Generic name: Mercaptopurine 20mg in 1mL
Dosage form: oral suspension
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The recommended starting dose of PURIXAN in multi-agent combination chemotherapy maintenance regimens is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) as a single daily dose.
After initiating PURIXAN, monitor complete blood counts (CBCs), transaminases, and bilirubin. Maintain ANC at a desirable level by reducing the dose in patients with excessive hematological toxicity. Evaluate the bone marrow in patients with prolonged or repeated marrow suppression to assess leukemia status and marrow cellularity. Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients with clinical or laboratory evidence of severe bone marrow toxicity, or repeated episodes of myelosuppression.
Dosage in Patients with TPMT and/or NUDT15 Deficiency
Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.5)].
Homozygous deficiency in either TPMT or NUDT15
Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard PURIXAN dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency.
Heterozygous deficiency in TPMT and/or NUDT15
Reduce the PURIXAN dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions.
Prior to initiation of PURIXAN and on each visit to the clinic, train patients or caregivers on proper handling, storage, administration, disposal and clean-up of accidental spillage of the medication. Since PURIXAN is supplied with 1 mL and 5 mL oral dispensing syringes, provide appropriate instructions regarding which syringe to use and how to administer a specified dose.
Prior to dispensing, shake the bottle vigorously for at least 30 seconds to ensure the oral suspension is well mixed. PURIXAN is a pink to brown viscous oral suspension.
Once opened, PURIXAN should be used within 8 weeks.
A press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL) are provided.
The oral dispensing syringe is intended for multiple use: wash the oral dispensing syringe with warm ‘soapy’ water and rinse well; hold the oral dispensing syringe under water and move the plunger up and down several times to make sure the inside of the oral dispensing syringe is clean; ensure the oral dispensing syringe is completely dry before use of the oral dispensing syringe again for dosing; and store the oral dispensing syringe in a hygienic place with the medicine.
PURIXAN is a cytotoxic drug. Follow special handling and disposal procedures.1
The most consistent, dose-related toxicity of PURIXAN is bone marrow suppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Monitor CBC and adjust the dose of PURIXAN for severe neutropenia and thrombocytopenia.
Evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency. 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 require substantial dosage reductions of PURIXAN [see Dosage and Administration (2.2), and Clinical Pharmacology (12.5)].
Avoid the concurrent use of allopurinol and PURIXAN. Concomitant allopurinol and PURIXAN can result in a significant increase in bone marrow toxicity. Myelosuppression can be exacerbated by coadministration with drugs that inhibit TPMT (e.g., olsalazine, mesalamine, or sulfasalazine) or drugs whose primary or secondary toxicity is myelosuppression [see Drug Interactions (7.1, 7.3 and 7.4)].
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 the start of treatment with 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 function more frequently in patients who are receiving mercaptopurine with other hepatotoxic drugs or with known pre-existing liver disease. Interrupt PURIXAN in patients with onset of clinical or laboratory evidence 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 children.
PURIXAN can cause fetal harm when administered to a pregnant woman. Women receiving PURIXAN in the first trimester of pregnancy have an increased incidence of abortion. Adverse embryo-fetal findings were reported in women receiving mercaptopurine after the first trimester of pregnancy and included abortion and stillbirth.
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 the drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving PURIXAN [see Use in Specific Populations (8.1)].
Treatment Related Malignancies
Cases of hepatosplenic T-cell lymphoma have 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 mercaptopurine. Monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the prescribing information:
- Myelosuppression [see Warnings and Precautions (5.1)]
- Hepatotoxicity [see Warnings and Precautions (5.2)]
- Immunosuppression [see Warnings and Precautions (5.3)]
- Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]
- Treatment Related Malignancies [see Warnings and Precautions (5.5)]
- Macrophage Activation Syndrome [see Warnings and Precautions (5.6)]
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Based on multicenter cooperative group ALL trials, the most common adverse reaction occurring in > 20% of patients is mylelosuppression including anemia, neutropenia, lymphopenia and thrombocytopenia. Adverse reactions occurring 5 to 20 % include anorexia, nausea, vomiting, diarrhea, malaise, and rash. Adverse reactions occurring in < 5 % of patients include urticaria, hyperuricemia, oral lesions, elevated transaminases, hyperbilirubinemia, hyperpigmentation, infections, and pancreatitis. Oral lesions resemble thrush rather than antifolic ulcerations. Delayed or late toxicities include hepatic fibrosis, hyperbilirubinemia, alopecia, pulmonary fibrosis, oligospermia and secondary malignancies. [see Warnings and Precautions (5.1 and 5.2)].
Drug fever has been reported with PURIXAN. Before attributing fever to PURIXAN, every attempt should be made to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia.
The following adverse reactions have been identified during post-approval use of PURIXAN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: photosensitivity, hypoglycemia, portal hypertension and pancreatitis.
Avoid concomitant use of PURIXAN and allopurinol. Concomitant use of allopurinol with PURIXAN inhibits the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, leading to mercaptopurine toxicity (bone marrow suppression, nausea, vomiting) [see Warnings and Precautions (5.1)].
Concurrent use of PURIXAN and warfarin may result in decreased anticoagulant effectiveness. Monitor prothrombin time or international normalized ratio (INR) in patients receiving oral anticoagulant therapy with warfarin. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.
Bone marrow suppression may be increased when PURIXAN is combined with other drugs whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole. Monitor CBC and adjust the dose of PURIXAN for severe neutropenia and thrombocytopenia [see Warnings and Precautions (5.1)].
Concurrent use of PURIXAN and aminosalicylate derivatives (e.g., olsalazine, mesalamine, or sulfasalazine) may inhibit the TPMT enzyme, resulting in an increased risk of bone marrow suppression. Should aminosalicylate derivatives and PURIXAN be coadministered, use the lowest possible doses of each drug and closely monitor the patient for bone marrow suppression [see Warnings and Precautions (5.1)].
PURIXAN can cause fetal harm when administered to a pregnant woman. Women receiving PURIXAN have an increased incidence of abortion and stillbirth. Advise women to avoid becoming pregnant while receiving PURIXAN. 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 a fetus.
Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of abortion; 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 delivered, 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).
It is not known whether mercaptopurine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mercaptopurine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The evidence for efficacy of mercaptopurine in children with ALL is derived from the published literature and clinical experience. Cases of symptomatic hypoglycemia have been reported in children with ALL receiving mercaptopurine. Reported cases were in children under the age of six 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 other drug therapy.
No formal clinical or pharmacokinetic studies have been conducted in patients with renal impairment.
Starting at the low end of the PURIXAN dosing range, or increasing the dosing interval to 36-48 hours can be considered in patients with baseline renal impairment. Subsequent PURIXAN doses should be adjusted based on efficacy and toxicity [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].
No formal clinical or pharmacokinetic studies have been conducted in patients with hepatic impairment.
Mercaptopurine is hepatotoxic. In patients with baseline hepatic impairment, starting at the low end of the PURIXAN dose range should be considered and patients should be monitored for toxicity [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.2)].
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