Nelarabine

Nelarabine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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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

Nelarabine is a prodrug of ara-G that is FDA approved for the {{{indicationType}}} of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• 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.

Pregnancy Category (AUS):

• 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.

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.

• 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.

IV Compatibility

• There is limited information regarding IV Compatibility of Nelarabine in the drug label.

Overdosage

• There is no known antidote for overdoses of ARRANON. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death. In the event of overdose, supportive care consistent with good clinical practice should be provided.

• Nelarabine has been administered in clinical trials up to a dose of 2,900 mg/m2 on Days 1, 3, and 5 to 2 adult patients. At a dose of 2,200 mg/m2 given on Days 1, 3, and 5 every 21 days, 2 patients developed a significant Grade 3 ascending sensory neuropathy. MRI evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.

Pharmacology

There is limited information regarding Nelarabine Pharmacology in the drug label.

Mechanism of Action

Structure

• ARRANON (nelarabine) is a prodrug of the cytotoxic deoxyguanosine analogue, 9-β-D-arabinofuranosylguanine (ara-G).

The chemical name for nelarabine is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27. Nelarabine has the following structural formula:

Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209° and 217° C.

ARRANON Injection is supplied as a clear, colorless, sterile solution in glass vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. ARRANON is intended for intravenous infusion.

Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Nelarabine in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Nelarabine in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Nelarabine in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Nelarabine in the drug label.

How Supplied

Storage

There is limited information regarding Nelarabine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Nelarabine in the drug label.

Precautions with Alcohol

• Alcohol-Nelarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Arranon

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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