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About ARRANON
Additional Important
Safety Information [1]
Contraindications
Warnings
Precautions
Overdosage
Special Populations
Adverse Reactions
CONTRAINDICATIONS
ARRANON is contraindicated in patients who have a history of hypersensitivity to nelarabine or any other components of ARRANON.
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WARNINGS
ARRANON should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Neurologic Events (see boxed WARNING): ARRANON is a potent antineoplastic agent with potentially significant toxic side effects. Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ARRANON should be closely observed for signs and symptoms of neurologic toxicity.
Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paraesthesias, 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. See DOSAGE AND ADMINISTRATION.
Pregnancy Category D: ARRANON may cause fetal harm when administered to a pregnant woman. There are no studies of ARRANON in pregnant women. When compared to controls, nelarabine administration during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits at doses ≥360 mg/m²/day (8-hour IV infusion; approximately 1/4 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 3/4 the adult dose), while absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification were 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
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PRECAUTIONS
Hematologic: Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
General: 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. Administration of live vaccines to immunocompromised patients should be avoided.
Information for Patients: Since patients receiving nelarabine therapy may experience somnolence, they should be cautioned about operating hazardous machinery, including automobiles.
Patients should be instructed to contact their physician if they experience new or worsening symptoms of peripheral neuropathy (see WARNINGS and DOSAGE AND ADMINISTRATION). These signs and symptoms include: tingling or numbness in fingers, hands, toes, or feet; difficulty with the fine motor coordination tasks such as buttoning clothing; unsteadiness while walking; weakness arising from a low chair; weakness in climbing stairs; increased tripping while walking over uneven surfaces.
Patients should be instructed that seizures have been known to occur in patients who receive nelarabine. If a seizure occurs, the physician administering ARRANON should be promptly informed.
Patients who develop fever or signs of infection while on therapy should notify their physician promptly.
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breast feeding during treatment with ARRANON.
Drug Interactions: Nelarabine and ara-G did not significantly inhibit the activities of the human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at concentrations of nelarabine and ara-G up to 100 µM.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity testing of nelarabine has not been done. However, nelarabine was mutagenic when tested in vitro in L5178Y/TK mouse lymphoma cells with and without metabolic activation. No studies have been conducted in animals to assess genotoxic potential or effects on fertility. The effect on human fertility is unknown.
Pregnancy: Pregnancy Category D. (See WARNINGS.)
Nursing Mothers: It is not known whether nelarabine or ara-G is 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, nursing should be discontinued in women who are receiving therapy with ARRANON.
Pediatric Use: (See Pediatric Clinical Study.)
Geriatric Use: Clinical studies of ARRANON did not include sufficient numbers of patients aged 65 years 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 events.
Use in Renally Impaired Patients: Ara-G clearance decreased as renal function decreased. Because the risk of adverse reactions to this drug may be greater in patients with severe renal impairment (CLcr <30 mL/min), these patients should be closely monitored for toxicities when treated with ARRANON (see DOSAGE AND ADMINISTRATION).
Use in Hepatically Impaired Patients: 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 (bilirubin >3.0 mg/dL), these patients should be closely monitored for toxicities when treated with ARRANON.
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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 two 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.
A single IV dose of 4,800 mg/m² was lethal in monkeys, and was associated with CNS signs including reduced/shallow respiration, reduced reflexes, and flaccid muscle tone.
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SPECIAL POPULATIONS
Gender: Gender has no effect on nelarabine or ara-G pharmacokinetics.
Race: Most patients enrolled in Phase I studies were Whites. In general, nelarabine mean clearance and volume of distribution values tend to be higher in Whites (n = 63) than in Blacks (by about 10%) (n = 15). The opposite is true for ara-G; mean apparent clearance and volume of distribution values tend to be lower in Whites than in Blacks (by about 15% to 20%). No differences in safety or effectiveness were observed between these groups.
