Nova Laboratories, Ltd
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2.1 Maintenance Therapy
The starting dose of PURIXAN in multi-agent combination chemotherapy maintenance regimens is 1.5 to 2.5mg/kg (50 to 75 mg/m2) as a single daily dose. After initiating PURIXAN, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.
2.2 Dosage in TPMT-deficient Patients
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require dose reduction. Testing for TPMT gene polymorphism should be considered in patients who experience severe bone marrow toxicities [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.5)]. Homozygous deficient patients may require up to a 90% dosage reduction (10% of the standard PURIXAN dose). Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some require dose reduction based on toxicities.
2.3 Administration Instructions
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. The bottle should be shaken 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 6 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
3. DOSAGE FORMS AND STRENGTHS
Oral Suspension: 2000 mg/100 mL (20 mg/mL) - pink to brown in color.
5. WARNINGS AND PRECAUTIONS
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) deficiency. Patients with homozygous-TPMT deficiency require substantial dose reductions of PURIXAN [see Dosage and Administration (2.1), 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.
5.4 Embryo-Fetal Toxicity
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)].
5.5 Treatment Related Malignancies
Cases of hepatosplenic T-cell lymphoma have been reported in patients treated with mercaptopurine for inflammatory bowel disease, for which mercaptopurine is not approved. Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies.
5.6 Laboratory Tests
Monitor the following laboratory tests in patients receiving PURIXAN: Complete blood counts (CBCs), transaminases, and bilirubin. Evaluate the bone marrow in patients with prolonged or repeated marrow suppression to assess leukemia status and marrow cellularity. Evaluate TPMT status in patients with clinical or laboratory evidence of severe bone marrow toxicity, or repeated episodes of myelosuppression.
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)]
6.1 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. Rare adverse reactions occuring < 5 % include urticaria, hyperuricemia, oral lesions, elevated transaminases, hyperbilirubinemia, hyperpigmentation, 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 very rarely 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.
7. DRUG INTERACTIONS
Certain drugs have been shown to interact with PURIXAN through pharmacokinetic and pharmacodynamic mechanisms. Interactions known to decrease the clearance of PURIXAN include inhibition of first-pass oxidative metabolism by xanthine oxidase and inhibition of thiopurine methyltransferase (TPMT). Consult the labeling of all concurrently used drugs to obtain further information about drug interactions with PURIXAN.
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)].
7.4 Aminosalicylate Derivatives
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)].
8. USE IN SPECIFIC POPULATIONS
Pregnancy Category D [see Warnings and Precautions (5.4)].
Risk Summary 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.Human Data 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.Animal Data Mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse, rabbit, and hamster).
8.3 Nursing Mothers
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.
8.4 Pediatric Use
The safety and effectiveness of mercaptopurine for the treatment of ALL in pediatric patients have not been established in adequate and well-controlled trials. The evidence for efficacy of mercaptopurine is derived from the published literature and clinical experience. The toxicities of mercaptopurine are similar in adults and children.
8.5 Geriatric Use
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.
8.6 Renal Impairment
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)].
8.7 Hepatic Impairment
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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