis with ulcerative colitis (n=1). Three additional cases of HSTCL occurred in patients receiving mercaptopurine alone (all fatal). Among the 3 cases, the mean patient age was 24 years (range, 18 to 33 years), all of the patients were male, and the duration of use was 3 to 8 years for Crohn's disease (US Food and Drug Administration, 2011).
    B) CARCINOMA
    1) There is a higher risk of malignancy reported in transplant patients receiving azathioprine (Dorr & Von Hoff, 1994a).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Determine baseline CBC and liver function tests.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) White blood cell count should be monitored.
    B) BLOOD/SERUM CHEMISTRY
    1) Measurement of red blood cell 6-thioguanine nucleotide concentration may help in predicting bone marrow toxicity (Maddocks et al, 1986).
    2) liver function tests should also be monitored.

Methods

    A) CHROMATOGRAPHY
    1) Measurement of 6-MP concentrations in the plasma has been reported using high pressure liquid chromatography (HPLC) techniques (Sulh et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Determine baseline CBC and liver function tests.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Literature reporting overdose of these drugs is limited; therefore treatment should be symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Obtain a baseline CBC and monitor hepatic and renal function closely. Monitor serial CBC with differential because of possible delayed neutropenia.
    C) NEUTROPENIA
    a) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    1) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    2) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    3) Monitor CBC with differential.
    D) ACETYLCYSTEINE
    1) In a rat model, pretreatment with either N-acetylcysteine or aminoguanidine prevented azathioprine-induced hepatotoxicity. NAC also prevented azathioprine-induced increases in liver lipid peroxidases (malondialdehyde) and prevented azathioprine-induced reductions in glutathione (Raza et al, 2003).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    B) DISPOSAL GUIDELINES
    1) LABELING: Cytotoxic waste should be regarded as HAZARDOUS or TOXIC waste. It must be handled differently from other trash and should be clearly labeled "HAZARDOUS CHEMICAL WASTE - DISPOSE OF PROPERLY" (Anon, 1990).
    2) CONTAINER: Cytotoxic waste may be placed in a leakproof, puncture resistant container which is then placed in disposable wire-tie or sealable 4-mil-thick polyethylene or 2-mil-thick propylethylene bags. These bags should be colored so as to be easily distinguishable from other trash bags, and labeled with a "Cytotoxic Hazard" label (Jeffrey LP, Anderson RW & Fortner CL et al, 1984; Anon, 1986).
    3) SPILL PROCEDURE: Spills should be cleaned up immediately by a person trained in such procedures and wearing appropriate protective clothing (commercial spill kits are available) (Anon, 1990). The area of the spill should be marked so that while cleanup is occurring someone in the area is not accidentally contaminated. Broken glass should be carefully removed possibly by using a scoop. A broom or mop is not advised due to the risk of further contamination of the environment.
    4) DISPOSAL: Cytotoxic waste may be disposed of at an EPA permitted hazardous waste incinerator, an EPA permitted hazardous waste burial site, or by a licensed hazardous waste disposal company and in accordance with all applicable state, federal, and local regulations (Anon, 1990; Jeffrey LP, Anderson RW & Fortner CL et al, 1984).
    C) SMALL SPILL DECONTAMINATION
    1) SUMMARY: Small spills (less than 5 milliliters or 5 grams) should be cleaned immediately by personnel wearing double surgical latex gloves, disposable gown, a face shield or splash goggles and a dust/mist respirator mask (Anon, 1986; Chasse & Gaudet, 1992; Peters, 1995).
    a) CLEAN UP PROCEDURE: Liquids should be adsorbed with gauze pads; solids should be wiped up with wet absorbent gauze (Anon, 1986).
    b) DECONTAMINATION: The spill area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
    c) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).
    D) LARGE SPILL DECONTAMINATION
    1) SUMMARY: Large spills (greater than 5 milliliters or 5 grams) should be covered immediately with absorbent sheets or spill control pads to reduce the spread. If a powder was spilled use a damp cloth or towel (Anon, 1986).
    a) SECURE AREA: Restrict access to the spill area and take precautions to minimize the generation of aerosols (Anon, 1986).
    b) PERSONNEL PROTECTION: Protective clothing should be worn as with the small spill with the addition of a respirator or breathing apparatus when there is an airborne contamination danger (Anon, 1986).
    c) DECONTAMINATION: The area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
    d) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).
    E) PERSONNEL PROTECTION
    1) PROTECTIVE CLOTHING: A double layer of disposable surgical latex gloves, protective disposable gowns (non-permeable, made of lint-free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs) with cuff tucked into glove, eye protection (splash goggles), breathing apparatus, in ventilated cabinets when there is airborne contamination danger (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a; Anon, 1986).
    2) DECONTAMINATION/CLOTHING: Laundering of non-disposable materials has not been demonstrated to remove cytotoxic contaminants. DISPOSAL: The appropriate procedure for the disposal of these materials should be determined by the institution (or as required by state or local regulation or disposal contractor) (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Azathioprine and its metabolites are hemodialyzable (Sharpstone, 1977; Bennett et al, 1980).
    2) 43.47 percent +/- 14.29 percent of the total amount removed during 8 hours (95.38 +/- 31.02 milliliters/minute) in 3 women and 3 men on chronic hemodialysis and receiving immunosuppressive doses of azathioprine (Schusziarra et al, 1976).
    3) Mercaptopurine is rapidly distributed intracellularly and is then not amenable to hemodialysis. Hemodialysis might be effective within a few hours of a very large overdose, but this has not been evaluated clinically (Chow et al, 2004).

