Linked Life Data

ARRANON (Injection)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2101

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dailymed-drugs:2101rdf:typehttp://www4.wiwiss.fu-berli...lld:dailymed
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dailymed-drugs:2101rdfs:labelARRANON (Injection)lld:dailymed
dailymed-drugs:2101dailymed-instance:dosagePreparation for Administration: ARRANON is not diluted 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.<br/>Adult Dosage: The recommended adult dose of ARRANON is 1,500 mg/madministered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. ARRANON is administered undiluted.<br/>Pediatric Dosage: The recommended pediatric dose of ARRANON is 650 mg/madministered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. ARRANON is administered 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 unacceptabletoxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.<br/>Supportive Care: Appropriate measures (e.g., hydration, urine alkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia of tumor lysis syndrome.<br/>Dose Modification: ARRANON should be discontinued for neurologic events of NCI Common Toxicity Criteria grade 2 or greater. Dosage may be delayed for other toxicity including hematologic toxicity.<br/>Adjustment of Dose in Special Populations: ARRANON has not been studied in patients with hepatic or renal dysfunction (see PRECAUTIONS). No dose adjustment is recommended for patients with a CL���50 mL/min (see CLINICAL PHARMACOLOGY, Renal Impairment). There are insufficient data to support a dose recommendation for CL<50 mL/min.<br/>Precautions: 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.<br/>Stability: Nelarabine Injection is stable in polyvinylchloride (PVC) infusion bags and glass containers for up to 8 hours at up to 30��C.<br/>Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.lld:dailymed
dailymed-drugs:2101dailymed-instance:descripti...ARRANON (nelarabine) is a pro-drug of the cytotoxic deoxyguanosine analogue, 9-��-D-arabinofuranosylguanine (ara-G). The chemical name for nelarabine is 2-amino-9-��-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula CHNOand 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.lld:dailymed
dailymed-drugs:2101dailymed-instance:clinicalP...Mechanism of Action: Nelarabine is a pro-drug of the deoxyguanosine analogue 9-��-D-arabinofuranosylguanine (ara-G). Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5'-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.<br/>Pharmacokinetics: Pharmacokinetic studies in adult patients with refractory leukemia or lymphoma have demonstrated that nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours, respectively, after a 1,500 mg/mnelarabine dose. No pharmacokinetic data are available in pediatric patients at the once daily 650 mg/mnelarabine dose. Plasma ara-G Cvalues generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cvalues, suggesting rapid and extensive conversion of nelarabine to ara-G. Mean plasma nelarabine and ara-G Cvalues were 5.0��3.0��g/mL and 31.4��5.6��g/mL, respectively, after a 1,500 mg/mnelarabine dose infused over 2 hours in adult patients. Exposure to ara-G (AUC) is 37 times higher than that for nelarabine on Day 1 after nelarabine IV infusion of 1,500 mg/mdose (162��49��g.h/mL versus 4.4��2.2��g.h/mL, respectively). Comparable Cand AUC were obtained for nelarabine between Days 1 and 5 at the proposed nelarabine adult dosage of 1,500 mg/m, indicating that the pharmacokinetics of nelarabine after multiple-dosing are predictable from single dosing. There are not enough data for ara-G to make a comparison between Day 1 and Day 5. After a nelarabine adult dosage of 1,500 mg/m, a mean intracellular Cfor ara-GTP appeared within 3 to 25 hours on Day 1. Exposure (AUC) to intracellular ara-GTP was 532 times higher than that for nelarabine and 14 times higher than that for ara-G (2,339��2,628��g.h/mL versus 4.4��2.2��g.h/mL and 162��49��g.h/mL, respectively). Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated. Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/mindicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259��409 L/h/mversus 197��189 L/h/m, 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/min adult patients and 11.3��4.2 L/h/min pediatric patients) on Day 1. Nelarabine and ara-G are extensively distributed throughout the body. Specifically, for nelarabine, Vvalues were 197��216 L/mand 213��358 L/min adult and pediatric patients, respectively. For ara-G, V/F values were 50��24 L/mand 33��9.3 L/min adult and pediatric patients, respectively. Nelarabine and ara-G are not substantially bound to human plasma proteins (<25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 600��M.<br/>Metabolism: 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. Ring opening of uric acid followed by further oxidation results in the formation of allantoin.<br/>Excretion: Nelarabine and ara-G are partially eliminated by the kidneys. Mean urinary excretion of nelarabine and ara-G was 6.6��4.7% and 27��15% of the administered dose, respectively, in 28 adult patients over the 24 hours after nelarabine infusion on Day 1. Renal clearance averaged 24��23 L/h for nelarabine and 6.2��5.0 L/h for ara-G in 21 adult patients.<br/>Special Populations:<br/>Gender: Gender has no effect on nelarabine or ara-G pharmacokinetics.<br/>Race: Most patients enrolled in Phase 1 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 15-20%). No differences in safety or effectiveness were observed between these groups.