caused [50 mL/min.:<30 mL/min) renal impairment, these patients should be closely monitored for toxicities when treated with Arranon [ see Dosage and Administration (2.3 ) ] . Hepatic Impairment 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 (total bilirubin> 3 times upper limit of normal), these patients should be closely monitored for toxicities when treated with Arranon. 10 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/m 2 on Days 1, 3, and 5 to 2 adult patients. At a dose of 2,200 mg/m 2 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. 11 DESCRIPTION Arranon (nelarabine) is a prodrug of the cytotoxic deoxyguanosine analogue, 9-β- D -arabinofuranosylguanine (ara-G). The chemical name for nelarabine is 2-amino-9-β- D -arabinofuranosyl-6-methoxy-9 H -purine. It has the molecular formula C 11 H 15 N 5 O 5 and 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 209º and 217º 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. 12 CLINICAL PHARMACOLOGY Mechanism of Action Nelarabine is a prodrug of the deoxyguanosine analogue 9-β- D -arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. 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. Pharmacokinetics Absorption: Following intravenous administration of nelarabine to adult patients with refractory leukemia or lymphoma, plasma ara-G C max values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine C max values, suggesting rapid and extensive conversion of nelarabine to ara-G. Mean plasma nelarabine and ara-G C max values were 5.0 3.0 mcg/mL and 31.4 5.6 mcg/mL, respectively, after a 1,500 mg/m 2 nelarabine dose infused over 2 hours in adult patients. The area under the concentration-time curve (AUC) of ara-G is 37 times higher than that for nelarabine on Day 1 after nelarabine IV infusion of 1,500 mg/m 2 dose (162 49 mcg.h/mL versus 4.4 2.2 mcg.h/mL, respectively). Comparable C max and AUC values were obtained for nelarabine between Days 1 and 5 at the nelarabine adult dosage of 1,500 mg/m 2 , indicating that nelarabine does not accumulate after multiple-dosing. There are not enough ara-G data to make a comparison between Day 1 and Day 5. After a nelarabine adult dose of 1,500 mg/m 2 , intracellular C max for 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 mcg.h/mL versus 4.4 2.2 mcg.h/mL and 162 49 mcg.h/mL, respectively). Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated. Distribution: Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, V SS values were 197 216 L/m 2 in adult patients. For ara-G, V SS /F values were 50 24 L/m 2 in adult patients. 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 μM. 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. 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. Combined Phase I pharmacokinetic data at nelarabine doses of 199 to 2,900 mg/m 2 (n = 66 adult patients) indicate that the mean clearance (CL) of nelarabine is 197 189 L/h/m 2 on Day 1. The apparent clearance of ara-G (CL/F) is 10.5 4.5 L/h/m 2 on Day 1. Nelarabine and ara-G are rapidly eliminated from plasma with a mean half-life of 18 minutes and 3.2 hours, respectively, in adult patients. Pediatrics: No pharmacokinetic data are available in pediatric patients at the once-daily 650 mg/m 2 nelarabine dosage. Combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m 2 indicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259 409 L/h/m 2 versus 197 189 L/h/m 2 , 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/m 2 in adult patients and 11.3 4.2 L/h/m 2 in pediatric patients) on Day 1. Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, V SS values were 213 358 L/m 2 in pediatric patients. For ara-G, V SS /F values were 33 9.3 L/m 2 in pediatric patients. Nelarabine and ara-G are rapidly eliminated from plasma in pediatric patients, with a half-life of 13 minutes and 2 hours, respectively. Effect of Age: Age has no effect on the pharmacokinetics of nelarabine or ara-G in adults. Decreased renal function, which is more common in the elderly, may reduce ara-G clearance [see Use in Specific Populations (8.5) . Effect of Gender: Gender has no effect on nelarabine or ara-G pharmacokinetics. Effect of Race: 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. Effect of 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). In the combined Phase I trials, patients were categorized into 3 groups: normal with CL cr> 80 mL/min (n = 67), mild with CL cr = 50 to 80 mL/min (n = 15), and moderate with CL cr <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 Use in Specific Populations (8.6), Dosage and Administration (2.3)] . No differences in safety or effectiveness were observed. Effect of Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated [see Use in Specific Populations (8.7)] . Drug Interactions: Cytochrome P450: 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. Fludarabine: Administration of fludarabine 30 mg/m 2 as a 30-minute infusion 4 hours before a 1,200-mg/m 2 infusion of nelarabine did not affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP in 12 patients with refractory leukemia. Pentostatin: There is in vitro evidence that pentostatin is a strong inhibitor of adenosine deaminase. Inhibition of adenosine deaminase may result in a reduction in the conversion of the prodrug nelarabine to its active moiety and consequently in a reduction in efficacy of nelarabine and/or change in adverse reaction profile of either drug [see Drug Interactions (7)] . 