Abstracts

Case Reports

    A) Ingestion of 7500 mg of azathioprine in a renal transplant patient has been reported to result in vomiting and diarrhea within 6 to 8 hours (Prod Info IMURAN(R) oral tablets, IV injection, 2005).
    1) Three days post-ingestion WBC dropped to 4100/cu mm with a normal alkaline phosphatase. SGOT and bilirubin were noted to rise with subsequent return to normal in association with improvement in renal function.
    2) Six days post-ingestion WBC was within normal limits. Reinstituting 50 mg/day of azathioprine resulted in a drop in WBC three days later.
    B) The manufacturer has knowledge of one unpublished case of another azathioprine overdose of 850 mg who developed no symptoms or laboratory abnormalities (Prod Info Imuran(R), azathioprine, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. ADULT: An adult developed transient neutropenia after ingesting azathioprine 7500 mg. CHILD: Transient neutropenia occurred in a 22-month-old child following ingestion of 1 g of 6-mercaptopurine (86 mg/kg). A 30-month-old child developed elevated liver enzymes following ingestion of 400 mg (500 mg/m(2)) of 6-MP.
    B) THERAPEUTIC DOSE: ADULT: Azathioprine: 1 to 5 mg/kg/day orally. 6-mercaptopurine: 1.5 to 2.5 mg/kg/day orally as a single dose. PEDIATRIC: Azathioprine: Safety and efficacy not established. 6-mercaptopurine: 1.5 to 2.5 mg/kg/day as a single dose, usually in combination with methotrexate.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AZATHIOPRINE
    a) RENAL TRANSPLANTATION: Initial dose is usually 3 to 5 mg/kg daily beginning on the day of the transplant. Maintenance dose may be 1 to 3 mg/kg daily (Prod Info IMURAN(R) oral tablets, 2014).
    b) RHEUMATOID ARTHRITIS: Initial dose is approximately 1 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. After 6 to 8 weeks, the dose may be increased by dose increments of 0.5 mg/kg daily at 4-week intervals, up to a maximum daily dose of 2.5 mg/kg (Prod Info IMURAN(R) oral tablets, 2014). Maintenance therapy should be at the lowest effective dose.
    2) MERCAPTOPURINE
    a) SOLUTION
    1) The recommended dose for a multiagent combination chemotherapy maintenance regimen is 1.5 to 2.5 mg/kg (50 to 75 mg/m(2)) administered as a single daily dose (Prod Info PURIXAN(TM) oral suspension, 2014).
    b) TABLETS
    1) Maintenance: 1.5 to 2.5 mg/kg/day orally as a single dose (Prod Info mercaptopurine oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) AZATHIOPRINE
    a) Safety and efficacy have not been established in pediatric patients (Prod Info IMURAN(R) oral tablets, 2014).
    2) MERCAPTOPURINE
    a) SOLUTION
    1) The safety and effectiveness of mercaptopurine oral solution have not been established in the pediatric population (Prod Info PURIXAN(TM) oral suspension, 2014).
    b) TABLETS
    1) Maintenance, 1.5 to 2.5 mg/kg/day orally; usually used in combination with methotrexate for the maintenance therapy of children diagnosed with acute lymphatic leukemia (Prod Info mercaptopurine oral tablets, 2013)

