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英文药名：Atriance(nelarabine Injection) 中文药名：奈拉滨注射剂 生产厂家：葛兰素史克 Full recovery from these reactions has not always occurred with cessation of nelarabine. Therefore, close monitoring for neurological reactions is strongly recommended, and nelarabine must be discontinued at the first sign of neurological reactions of NCI CTCAE Grade 2 or greater.
There have been reports of sometimes fatal opportunistic infections in patients receiving nelarabine therapy. Nervous System disorders There have been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome. One subject in the paediatric group had a fatal neurological event of status epilepticus. Data from NCI studies/compassionate use programme and phase I studies In addition to the adverse reactions seen in the pivotal clinical trials, there are also data from 875 patients from NCI studies/compassionate use programme (694 patients) and Phase I (181 patients) studies of nelarabine. The following additional adverse reactions were seen: Neoplasms benign and malignant (including cysts and polyps) Tumour lysis syndrome – 7 cases (see sections 4.2 and 4.4) Post – Marketing Data The following adverse reactions have been identified during post-approval use of nelarabine. This includes spontaneous case reports as well as serious adverse events from ongoing studies. Musculoskeletal and connective tissue disorders Rare Rhabdomyolysis, blood creatine phosphokinase increased Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose No case of overdose has been reported. Nelarabine has been administered in clinical trials up to a dose of 75 mg/kg (approximately 2,250 mg/m2) daily for 5 days to a paediatric patient, up to a dose of 60 mg/kg (approximately 2,400 mg/m2) daily for 5 days to 5 adult patients and up to 2,900 mg/m2 in a further 2 adults on days 1, 3 and 5. Symptoms and signs It is likely that nelarabine overdose would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression and potentially death. At a dose of 2200 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. Treatment There is no known antidote for nelarabine overdose. Supportive care consistent with good clinical practice should be provided. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, purine analogues, ATC code: L01B B 07 Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated by adenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosine kinase and deoxycytidine kinase to its 5'-monophosphate metabolite. The monophosphate metabolite is subsequently converted to the active 5'-triphosphate form, ara-GTP. Accumulation of ara-GTP in leukaemic blasts allows for preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA) leading to inhibition of DNA synthesis. This results in cell death. Other mechanisms may contribute to the cytotoxic effects of nelarabine. In vitro, T-cells are more sensitive than B-cells to the cytotoxic effects of nelarabine. Clinical studies Adult studies In an open-label study carried out by the Cancer and Leukaemia Group B and the Southwest Oncology Group, the safety and efficacy of nelarabine were evaluated in 39 adults with T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL). Twenty–eight of the 39 adults had relapsed or were refractory to at least two prior induction regimens and aged between 16 to 65 years of age (mean 34 years). Nelarabine at a dose of 1500 mg/m2/day was administered intravenously over two hours on days 1, 3 and 5 of a 21 day cycle. Five of the 28 patients (18 %) [95 % CI: 6 %—37 %] treated with nelarabine achieved a complete response (bone marrow blast counts ≤ 5 %, no other evidence of disease, and full recovery of peripheral blood counts). A total of 6 patients (21 %) [95 % CI: 8 %–41 %] achieved a complete response with or without haematological recovery. Time to complete response in both classifications of response ranged from 2.9 to 11.7 weeks. Duration of response (in both classifications of response (n=5) ranged between 15 and 195+ weeks. Median overall survival was 20.6 weeks [95 % CI: 10.4–36.4]. Survival at one year was 29% [95 % CI: 12 %–45 %]. Paediatric studies In an open-label, multicenter study carried out by Childrens Oncology Group, nelarabine was administered intravenously over 1 hour for 5 days to 151 patients ≤ 21 years of age, 149 of whom had relapsed or refractory T-cell acute lymphoblastic leukaemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens and 31 whom had received one prior induction regimen, were treated with 650 mg/m2/day of nelarabine administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. Of the 39 patients who had received two or more prior induction regimens, 5 (13 %) [95 % CI: 4 %–27 %] achieved a complete response (bone marrow blast counts ≤ 5 %, no other evidence of disease, and full recovery of peripheral blood counts) and 9 (23 %) [95 % CI: 11 %–39 %] achieved complete responses with or without full haematological recovery. Duration of response in both classifications of response ranged between 4.7 and 36.4 weeks and median overall survival was 13.1 weeks [95 % CI: 8.7–17.4] and survival at one year was 14 % [95 % CI: 3 %–26 %]. Thirteen (42 %) of the 31 patients treated with one prior induction regimen achieved a complete response overall. Nine of these 31 patients failed to respond to prior induction (refractory patients). Four (44 %) of the nine refractory patients experienced a complete response to nelarabine. This medicinal product has been authorised under “exceptional circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary. 5.2 Pharmacokinetic properties Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated by adenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosine kinase and deoxycytidine kinase to its 5'-monophosphate metabolite. The monophosphate metabolite is subsequently converted to the active 5'-triphosphate from, ara-GTP. Accumulation of ara-GTP in leukaemic blasts allows for preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA) leading to inhibition of DNA synthesis. This results in cell death. Other mechanisms may contribute to the cytotoxic effects of nelarabine. In vitro, T-cells are more sensitive than B-cells to the cytotoxic effects of nelarabine. In a cross-study analysis using data from four Phase I studies, the pharmacokinetics of nelarabine and ara-G were characterized in patients aged less than 18 years and adult patients with refractory leukaemia or lymphoma. Absorption Adults 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. After infusion of 1,500 mg/m2 nelarabine over two hours in adult patients, mean (%CV) plasma nelarabine Cmax and AUCinf values were 13.9 µM (81 %) and 13.5 µM.h (56 %) respectively. Mean plasma ara-G Cmax and AUCinf values were 115 µM (16 %) and 571 µM.h (30 %), respectively. Intracellular Cmax for ara-GTP appeared within 3 to 25 hours on day 1. Mean (%CV) intracellular ara-GTP Cmax and AUC values were 95.6 µM (139 %) and 2214 µM.h (263 %) at this dose. Paediatric patients After infusion of 400 or 650 mg/m2 nelarabine over one hour in 6 paediatric patients, mean (%CV) plasma nelarabine Cmax and AUCinf values, adjusted to a 650 mg/m2 dose, were 45.0 µM (40 %) and 38.0 µM.h (39 %), respectively. Mean plasma ara-G Cmax and AUCinf values were 60.1 µM (17 %) and 212 µM.h (18 %), respectively. Distribution Nelarabine and ara-G are extensively distributed throughout the body based on combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2. Specifically, for nelarabine, mean (%CV) VSS values were 115 l/m2 (159 %) and 89.4 l/m2 (278 %) in adult and paediatric patients, respectively. For ara-G, mean VSS/F values were 44.8 l/m2 (32 %) and 32.1 l/m2 (25 %) in adult and paediatric patients, respectively. Nelarabine and ara-G are not substantially bound to human plasma proteins (less than 25 %) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 600 µM. No accumulation of nelarabine or ara-G was observed in plasma after nelarabine administration on either a daily or a day 1, 3, 5 schedule. Intracellular ara-GTP concentrations in leukaemic blasts were quantifiable for a prolonged period after nelarabine administration. Intracellular ara-GTP accumulated with repeated administration of nelarabine. On the day 1, 3, and 5 schedule, Cmax and AUC(0-t) values on day 3 were approximately 50 % and 30 %, respectively, greater than Cmax and AUC(0-t) values on day 1. Biotransformation 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 hydrolysed 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. Elimination Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours, respectively. These findings were demonstrated in patients with refractory leukaemia or lymphoma given a dose of 1,500 mg/m2 nelarabine (adults) or a 650 mg/m2 (paediatrics). Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2 indicate that mean (%CV) clearance (Cl) values for nelarabine are 138 l/h/m2 (104 %) and 125 l/h/m2 (214 %) in adult and paediatric patients, respectively, on day 1 (n = 65 adults, n = 21 paediatric patients). The apparent clearance of ara-G (Cl/F) is comparable between the two groups [9.5 l/h/m2 (35 %) in adult patients and 10.8 l/h/m2 (36 %) in paediatric patients] on day 1. Nelarabine and ara-G are partially eliminated by the kidneys. In 28 adult patients, 24 hours after nelarabine infusion on day 1, mean urinary excretion of nelarabine and ara-G was 5.3 % and 23.2 % of the administered dose, respectively. Renal clearance averaged 9.0 l/h/m2 (151 %) for nelarabine and 2.6 l/h/m2 (83%) for ara-G in 21 adult patients. Because the timecourse of intracellular ara-GTP was prolonged, its elimination half-life could not be accurately estimated. Paediatric population Limited clinical pharmacology data are available for patients below the age of 4 years. Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2 indicate that the clearance (Cl) and Vss values for nelarabine and ara-G are comparable between the two groups. Further data with respect to nelarabine and ara-G pharmacokinetics in the paediatric population are provided in other subsections. Gender Gender has no effect on nelarabine or ara-G plasma pharmacokinetics. Intracellular ara-GTP Cmax and AUC(0–t) values at the same dose level were 2– to 3– fold greater on average in adult female than in adult male patients. Race The effect of race on nelarabine and ara-G pharmacokinetics has not been specifically studied. In a pharmacokinetic/pharmacodynamic cross study analysis, race had no apparent effect on nelarabine, ara-G, or intracellular ara-GTP pharmacokinetics. Renal Impairment The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired or haemodialysed 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). Adults and children in clinical studies were categorized into the three groups according to renal impairment: normal with Clcr greater than 80 ml/min (n = 56), mild with Clcr equalling 50 to 80 ml/min (n = 12), and moderate with Clcr less than 50 ml/min (n = 2). The mean apparent clearance (Cl/F) of ara-G was about 7 % lower in patients with mild renal impairment than in patients with normal renal function (see section 4.2). No data are available to provide a dose advice for patients with Clcr less than 50 ml/min. Elderly 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 section 4.2). 5.3 Preclinical safety data Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: nelarabine caused histopathological changes to the central nervous system (white matter) vacuolation and degenerative changes in cerebrum, cerebellum and spinal cord of monkeys after treatment with nelarabine daily during 23 days, at exposures below the human therapeutic exposure. Nelarabine showed in vitro cytotoxicity to monocytes and macrophages. Carcinogenicity Carcinogenicity testing of nelarabine has not been performed. Mutagenicity Nelarabine was mutagenic to L5178Y/TK mouse lymphoma cells with and without metabolic activation. Reproduction toxicity Compared to controls, nelarabine caused increased incidences of foetal malformations, anomalies, and variations in rabbits when given at doses approximately 24 % of the adult human dose on a mg/m2 basis during the period of organogenesis. Cleft palate was seen in rabbits given a dose approximately 2-fold the adult human dose, absent pollices in rabbits given a dose approximately 79 % of the adult human dose while absent gall bladder, accessory lung lobes, fused or extra sternebrae and delayed ossification was seen at all doses. Maternal body weight gain and foetal body weights were reduced in rabbits given a dose approximately 2-fold the adult human dose. Fertility No studies have been conducted in animals to assess the effects of nelarabine on fertility. However, no undesirable effects were seen in the testes or ovaries of monkeys given nelarabine intravenously at doses up to approximately 32 % of the adult human dose on a mg/m2 basis for 30 consecutive days. 6. Pharmaceutical particulars 6.1 List of excipients Sodium chloride Water for injections Hydrochloric acid (to adjust the pH) Sodium hydroxide (to adjust the pH) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. Atriance is stable for up to 8 hours at up to 30°C once the vial is opened. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Clear glass (Type I) vials with a bromobutyl rubber stopper, sealed with an aluminium cap. Each vial contains 50 ml. Atriance is supplied in packs of 6 vials. 6.6 Special precautions for disposal and other handling The normal procedures for proper handling and disposal of anti-tumour medicinal products should be adopted, namely: — Staff should be trained in how to handle and transfer the medicinal product. — Pregnant staff should be excluded from working with this medicinal product. — Personnel handling this medicinal product during handling/transfer should wear protective clothing including mask, goggles and gloves. — All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration. Any liquid waste from the preparation of the nelarabine solution for infusion may be flushed with large amounts of water. — Accidental contact with the skin or eyes should be treated immediately with copious amounts of water. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Novartis Europharm Limited Frimley Business Park Camberley GU16 7SR United Kingdom 8. Marketing authorisation number(s) EU/1/07/403/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 22 August 2007 Date of latest renewal: 18 June 2012 10. Date of revision of the text 24 April 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||