Geriatrics: Age has no effect on the pharmacokinetics of nelarabine or ara-G. Decreased renal function, which is more common in the elderly, may reduce ara-G clearance (see PRECAUTIONS, Geriatric Use).
Pediatrics: No pharmacokinetic data are available in pediatric patients at the once-daily 650 mg/m² nelarabine dosage. Combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m² indicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259 ± 409 L/h/m² versus 197 ± 189 L/h/m², respectively) (n = 66 adults, n = 22 pediatric patients) on Day 1. The apparent clearance of ara-G (CL/F) is comparable between the two groups (10.5 ± 4.5 L/h/m² in adult patients and 11.3 ± 4.2 L/h/m² in pediatric patients) on Day 1.
Nelarabine and ara-G are extensively distributed throughout the body. Specifically, for nelarabine, VSS values were 197 ± 216 L/m² and 213 ± 358 L/m² in adult and pediatric patients, respectively. For ara-G, VSS/F values were 50 ± 24 L/m² and 33 ± 9.3 L/m² in adult and pediatric patients, respectively.
Renal Impairment: The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired or hemodialyzed patients. Nelarabine is excreted by the kidney to a small extent (5% to 10% of the administered dose). Ara-G is excreted by the kidney to a greater extent (20% to 30% of the administered nelarabine dose). Patients were categorized into 3 groups: normal with CLcr >80 mL/min (n = 67), mild with CLcr = 50 mL/min to 80 mL/min (n = 15), and moderate with CLcr <50 mL/min (n = 3). The mean apparent clearance (CL/F) of ara-G was about 15% and 40% lower in patients with mild and moderate renal impairment, respectively, than in patients with normal renal function (see PRECAUTIONS) and DOSAGE AND ADMINISTRATION). No differences in safety or effectiveness were observed.
Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated.
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ADVERSE REACTIONS
ARRANON was studied in 459 patients in Phase I and Phase II clinical trials. The safety profile for the recommended dosages of ARRANON is based on data from 103 adult patients enrolled and treated in CALGB 19801 and an adult chronic lymphocytic leukemia study (PGAA2003) who were treated with the recommended dose and schedule. The safety profile for children is based on data from 84 pediatric patients enrolled and treated in COG P9673 who were treated with the recommended dose and schedule.
Pediatric Patients: The most common adverse events in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the nonhematologic adverse events in pediatric patients, the most frequent events reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.
Most Commonly Reported Adverse Events (≥5% overall) in Pediatric Patients Receiving ARRANON 650 mg/m² (N = 84)
| NCI Common Toxicity Criteria |
| Grade 3 (%) | Grade 4+ (%)* | All Grades (%) |
 |
| Hematologic |
|
| 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 click here | |
| Gastrointestinal disorders |
|
| Vomiting |
0 |
0 |
10 |
|
| General disorders and administration site conditions |
|
| Asthenia |
1 |
0 |
6 |
|
| Infections and infestations |
|
| Infection |
2 |
1 |
5 |
|
*Grade 4+ = grade 4 and grade 5
Three (3) patients had a fatal event. Fatal events included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1). The status epilepticus was thought to be related to treatment with ARRANON. All other fatal events were unrelated to treatment with ARRANON.
Adult Patients: The most common adverse events 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.
Most Commonly Reported Adverse Events (≥5% overall) in Adult Patients Receiving ARRANON 1,500 mg/m² (N = 103)
| NCI Common Toxicity Criteria |
| Grade 3 (%) | Grade 4+ (%)* | All Grades (%) |
|
| Blood and lymphatic system |
|
| 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 |
|
| Abdonimal 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 |
|
| Hyperflycemia |
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 click here |
|
| 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 |
|
*Grade 4+ = grade 4 and grade 5
Five (5) patients had a fatal event. Fatal events included hypotension (n = 1), respiratory arrest (n = 1), pleural effusion/pneumothorax (n = 1), pneumonia (n = 1), and cerebral hemorrhage/coma/leukoencephalopathy (n = 1). The cerebral hemorrhage/coma/leukoencephalopathy was thought to be related to treatment with ARRANON. All other fatal events were unrelated to treatment with ARRANON.
