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Black Box Warning
WARNING: NEUROLOGIC ADVERSE REACTIONS
See full prescribing information for complete Boxed 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.
Full recovery from these adverse reactions has not always occurred with cessation of therapy with ARRANON. * Close monitoring for neurologic adverse reactions is strongly recommended, and ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater.
Overview
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Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
T-cell acute lymphoblastic leukemia, relapsed or refractory
Dosing Information
a) The recommended dose of nelarabine is 1500 mg/m(2) administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in adults has not been 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 bone marrow transplant, or the patient no longer continued to benefit from treatment [1].
b) Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol) [1].
T-cell lymphoma, T-cell lymphoblastic lymphoma, relapsed or refractory
Dosing Information
a) The recommended dose of nelarabine is 1500 milligrams/square meter (mg/m(2)) administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in adults has not been 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 bone marrow transplant, or the patient no longer continued to benefit from treatment [1].
b) Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol) [1].
Condition3
Dosing Information
Dosage
Condition4
Dosing Information
Dosage
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Nelarabine in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelarabine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
T-cell acute lymphoblastic leukemia, relapsed or refractory
Dosing Information
a) The recommended pediatric dose of nelarabine is 650 milligrams/square meter (mg/m(2)) administered intravenously over 1 hour daily for 5 consecutive days and repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in pediatric patients has not been 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 bone marrow transplant, or the patient no longer continued to benefit from treatment [1].
b) Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol) [1].
T-cell lymphoma, T-cell lymphoblastic lymphoma, relapsed or refractory
a) The recommended pediatric dose of nelarabine is 650 milligrams/square meter (mg/m(2)) administered intravenously over 1 hour daily for 5 consecutive days and repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in pediatric patients has not been 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 bone marrow transplant, or the patient no longer continued to benefit from treatment [1].
b) Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol) [1].
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Nelarabine in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelarabine in pediatric patients.
Contraindications
None.
Warnings
WARNING: NEUROLOGIC ADVERSE REACTIONS
See full prescribing information for complete Boxed 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.
Full recovery from these adverse reactions has not always occurred with cessation of therapy with ARRANON. * Close monitoring for neurologic adverse reactions is strongly recommended, and ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater.
5.1 Neurologic Adverse Reactions
Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ARRANON should be closely observed for signs and symptoms of neurologic toxicity [see Boxed Warning, Dosage and Administration (2.2)]. Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome.
Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.
5.2 Hematologic Adverse Reactions
Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia, have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly [see Dosage and Administration (2.2), Adverse Reactions (6.1)].
5.3 Pregnancy
Pregnancy Category D
ARRANON can cause fetal harm when administered to a pregnant woman.
Nelarabine administered during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits (see Use in Specific Populations (8.1)].
There are no adequate and well-controlled studies of ARRANON in pregnant women. 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 the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
5.4 Hyperuricemia
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
Administration of live vaccines to immunocompromised patients should be avoided.
Precautions
Description
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Neurologic [see Boxed Warning, Warnings and Precautions (5.1)]
Hematologic [see Warnings and Precautions (5.2)]
Hyperuricemia [see Warnings and Precautions (5.4)]
6.1 Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ARRANON was studied in 459 patients in Phase I and Phase II clinical trials.
Adults: The safety profile of ARRANON is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) trial and an adult chronic lymphocytic leukemia trial.
The most common adverse reactions in adults, regardless of causality, were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia.
The most common adverse reactions in adults, by System Organ Class, regardless of causality, including severe or life-threatening adverse reactions (NCI Common Toxicity Criteria Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 1.
Other Adverse Events: Blurred vision was also reported in 4% of adult patients.
There was a single report of biopsy-confirmed progressive multifocal leukoencephalopathy in the adult patient population.
Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 76% of adult patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥2%) in adult patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 2.
One patient had a fatal neurologic adverse reaction, cerebral hemorrhage/coma/leukoencephalopathy.
Most nervous system adverse reactions in the adult patients were evaluated as Grade 1 or 2. The additional Grade 3 adverse reactions in adult patients, regardless of causality, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions, regardless of causality, were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).
The other neurologic adverse reactions, regardless of causality, reported as Grade 1, 2, or unknown in adult patients were abnormal coordination, burning sensation, disturbance in attention, dysarthria, hyporeflexia, neuropathic pain, nystagmus, peroneal nerve palsy, sciatica, sensory disturbance, sinus headache, and speech disorder, each reported in one patient (1%).
