Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2101
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ARRANON (Injection)
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Preparation 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.
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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.
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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.
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ARRANON is contraindicated in patients who have a history
of hypersensitivity to nelarabine or any other components of ARRANON.
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ARRANON 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].
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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.
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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.
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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.
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nelarabine
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ARRANON (Injection)
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ARRANON 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.
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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.
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ARRANON
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