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About ARRANON
Pharmacokinetics [1]
Nelarabine and ara-G
Plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G.
In addition, Cmax and AUC for nelarabine between Days 1 and 5 at the indicated adult dosage of 1,500 mg/m² were comparable, indicating that the pharmacokinetics of nelarabine after multiple dosing are predictable from single dosing.
Nelarabine and ara-G are extensively distributed throughout the body and are not substantially bound to human plasma proteins (<25%) in vitro.
The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid.
Nelarabine and ara-G are rapidly eliminated from plasma with a half-life in adults of approximately 30 minutes and 3 hours, respectively, after a 1,500 mg/m² nelarabine dose. Nelarabine and ara-G are partially eliminated by the kidneys (5% to 10% nelarabine; 20% to 30% ara-G). Mean clearance of nelarabine is about 30% higher in pediatric patients than adult patients on Day 1. The apparent clearance of ara-G is comparable between the two groups on Day 1.
No pharmacokinetic data are available in pediatric patients at the once-daily 650 mg/m² nelarabine dose. Combined Phase 1 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.
Intracellular ara-GTP
- Intracellular ara-GTP exposure (AUC) was significantly higher than plasma nelarabine and ara-G exposure
- Intracellular ara-GTP exposure in leukemic blasts correlates with response
| – | Intracellular ara-GTP Cmax values higher in responders (CR/PR) than nonresponders (Study PGAA1001) [2]
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| – | No relationship seen between nelarabine or ara-G plasma exposure and response [2] |
- Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated
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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