Pediatrics: The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) treatment trial.
The most common adverse reactions in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non-hematologic adverse reactions in pediatric patients, the most frequent adverse reactions reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.
The most common adverse reactions in pediatric patients, by System Organ Class, regardless of causality, including severe or life threatening adverse reactions (NCI Common Toxicity Criteria Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 3.
Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 42% of pediatric patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥2%) in pediatric patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 4.
The other Grade 3 neurologic adverse reaction in pediatric patients, regardless of causality, was hypertonia reported in 1 patient (1%). The additional Grade 4 neurologic adverse reactions, regardless of causality, were 3rd nerve paralysis, and 6th nerve paralysis, each reported in 1 patient (1%).
The other neurologic adverse reactions, regardless of causality, reported as Grade 1, 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in 1 patient (1%).
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ARRANON. 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.
Infections and Infestations: Fatal opportunistic infections.
Metabolism and Nutrition Disorders: Tumor lysis syndrome.
Nervous System Disorders: Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Musculoskeletal and Connective Disorders: Rhabdomyolysis, blood creatine phosphokinase increased.
Drug Interactions
Administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended.
ARRANON can cause fetal harm when administered to a pregnant woman. Nelarabine administered to rabbits during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations at doses ≥360 mg/m2/day (8-hour IV infusion; approximately ¼ the adult dose compared on a mg/m2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,600 mg/m2/day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given ≥1,200 mg/m2/day (approximately ¾ the adult dose), while absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification was seen at all doses. Maternal body weight gain and fetal body weights were reduced in rabbits given 3,600 mg/m2/day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses.
There are no adequate and well-controlled studies of ARRANON in pregnant women. 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 the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nelarabine in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Nelarabine during labor and delivery.
Nursing Mothers
It is not known whether nelarabine or ara-G are 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 ARRANON, 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.
Pediatric Use
The safety and effectiveness of ARRANON has been established in pediatric patients.
Geriatic Use
Clinical studies of ARRANON did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In an exploratory analysis, increasing age, especially age 65 years and older, appeared to be associated with increased rates of neurologic adverse reactions. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Gender
There is no FDA guidance on the use of Nelarabine with respect to specific gender populations.
Race
There is no FDA guidance on the use of Nelarabine with respect to specific racial populations.
Renal Impairment
Ara-G clearance decreased as renal function decreased. Because the risk of adverse reactions to this drug may be greater in patients with moderate (CLcr 30 to 50 mL/min) or severe (CLcr <30 mL/min) renal impairment, these patients should be closely monitored for toxicities when treated with ARRANON.
Hepatic Impairment
The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated. Because the risk of adverse reactions to this drug may be greater in patients with severe hepatic impairment (total bilirubin >3 times upper limit of normal), these patients should be closely monitored for toxicities when treated with ARRANON.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nelarabine in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Nelarabine in patients who are immunocompromised.
Administration and Monitoring
Administration
Recommended Dosage
This product is for intravenous use only.
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 bone marrow transplant, or the patient no longer continued to benefit from treatment.
Adult Dosage: The recommended adult dose of ARRANON is 1,500 mg/m² administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. ARRANON is administered 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. ARRANON is administered undiluted.
Dosage Modification
Administration of ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater. Dosage may be delayed for other toxicity including hematologic toxicity.
Adjustment of Dose in Special Populations
ARRANON has not been studied in patients with renal or hepatic dysfunction. No dose adjustment is recommended for patients with a creatinine clearance (CLcr) ≥50 mL/min. There are insufficient data to support a dose recommendation for patients with a CLcr <50 mL/min.
Prevention of Hyperuricemia
Appropriate measures (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia [see Warnings and Precautions (5.4)].
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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.1-4
Preparation and Administration: Do not dilute ARRANON prior to administration. The appropriate dose of ARRANON is transferred into polyvinylchloride (PVC) infusion bags or glass containers and administered 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 polyvinylchloride (PVC) infusion bags and glass containers for up to 8 hours at up to 30° C.
DOSAGE FORMS AND STRENGTHS
250 mg/50 mL (5 mg/mL) vial
Monitoring
There is limited information regarding Monitoring of Nelarabine in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Nelarabine in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Nelarabine in the drug label.
Pharmacology
There is limited information regarding Nelarabine Pharmacology in the drug label.