Maximum Tolerated Exposure

    A) AZATHIOPRINE
    1) Overdose ingestion of 850 mg azathioprine was tolerated by an adult without producing symptoms; ingestion of 7500 mg transiently produced elevated liver enzymes and leukopenia in another adult (Carney et al, 1974).
    B) MERCAPTOPURINE
    1) CASE REPORT/CHILD: A 22-month-old who ingested 1 gram 6-mercaptopurine (86 mg/kg, 2600 mg/m(2)) presented with vomiting, and developed neutropenia with nadir 11 days postingestion but recovered (Chow et al, 2004).
    2) CASE REPORT/CHILD: A 31-month-old with a maximum potential ingestion of 400 mg (26 mg/kg, 785 mg/m(2)) did not develop clinical or laboratory evidence of toxicity (Chow et al, 2004).
    3) CASE REPORT/CHILD: A 30-month-old child unintentionally ingested 8 6-mercaptopurine tablets (total ingestion: 400 mg (500 mg/m2)). Liver cytolysis on days 1 and 3 revealed a peak AST concentration of greater than 3 times normal and a peak ALT concentration of greater than 5 times normal, respectively. There was no evidence of cholestasis or cytopenia during this time, and his liver enzymes normalized within 12 days. Crystals in the urine confirmed 6-mercaptopurine ingestion (Fernandez et al, 2015).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) 6-MERCAPTOPURINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 80 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) 260 mg/kg (RTECS, 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 159 mg/kg (RTECS, 2001)
    4) LD50- (ORAL)RAT:
    a) 277 mg/kg (RTECS, 2001)
    B) AZATHIOPRINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 273 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) 2500 mg/kg (RTECS, 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 300 mg/kg (RTECS, 2001)
    4) LD50- (ORAL)RAT:
    a) 400 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Azathioprine is an imidazolyl derivative of mercaptopurine (6-mercaptopurine or 6-MP) and functions as an "antimetabolite" or structural analogue by interfering with the synthesis of nucleic acids, thereby preventing cell proliferation.
    B) Azathioprine's immunosuppressive effect is believed to be due to 6-MP, to which azathioprine is metabolized. Azathioprine itself may have cytostatic and cytocidal effects (Sauer et al, 1988).

Physicochemical

Physical Characteristics

    A) AZATHIOPRINE: pale yellow, odorless powder (Sweetman, 2001)
    B) MERCAPTOPURINE is a yellow, odorless or practically odorless, crystalline powder (Prod Info PURIXAN(TM) oral suspension, 2014). that is insoluble in water but soluble in hot alcohol (Dorr & Von Hoff, 1994). The oral suspension is a pink to brown viscous solution (Prod Info PURIXAN(TM) oral suspension, 2014).

Ph

    A) AZATHIOPRINE: Solutions for injection are alkaline (Reynolds, 1982).
    B) MERCAPTOPURINE: 10 to 11 (1% solution of mercaptopurine sodium in water for injection) (Reynolds, 1982)

Molecular Weight

    A) AZATHIOPRINE: 277.3
    B) MERCAPTOPURINE: 152.2
    C) MERCAPTOPURINE MONOHYDRATE: 170.2 (Prod Info PURIXAN(TM) oral suspension, 2014)

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