PURIXAN

PURIXAN — mercaptopurine suspension
Nova Laboratories, Ltd

1 INDICATIONS AND USAGE

1.1 Acute Lymphoblastic Leukemia

PURIXAN is indicated for the treatment of patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended starting dose of PURIXAN is 1.5 to 2.5 mg/kg (50 to 75 mg/m2) orally once daily as part of combination chemotherapy maintenance regimen. Take PURIXAN either consistently with or without food.
After initiating PURIXAN, monitor complete blood counts (CBC) and adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for excessive myelosuppression. Evaluate the bone marrow in patients with prolonged myelosuppression or repeated episodes of myelosuppression to assess leukemia status and marrow cellularity.
Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients with severe myelosuppression or repeated episodes of myelosuppression [see Dosage and Administration (2.2)].
If a patient misses a dose, instruct the patient to continue with the next scheduled dose.

2.2 Dosage Modifications in Patients with TPMT and/or NUDT15 Deficiency

Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression 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 recommended dosage. Reduce the recommended starting dosage of PURIXAN 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 dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

2.3 Dosage Modifications in Renal and Hepatic Impairment

Renal Impairment
Use the lowest recommended starting dosage for PURIXAN in patients with renal impairment (CLcr less than 50 mL/min). Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.6)].
Hepatic Impairment
Use the lowest recommended starting dosage for PURIXAN in patients with hepatic impairment. Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.7)].

2.4 Dosage Modification with Concomitant Use of Allopurinol

Reduce the dose of PURIXAN to one-third to one-quarter of the current dosage when coadministered with allopurinol [see Drug Interactions (7.1)].

2.5 Administration

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.
Provide a press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL).
Train patients or caregivers on proper handling, storage, administration, disposal and clean-up of accidental spillage prior to initiation of PURIXAN and during each visit to the clinic.
Advise patients and caregivers to use PURIXAN within 8 weeks and properly discard remaining PURIXAN after 8 weeks.
Provide instructions regarding which syringe to use and how to administer the specified dose, since PURIXAN is supplied with 1 mL and 5 mL oral dispensing syringes.
Advise patients that the oral dispensing syringe is intended for multiple uses and provide the following instructions:

  • 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; and
  • Store the oral dispensing syringe in a hygienic place with PURIXAN.

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.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

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 (2.1)].
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 (2.2), Clinical Pharmacology (12.5)].
Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression. [see Drug Interactions (7.1, 7.3 and 7.4)]. Reduce the dosage of PURIXAN when coadministered with allopurinol [see Dosage and Administration (2.4)].

5.2 Hepatotoxicity

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 (7.5)] or with known pre-existing liver disease. Withhold PURIXAN at onset of hepatotoxicity.

5.3 Immunosuppression

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.

5.4 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.

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