Included as part of the "PRECAUTIONS" Section
The most consistent, dose-related adverse reaction of PURIXAN is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Monitor CBC and adjust the dosage of PURIXAN for excessive myelosuppression [see DOSAGE AND ADMINISTRATION].
Consider testing for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression. TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes. Patients with homozygous TPMT or NUDT15 deficiency may require a dose reduction [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression [see DRUG INTERACTIONS]. Reduce the dosage of PURIXAN when coadministered with allopurinol [see DOSAGE AND ADMINISTRATION].
Mercaptopurine is hepatotoxic. There are reports of deaths attributed to hepatic necrosis associated with the administration of mercaptopurine. Hepatic injury can occur with any dosage but seems to occur with greater frequency when the recommended dosage is exceeded. In some patients, jaundice has cleared following withdrawal of mercaptopurine and reappeared with rechallenge.
Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months); however, jaundice has been reported as early as 1 week and as late as 8 years after starting mercaptopurine. The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites. Hepatic encephalopathy has occurred.
Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when first beginning therapy and at monthly intervals thereafter. Monitor liver tests more frequently in patients who are receiving PURIXAN with other hepatotoxic drugs [see DRUG INTERACTIONS] or with known pre-existing liver disease. Withhold PURIXAN at onset of hepatotoxicity.
Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines. Due to the immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines. Consult immunization guidelines for immunocompromised patients.
Treatment Related Malignancies
Hepatosplenic T-cell lymphoma has been reported in patients treated with mercaptopurine for inflammatory bowel disease (IBD), an unapproved use. Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies.
Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.
A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.
Macrophage Activation Syndrome
Macrophage activation syndrome (MAS) (hemophagocytic lymphohistiocytosis) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine (an unapproved use). If MAS occurs, or is suspected, discontinue PURIXAN. Monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
PURIXAN can cause fetal harm when administered to a pregnant woman. An increased incidence of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy. Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who received mercaptopurine after the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PURIXAN and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PURIXAN and for 3 months after the last dose [see Use In Specific Populations].
Patient Counseling Information
Advise the patients and caregivers to read the FDA-approved patient labelling (PATIENT INFORMATION and Instructions for Use).
Major Adverse Reactions
Advise patients and caregivers that PURIXAN can cause myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Advise patients to contact their healthcare provider if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia [see WARNINGS AND PRECAUTIONS].
Proper Preparation And Administration
Advise patients or caregivers on proper handling, storage, preparation, administration, and disposal and clean-up of accidental spillage of the medication prior to initiation and on each visit to the clinic [see DOSAGE AND ADMINISTRATION].
- Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
- Advise females of reproductive potential to use effective contraception during treatment with PURIXAN and for 6 months after the last dose [see Use In Specific Populations].
- Advise males with female partners of reproductive potential to use effective contraception during treatment with PURIXAN and for 3 months after the last dose [see Use In Specific Populations, Nonclinical Toxicology].
Advise women not to breastfeed during treatment with PURIXAN and for 1 week after the last dose [see Use In Specific Populations].
Advise males and females of reproductive potential that PURIXAN can impair fertility [see Use In Specific Populations].
Other Adverse Reactions
Instruct patients to minimize sun exposure due to risk of photosensitivity [see ADVERSE REACTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Mercaptopurine is carcinogenic in animals.
Mercaptopurine causes chromosomal aberrations in cells derived from animals and humans and induces dominant-lethal mutations in the germ cells of male mice.
Mercaptopurine can impair fertility. In mice, surviving female offspring of mothers who received chronic low doses of mercaptopurine during pregnancy were found sterile, or if they became pregnant, had smaller litters and more dead fetuses as compared to control animals.
Use In Specific Populations
PURIXAN can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. Pregnant women who receive mercaptopurine have an increased incidence of miscarriage and stillbirth (see Data). Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of miscarriage; the risk of malformation in offspring surviving first trimester exposure is not known. In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died prior to delivery, 1 delivered a stillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses.
Mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse, rabbit, and hamster) at doses less than the recommended human dose.
There are no data on the presence of mercaptopurine or its metabolites in human milk, the effects on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with PURIXAN and for 1 week after the last dose.
Females And Males Of Reproductive Potential
PURIXAN can cause fetal harm when administered to pregnant women [see Pregnancy].
Verify the pregnancy status in females of reproductive potential prior to initiating PURIXAN [see Pregnancy].
Advise females of reproductive potential to use effective contraception during treatment with PURIXAN and for 6 months after the last dose.
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with PURIXAN and for 3 months after the last dose [see Nonclinical Toxicology].
Females and Males
Based on findings from animal studies, PURIXAN can impair female and male fertility [see Nonclinical Toxicology]. The long-term effects of mercaptopurine on female and male fertility, including the reversibility have not been studied.
Safety and effectiveness of PURIXAN has been established in pediatric patients. Use of PURIXAN in pediatrics is supported by evidence from the published literature and clinical experience. Symptomatic hypoglycemia has been reported in pediatric patients with ALL receiving mercaptopurine. Reported cases were in pediatrics less than 6 years or with a low body mass index.
Clinical studies of mercaptopurine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or another drug therapy.
Use the lowest recommended starting dosage for PURIXAN or increase the dosing interval to every 36 to 48 hours in patients with renal impairment (CLcr less than 50 mL/min). Adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see DOSAGE AND ADMINISTRATION].
Use the lowest recommended starting dosage for PURIXAN in patients with hepatic impairment. Adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see DOSAGE AND ADMINISTRATION].