Arranon

nelarabine

Dosage Form: injection
FULL PRESCRIBING INFORMATION

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. 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 [see Warnings and Precautions (5.1)].

Indications and Usage for Arranon

Arranon® is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

Arranon Dosage and 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

Arranon administration 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. [See Boxed Warning and Warnings and Precautions (5.1, 5.2).]

Adjustment of Dose 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) ≥50 mL/min [see Clinical Pharmacology (12.3)]. 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)].

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.1-4

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 two-hour infusion in adult patients and as a one-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

Contraindications

None.

Warnings and Precautions

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 and 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.

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) and Adverse Reactions (6.1)].

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.

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)].

Vaccinations

Administration of live vaccines to immunocompromised patients should be avoided.

Adverse Reactions

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Neurologic [see Boxed Warning and Warnings and Precautions (5.1)]


• Hematologic [see Warnings and Precautions (5.2)]


• Hyperuricemia [see Warnings and Precautions (5.4)]

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 to 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) study and an adult chronic lymphocytic leukemia study.

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.

Table 1. Most Commonly Reported (≥5% Overall) Adverse Reactions Regardless of Causality in Adult Patients Treated with 1,500 mg/m2 of Arranon Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

System Organ Class    Preferred Term	Percentage of Patients (N = 103)
	Toxicity Grade
	Grade 3 %	Grade 4 and 5a %	All Grades %
Blood and Lymphatic System Disorders
Anemia	20	14	99
Thrombocytopenia	37	22	86
Neutropenia	14	49	81
Febrile neutropenia	9	1	12
Cardiac Disorders
Sinus tachycardia	1	0	8
Gastrointestinal Disorders
Nausea	0	0	41
Diarrhea	1	0	22
Vomiting	1	0	22
Constipation	1	0	21
Abdominal pain	1	0	9
Stomatitis	1	0	8
Abdominal distension	0	0	6
General Disorders and Administration Site Conditions
Fatigue	10	2	50
Pyrexia	5	0	23
Asthenia	0	1	17
Edema, peripheral	0	0	15
Edema	0	0	11
Pain	3	0	11
Rigors	0	0	8
Gait, abnormal	0	0	6
Chest pain	0	0	5
Non-cardiac chest pain	0	1	5
Infections
Infection	2	1	9
Pneumonia	4	1	8
Sinusitis	1	0	7
Hepatobiliary Disorders
AST increased	1	1	6
Metabolism and Nutrition Disorders
Anorexia	0	0	9
Dehydration	3	1	7
Hyperglycemia	1	0	6
Musculoskeletal and Connective Tissue Disorders
Myalgia	1	0	13
Arthralgia	1	0	9
Back pain	0	0	8
Muscular weakness	5	0	8
Pain in extremity	1	0	7
Nervous System Disorders (see Table 2)
Psychiatric Disorders
Confusional state	2	0	8
Insomnia	0	0	7
Depression	1	0	6
Respiratory, Thoracic, and Mediastinal Disorders
Cough	0	0	25
Dyspnea	4	2	20
Pleural effusion	5	1	10
Epistaxis	0	0	8
Dyspnea, exertional	0	0	7
Wheezing	0	0	5
Vascular Disorders
Petechiae	2	0	12
Hypotension	1	1	8

a Five patients had a fatal adverse reaction. Fatal adverse reactions included hypotension (n = 1), respiratory arrest (n = 1), pleural effusion/pneumothorax (n = 1), pneumonia (n = 1), and cerebral hemorrhage/coma/leukoencephalopathy (n = 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 studies. 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.

Table 2. Neurologic Adverse Reactions (≥2%) Regardless of Causality in Adult Patients Treated with 1,500 mg/m2 of Arranon Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

Nervous System Disorders    Preferred Term	Percentage of Patients (N =103)
	Grade 1 %	Grade 2 %	Grade 3 %	Grade 4 %	All Grades %
Somnolence	20	3	0	0	23
Dizziness	14	8	0	0	21
Peripheral neurologic disorders, any adverse reaction	8	12	2	0	21
Neuropathy	0	4	0	0	4
Peripheral neuropathy	2	2	1	0	5
Peripheral motor neuropathy	3	3	1	0	7
Peripheral sensory neuropathy	7	6	0	0	13
Hypoesthesia	5	10	2	0	17
Headache	11	3	1	0	15
Paresthesia	11	4	0	0	15
Ataxia	1	6	2	0	9
Depressed level of consciousness	4	1	0	1	6
Tremor	2	3	0	0	5
Amnesia	2	1	0	0	3
Dysgeusia	2	1	0	0	3
Balance disorder	1	1	0	0	2
Sensory loss	0	2	0	0	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 study.

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.

Table 3. Most Commonly Reported (≥5% Overall) Adverse Reactions Regardless of Causality in Pediatric Patients Treated with 650 mg/m2 of Arranon Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

System Organ Class    Preferred Term	Percentage of Patients (N = 84)
	Toxicity Grade
	Grade 3 %	Grade 4 and 5a %	All Grades %
Blood and Lymphatic System Disorders
Anemia	45	10	95
Neutropenia	17	62	94
Thrombocytopenia	27	32	88
Leukopenia	14	7	38
Hepatobiliary Disorders
Transaminases increased	4	0	12
Blood albumin decreased	5	1	10
Blood bilirubin increased	7	2	10
Metabolic/Laboratory
Blood potassium decreased	4	2	11
Blood calcium decreased	1	1	8
Blood creatinine increased	0	0	6
Blood glucose decreased	4	0	6
Blood magnesium decreased	2	0	6
Nervous System Disorders (see Table 4)
Gastrointestinal Disorders
Vomiting	0	0	10
General Disorders & Administration Site Conditions
Asthenia	1	0	6
Infections & Infestations
Infection	2	1	5

a Three patients had a fatal adverse reaction. Fatal adverse reactions included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1).

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 studies. 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.

Table 4. Neurologic Adverse Reactions (≥2%) Regardless of Causality in Pediatric Patients Treated with 650 mg/m2 of Arranon Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

Nervous System Disorders    Preferred Term	Percentage of Patients (N = 84)
	Grade 1 %	Grade 2 %	Grade 3 %	Grade 4 and 5a %	All Grades %
Headache	8	2	4	2	17
Peripheral neurologic disorders, any adverse reaction	1	4	7	0	12
Peripheral neuropathy	0	4	2	0	6
Peripheral motor neuropathy	1	0	2	0	4
Peripheral sensory neuropathy	0	0	6	0	6
Somnolence	1	4	1	1	7
Hypoesthesia	1	1	4	0	6
Seizures	0	0	0	6	6
Convulsions	0	0	0	3	4
Grand mal convulsions	0	0	0	1	1
Status epilepticus	0	0	0	1	1
Motor dysfunction	1	1	1	0	4
Nervous system disorder	1	2	0	0	4
Paresthesia	0	2	1	0	4
Tremor	1	2	0	0	4
Ataxia	1	0	1	0	2

a One (1) patient had a fatal neurologic adverse reaction, status epilepticus.

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: Fata