Nelarabine Drug Information

Nelarabine injection 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 two chemotherapy regimens.

Recommended Dosage

This product is for intravenous use only. Administer nelarabine injection undiluted. Administer nelarabine injection 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.

Dosage Modification

Discontinue nelarabine injection 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.

Dosage in Special Populations

Nelarabine injection has not been studied in patients with renal or hepatic dysfunction. No dose adjustment is recommended for patients with a creatinine clearance (CLCr) greater than or equal to 50 mL/min. There are insufficient data to support a dose recommendation for patients with a CLCr less than 50 mL/min.

Prevention of Hyperuricemia

Take precautions against hyperuricemia (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol).

• Instructions for Handling, Preparation, and Administration Handling: Nelarabine injection 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 nelarabine injection undiluted. Transfer the appropriate dose of nelarabine injection 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. Discard unused portion.
• Stability: Nelarabine Injection is stable in PVC infusion bags and glass containers for up to 8 hours at up to 30°C.

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. Relapsed or Refractory T-ALL and T-LBL Nelarabine injection was studied in 459 patients in Phase I and Phase II clinical trials. Adult Patient: The safety profile of nelarabine injection 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 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 Body System, including severe or life-threatening adverse reactions (NCI CTCAE Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 1. Table 1.

Other Adverse Reactions: 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, 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 including all grades (NCI CTCAE) are shown in Table 2. Table 2. 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, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%). The other neurologic adverse reactions 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%).

Pediatric Patient: The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-ALL/T-LBL treatment trial. The most common adverse reactions in pediatric patientswere 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 including severe or life threatening adverse reactions (NCI CTCAE Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 3. Table 3. Fatal adverse reactions included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1).

Table 4. The other Grade 3 neurologic adverse reaction in pediatric patients was hypertonia reported in 1 patient (1%). Nelarabine Injection in Combination with Multi-Agent Chemotherapy in T-ALL and T-LBL Nelarabine injection was studied in combination with multi-agent chemotherapy in a randomized clinical trial.

Sixty-five percent of patients assigned to the nelarabine injection arms received at least 85% of the planned dose through the third course of maintenance therapy compared to 79% of patients on the control arms who received 3 courses of maintenance therapy. There was one fatal neurological adverse reaction in the nelarabine injection arm. The incidence of the following grades 3 and 4 adverse reactions were higher in the nelarabine injection treated arms compared to the control arms: abnormal transaminases, motor and sensory neuropathy, nausea and vomiting, and dehydration.

The incidence of seizures of any grade was 3% (14 of 411). Rhabdomyolysis was diagnosed in 2% (7 of 411) of nelarabine injection treated patients and occurred after the first course of nelarabine injection during the consolidation phase of therapy.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of nelarabine injection. 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.

Administration of nelarabine injection in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended.

Pregnancy Risk Summary Based on its mechanism of action and findings in animal studies, nelarabine injection can cause fetal harm when administered to a pregnant woman. Limited available data with nelarabine injection use in pregnant women are insufficient to determine a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the pregnant woman associated with untreated leukemia or lymphoma (see Clinical Considerations).

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/m 2 /day (see Data). Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk There are risks to the mother from untreated leukemia or lymphoma, including anemia, thrombocytopenia, and death.

Data Animal Data In an embryo-fetal development study in which pregnant rabbits were administered daily doses of nelarabine during organogenesis, increased incidences of fetal malformations, anomalies, and variations were observed at doses greater than or equal to 360 mg/m 2 /day (8-hour IV infusion; approximately 25% of the recommended human adult dose compared on a mg/m 2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,600 mg/m 2 /day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given greater than or equal to 1,200 mg/m 2 /day (approximately 75% of the recommended 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/m 2 /day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses.

Pediatric Use The safety and effectiveness of nelarabine injection for relapsed or refractory T-ALL and T-LBL has been established in pediatric patients age 1 year and older. The effectiveness of nelarabine injection in pediatric patients is supported by one single-arm clinical trial, and safety has been asssessed in 165 pediatric patients age 1 year and older across multiple Phase I and Phase II trials. The trial establishing efficacy included 84 patients age 21 years and younger, who had relapsed or refractory T-ALL or T-LBL.

The most frequent adverse reactions of any grade occurring on treatment in this study were hematologic laboratory abnormalities. Hematologic toxicity observed in the pediatric population was higher than that seen in the adult population. Nervous system adverse reactions have been reported for 42% of pediatric patients across the Phase I and Phase II trials.

The incidence of nervous system adverse reactions was less in the pediatric population than that seen in adult patients with relapsed/refractory T-ALL/T-LBL. In a phase III study of nelarabine injection in combination with multi-agent chemotherapy as first-line therapy, there were 411 patients with T-ALL or T-LBL treated with nelarabine injection. The safety profile in the 357 patients age 1 to 16 years was consistent with that seen in older patients in the study.

Due to lack of long-term follow up data, a determination of the impact of nelarabine injection on the growth and pubertal development of pediatric patients cannot be made.

There is no known antidote for overdoses of nelarabine injection. 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.

MRI evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.