<br/>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).<br/>Pediatrics: No pharmacokinetic data are available in pediatric patients at the once daily 650 mg/mnelarabine dosage. Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/mindicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259��409 L/h/mversus 197��189 L/h/m, 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/min adult patients and 11.3��4.2 L/h/min pediatric patients) on Day 1. Nelarabine and ara-G are extensively distributed throughout the body. Specifically, for nelarabine, Vvalues were 197��216 L/mand 213��358 L/min adult and pediatric patients, respectively. For ara-G, V/F values were 50��24 L/mand 33��9.3 L/min adult and pediatric patients, respectively.<br/>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 CL>80 mL/min (n = 67), mild with CL= 50-80 mL/min (n = 15), and moderate with CL<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.<br/>Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated.<br/>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��M. Administration of fludarabine 30 mg/mas a 30-minute infusion 4 hours before a 1,200 mg/minfusion of nelarabine did not affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP in 12 patients with refractory leukemia.lld:dailymed
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dailymed-drugs:2101dailymed-instance:contraind...ARRANON is contraindicated in patients who have a history of hypersensitivity to nelarabine or any other components of ARRANON.lld:dailymed
dailymed-drugs:2101dailymed-instance:supplyARRANON Injection is supplied as a clear, colorless, sterile solution in Type I, clear glass vials with a gray butyl rubber (latex-free) stopper and a red snap-off aluminum seal. 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. Vials are available in the following carton sizes: NDC 0007-4401-01 (package of 1) NDC 0007-4401-06 (package of 6) Store at 25��C (77��F); excursions permitted to 15��to 30��C (59��to 86��F) [see USP Controlled Room Temperature].lld:dailymed
dailymed-drugs:2101dailymed-instance:genericDr...http://www4.wiwiss.fu-berli...lld:dailymed
dailymed-drugs:2101dailymed-instance:boxedWarn...WARNING: 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.<br/>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-Barr��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.lld:dailymed
dailymed-drugs:2101dailymed-instance:activeMoi...dailymed-ingredient:nelarab...lld:dailymed
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dailymed-drugs:2101dailymed-instance:inactiveI...dailymed-ingredient:sodium_...lld:dailymed
dailymed-drugs:2101dailymed-instance:precautio...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).<br/>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.<br/>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.<br/>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��M. There is in vitro evidence that pentostatin is a strong inhibitor of adenosine deaminase. This may result in a reduction in the conversion of the pro-drug nelarabine to its active moiety and consequently in a reduction in efficacy of nelarabine and/or change in adverse event profile of either drug. Administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended.<br/>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.<br/>Pregnancy: Pregnancy Category D. (See WARNINGS.)<br/>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, nursing should be discontinued in women who are receiving therapy with ARRANON.<br/>Pediatric Use: (See CLINICAL STUDIES, Pediatric Clinical Study).<br/>Geriatric 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 events.<br/>Use in Renally Impaired Patients: Ara-G clearance decreased as renal function decreased (see CLINICAL PHARMACOLOGY). Because the risk of adverse reactions to this drug may be greater in patients with severe renal impairment (CL<30 mL/min), these patients should be closely monitored for toxicities when treated with ARRANON (see DOSAGE AND ADMINISTRATION).<br/>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.lld:dailymed
dailymed-drugs:2101dailymed-instance:overdosag...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/mon days 1, 3, and 5 to 2 adult patients. At a dose of 2,200 mg/mgiven 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/mwas lethal in monkeys, and was associated with CNS signs including reduced/shallow respiration, reduced reflexes, and flaccid muscle tone.lld:dailymed
dailymed-drugs:2101dailymed-instance:genericMe...nelarabinelld:dailymed
dailymed-drugs:2101dailymed-instance:fullNameARRANON (Injection)lld:dailymed
dailymed-drugs:2101dailymed-instance:warningARRANON should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.<br/>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, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barr��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.<br/>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/m/day (8-hour IV infusion; approximately��the adult dose compared on a mg/mbasis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,600 mg/m/day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given���1,200 mg/m/day (approximately��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/m/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.lld:dailymed
dailymed-drugs:2101dailymed-instance:indicatio...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.lld:dailymed
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