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 Events: Nervous system events, regardless of drug relationship, were reported for 64% of patients across the Phase I and Phase II studies.
Pediatric: The most commonly reported neurologic adverse events (≥2%), regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown below for pediatric patients.
Most Commonly Reported Neurologic Adverse Events (≥2%) in Pediatric Patients Receiving ARRANON 650 mg/m² (N = 84)
| NCI Common Toxicity Criteria |
|
Grade 1
(%) |
Grade 2
(%) |
Grade 3
(%) |
Grade 4+
(%)* |
All Grades
(%) |
|
| Nervous system disorders |
|
| Headache |
8 |
2 |
4 |
2 |
17 |
|
Peripheral neurologic
disorders, any event |
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 |
|
*Grade 4+ = grade 4 and grade 5
One (1) patient had a fatal neurologic event—status epilepticus. This event was thought to be related to treatment with ARRANON.
The other grade 3 event in pediatric patients, regardless of causality, was hypertonia reported in 1 patient (1%). The additional grade 4+ events, regardless of causality, were 3rd nerve paralysis and 6th nerve paralysis, each reported in 1 patient (1%).
The other neurologic adverse events, 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%).
Most Commonly Reported Neurologic Adverse Events (≥2%) in Adult Patients Receiving ARRANON 1,500 mg/m² (N = 103)
| NCI Common Toxicity Criteria |
|
Grade 1
(%) |
Grade 2
(%) |
Grade 3
(%) |
Grade 4+
(%)* |
All Grades
(%) |
|
| Nervous system disorders |
|
| Somnolence |
20 |
3 |
0 |
0 |
23 |
|
| Dizziness |
14 |
8 |
0 |
0 |
21 |
|
Peripheral neurologic
disorders, any event |
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 |
|
*Grade 4+ = grade 4 and grade 5
One (1) patient had a fatal neurologic event—cerebral hemorrhage/coma/leukoencephalopathy. This event was thought to be related to treatment with ARRANON.
Most nervous system events in the adult patients were evaluated as grade 1 or 2. The additional grade 3 events in adult patients, regardless of causality, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional grade 4 events, regardless of causality, were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).
The other neurologic adverse events, 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 1 patient (1%).
Other Neurologic Events: There have also been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Please see complete Prescribing Information for more information.
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Indication
ARRANON is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) 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.
Important Safety Information
ARRANON® (nelarabine) injection should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. This product is for intravenous use only.
Neurologic Events: Severe neurologic events have been reported with the use of ARRANON. These events 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 events associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Full recovery from these events has not always occurred with cessation of therapy with ARRANON. Close monitoring for neurologic events is strongly recommended, and ARRANON should be discontinued for neurologic events of NCI Common Toxicity Criteria grade 2 or greater.
In clinical studies of ARRANON, hematologic toxicity was the most common grade 3 (moderate) or 4 (severe) adverse event. For a complete list and incidence of adverse events: pediatric patients; adult patients. Hematologic toxicity included neutropenia, thrombocytopenia, anemia, febrile neutropenia, or neutropenia with infection.
Other common toxicities included laboratory abnormalities including increased transaminases, gastrointestinal toxicity, fatigue, and asthenia.
Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.
Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Appropriate measures (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia of tumor lysis syndrome.
Nursing should be discontinued in women who are receiving therapy with ARRANON.
Because the risk of adverse reactions to this drug may be greater in patients with severe renal impairment (CLcr <30 mL/min), these patients should be closely monitored for toxicities when treated with ARRANON.
Because the risk of adverse reactions to this drug may be greater in patients with severe hepatic impairment (bilirubin >3.0 mg/dL), these patients should be closely monitored for toxicities when treated with ARRANON.
Prescribing Information for ARRANON | Important Safety Information | Patient Information Leaflet
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