Arranon

ARRANON- nelarabine injection
Novartis Pharmaceuticals Corporation

WARNING: NEUROLOGIC ADVERSE REACTIONS

Severe neurologic adverse reactions have been reported with the use of ARRANON ® . These adverse reactions have included altered mental states including severe somnolence, central nervous system effects including convulsions, and peripheral neuropathy ranging from numbness and paresthesias to motor weakness and paralysis. There have also been reports of adverse reactions associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome [see Warnings and Precautions (5.1)].

Full recovery from these adverse reactions has not always occurred with cessation of therapy with ARRANON. Monitor frequently for signs and symptoms of neurologic toxicity during treatment with ARRANON. Discontinue ARRANON for neurologic adverse reactions of NCI Common Toxicity Criteria for Adverse Events (CTCAE) Grade 2 or greater [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

ARRANON is indicated for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in adult and pediatric patients age 1 year and older whose disease has not responded to or has relapsed following treatment with at least 2 chemotherapy regimens.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

This product is for intravenous use only.

Adult Dosage: The recommended adult dose of ARRANON is 1500 mg/m2 administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Administer ARRANON undiluted.

Pediatric Dosage: The recommended pediatric dose of ARRANON is 650 mg/m2 administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. Administer ARRANON undiluted.

The recommended duration of treatment for adult and pediatric patients has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for hematopoietic stem cell transplantation (HSCT), or the patient no longer continued to benefit from treatment.

2.2 Dosage Modification

Discontinue ARRANON if the patient develops a neurologic adverse reaction of NCI CTCAE Grade 2 or greater. Dosage may be delayed for other toxicity, including hematologic toxicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].

2.3 Dosage in Special Populations

ARRANON has not been studied in patients with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)]. No dose adjustment is recommended for patients with a creatinine clearance (CLCr) greater than or equal to 50 mL/min [see Clinical Pharmacology (12.3)]. There are insufficient data to support a dose recommendation for patients with a CLCr less than 50 mL/min.

2.4 Prevention of Hyperuricemia

Take precautions against hyperuricemia (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) [see Warnings and Precautions (5.4)].

2.5 Instructions for Handling, Preparation, and Administration

Handling: ARRANON is a cytotoxic agent. Caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. Proper aseptic technique should be used. Guidelines for proper handling and disposal of anticancer drugs have been published.1

Preparation and Administration: Administer ARRANON undiluted. Transfer the appropriate dose of ARRANON into polyvinylchloride (PVC) infusion bags or glass containers and administer as a 2-hour infusion in adult patients and as a 1-hour infusion in pediatric patients.

Prior to administration, inspect the drug product visually for particulate matter and discoloration.

Stability: ARRANON Injection is stable in PVC infusion bags and glass containers for up to 8 hours at up to 30ºC.

3 DOSAGE FORMS AND STRENGTHS

Injection: 250 mg/50 mL (5 mg/mL) single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Neurologic Adverse Reactions

Nervous system adverse reactions of any grade were reported for 223 (76%) adult patients across the Phase I and Phase II trials, and Grade 3 or higher (severe, life-threatening, or fatal) adverse reactions were reported for 55 (19%) patients following initiation of ARRANON therapy [see Adverse Reactions (6.1)]. Based on patients with complete data, the median time to onset of first event is 5 days from start of first infusion (range: 1-166), and the median duration is 6 days (range: 1-393 days).

Nervous system adverse reactions of any grade were reported for 69 (42%) pediatric patients across the Phase I and Phase II trials, and Grade 3 or higher (severe, life-threatening, or fatal) adverse reactions were reported for 25 (15%) patients following initiation of ARRANON therapy [see Adverse Reactions (6.1)]. Based on patients with complete data, the median time to onset of first event is 8 days from start of first infusion (range: 1-269), and the median duration is 2 days (range: 1-82 days).

Common signs and symptoms of ARRANON-related neurotoxicity include somnolence, headache, paresthesia and dysesthesia, dizziness, neuropathy (sensory and motor), cerebellar disturbances and tremor. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome.

Full recovery from these adverse reactions has not always occurred with cessation of therapy with ARRANON. Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.

Monitor patients frequently for signs and symptoms of neurologic toxicity during and for at least 24 hours after completion of treatment with ARRANON. Discontinue ARRANON for neurologic adverse reactions of NCI CTCAE Grade 2 or greater and provide supportive care [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

5.2 Hematologic Adverse Reactions

Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia, have been associated with ARRANON therapy. Complete blood counts including platelets should be monitored regularly [see Dosage and Administration (2. 2 ) , Adverse Reactions (6.1)].

5.3 Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animal studies, ARRANON can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal reproduction studies, intravenous administration of nelarabine to pregnant rabbits during the period of organogenesis resulted in teratogenicity at maternal doses below the recommended human adult dose of 1500 mg/m2 /day (see Data).

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ARRANON. Advise males with female partners of reproductive potential to use condoms during treatment with ARRANON and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.4 Tumor Lysis Syndrome

Patients receiving ARRANON should receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumor lysis syndrome. Consideration should be given to the use of allopurinol in patients at risk of hyperuricemia [see Dosage and Administration (2. 4) ].

5.5 Vaccinations

Avoid the administration of live vaccines to immunocompromised patients.

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