13 NONCLINICAL TOXICOLOGY 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. 14 CLINICAL STUDIES The safety and efficacy of Arranon were evaluated in two open-label, single-arm, multicenter trials. Adult Clinical Trial The safety and efficacy of Arranon in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that had relapsed following or was refractory to at least two prior induction regimens. A 1,500-mg/m 2 dose of Arranon was administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with Arranon. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with 2 prior inductions, the age range was 16 to 65 years (mean: 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNS) disease were not eligible. Complete response (CR) in this trial was defined as bone marrow blast counts 5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without complete hematologic recovery (CR*) was also assessed. The results of the trial for patients who had received 2 prior inductions are shown in Table 5. Table 5. Efficacy Results in Adult Patients with 2 Prior Inductions Treated with 1,500 mg/m 2 of Arranon Administered Intravenously over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days N = 28 CR plus CR* % (n) [95% CI] 21% (6) [8%, 41%] CR % (n) [95% CI] 18% (5) [6%, 37%] CR* % (n) [95% CI] 4% (1) [0%, 18%] Duration of CR plus CR* (range in weeks) a 4 to 195+ Median overall survival (weeks) [95% CI] 20.6 weeks [10.4, 36.4] CR = Complete response. CR* = Complete response without hematologic recovery. a Does not include 1 patient who was transplanted (duration of response was 156+ weeks). The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to CR plus CR* ranged from 2.9 to 11.7 weeks. Pediatric Clinical Trial The safety and efficacy of Arranon in pediatric patients were studied in a clinical trial which included patients aged 21 years and younger, who had relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with 650 mg/m 2 /day of Arranon administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 6). Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with Arranon. Table 6. Pediatric Clinical Trial - Patient Allocation Patient Population N Patients treated at 650 mg/m 2 /day x 5 days every 21 days. 84 Patients with T-ALL or T-LBL with two or more prior induction treated at 650 mg/m 2 /day x 5 days every 21 days. 39 Patients with T-ALL or T-LBL with one prior induction treated at 650 mg/m 2 /day x 5 days every 21 days. 31 The 84 patients ranged in age from 2.5 to 21.7 years (overall mean: 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). The majority (77%) of patients had a diagnosis of T-ALL. Complete response (CR) in this trial was defined as bone marrow blast counts 5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without full hematologic recovery (CR*) was also assessed as a meaningful outcome in this heavily pretreated population. Duration of response is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results are presented in Table 7. Table 7. Efficacy Results in Patients Aged 21 Years and Younger at Diagnosis with 2 Prior Inductions Treated with 650 mg/m 2 of Arranon Administered Intravenously over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days N = 39 CR plus CR* % (n) [95% CI] 23% (9) [11%, 39%] CR % (n) [95% CI] 13% (5) [4%, 27%] CR* % (n) [95% CI] 10% (4) [3%, 24%] Duration of CR plus CR* (range in weeks) a 3.3 to 9.3 Median overall survival (weeks) [95% CI] 13.1 [8.7, 17.4] CR = Complete response. CR* = Complete response without hematologic recovery. a Does not include 5 patients who were transplanted or had subsequent systemic chemotherapy (duration of response in these 5 patients was 4.7 to 42.1 weeks). The mean number of days on therapy was 46 days (range: 7 to 129 days). Median time to CR plus CR* was 3.4 weeks (95% CI: 3.0, 3.7). 15 REFERENCES Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm . 2006;63:1172-1193. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2 nd ed) Pittsburgh, PA: Oncology Nursing Society. 16 HOW SUPPLIED/STORAGE AND HANDLING Arranon Injection is supplied as a clear, colorless, sterile solution in Type I, clear glass vials with a gray bromobutyl rubber stopper (not made with natural rubber latex) 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 (NDC 0078-0683-61) are available in the following carton size: NDC 0078-0683-06 (package of 6) Store at 25 º C (77 º F); excursions permitted to 15 º to 30 º C (59 º to 86 º F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information. However, inform the patients of the following: 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 Boxed Warning, Warnings and Precautions (5.1), Dosage a nd Administration (2.3)] . 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 breastfeeding during treatment with Arranon. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Novartis T2015-67 June 2015 PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ PATIENT INFORMATION LEAFLET Arranon (AIR-ra-non) (n elarabine ) Injection Read the Patient Information that comes with Arranon before you or your child starts treatment with Arranon. Read the information you get each time before each treatment with Arranon. There may be new information. This information does not take the place of talking with the doctor about your or your child s medical condition or treatment. Talk to your or your child s doctor, if you have any questions. What is the most important information I should know about Arranon? Arranon may cause serious nervous system problems including: extreme sleepiness seizures coma numbness and tingling in the hands, fingers, feet, or toes (peripheral neuropathy) weakness and paralysis Call the doctor right away if you or your child has the following symptoms: seizures numbness and tingling in the hands, fingers, feet, or toes problems with fine motor skills such as buttoning clothes unsteadiness while walking increased tripping while walking weakness when getting out of a chair or walking up stairs These symptoms may not go away even when treatment with Arranon is stopped. What is Arranon? Arranon is an anti-cancer medicine used to treat adults and children who have: T-cell acute lymphoblastic leukemia T-cell lymphoblastic lymphoma What should you tell the doctor before you or your child starts Arranon? Tell the doctor about all health conditions you or your child have, including if you or your child: have any nervous system problems. have kidney problems. are breastfeeding or plan to breastfeed. It is not known whether Arranon passes through breast milk. You should not breastfeed during treatment with Arranon. are pregnant or plan to become pregnant. Arranon may harm an unborn baby. You should use effective birth control to avoid getting pregnant. Talk with your doctor about your choices. Tell the doctor about all the medicines you or your child take, including prescription and nonprescription medicines, vitamins, and herbal supplements. How is Arranon given? Arranon is an intravenous medicine. This means it is given through a tube in your vein. What should you or your child avoid during treatment with Arranon? You or your child should not drive or operate dangerous machines. Arranon may cause sleepiness. You or your child should not receive vaccines made with live germs during treatment with Arranon. What are the po ssible side effects of Arranon? Arranon may cause serious nervous system problems. See What is the most important information I should know about Arranon? Arranon may also cause: decreased blood counts such as low red blood cells, low white blood cells, and low platelets. Blood tests should be done regularly to check blood counts. Call the doctor right away if you or your child: is more tired than usual, pale, or has trouble breathing has a fever or other signs of an infection bruises easy or has any unusual bleeding stomach area problems such as nausea, vomiting, diarrhea, and constipation headache sleepiness blurry eyesight Call your doctor right away if you experience unexplained muscle pain, tenderness, or weakness while taking Arranon. This is because on rare occasions, muscle problems can be serious. These are not all the side effects associated with Arranon. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General Advice about Arranon This leaflet summarizes important information about Arranon. If you have questions or problems, talk with your or your child s doctor. You can ask your doctor or pharmacist for information about Arranon that is written for healthcare providers or it is available atwww.pharma.us.novartis.com. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Novartis T2015-67/T2015-68 June 2015/June 2015 PRINCIPAL DISPLAY PANEL Arranon (nelarabine) Injection Rx Only NDC 0078-0683-06 For I.V. Infusion Only 250 mg/50 mL (5 mg/mL) Six 50-mL Vials Novartis Arranon nelarabine injection Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0078-0683 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NELARABINE (NELARABINE) NELARABINE 5 mg in 1 mL Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE WATER Packaging # Item Code Package Description 1 NDC:0078-0683-06 6 VIAL in 1 CARTON 1 NDC:0078-0683-61 50 mL in 1 VIAL Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021877 10/05/2016 Labeler - Novartis Pharmaceuticals Corporation (002147023) Revised: 06/2015 Novartis Pharmaceuticals Corporation Next Interactions Print this page Add to My Med List More about Arranon (nelarabine) Side Effects During Pregnancy Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: antimetabolites Consumer resources Arranon Arranon (Advanced Reading) Professional resources Arranon (AHFS Monograph) Related treatment guides Acute Lymphoblastic Leukemia Lymphoma> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only D Pregnancy Category Positive evidence of risk N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturer Novartis Pharmaceuticals Corporation Drug Class Antimetabolites Related Drugs antimetabolites methotrexate , fluorouracil , hydroxyurea , Xeloda , capecitabine , Hydrea Acute Lymphoblastic Leukemia methotrexate , Gleevec , mercaptopurine , imatinib , Adriamycin , doxorubicin , Sprycel , Trexall , dasatinib , Purinethol , Kymriah , More... Lymphoma prednisone , methotrexate , dexamethasone , Decadron , Deltasone , Revlimid , cortisone , Imbruvica , Adriamycin , doxorubicin , Velcade , More... Arranon Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first!} } looking ahead to
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