英文药名:AKYNZEO(netupitant/palonosetron hard capsules) 中文药名:奈妥吡坦/帕洛诺司琼复方硬胶囊 生产厂家:中外制药
No common adverse reactions are attributable to netupitant, the new component of the fixed combination, since their frequency was similar with oral palonosetron alone. In addition eye swelling, dyspnoea and myalgia as adverse reactions have been reported with oral palonosetron but not observed during the development of Akynzeo. All these reactions were uncommon. Very rare cases of anaphylaxis, anaphylactic/anaphylactoid reactions and shock have been reported from the post-marketing use of intravenous palonosetron. 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, Website: www.mhra.gov.uk/yellowcard. 4.9 Overdose No specific information is available on the treatment of overdose with Akynzeo. Netupitant doses up to 600 mg and palonosetron doses up to 6 mg have been used in clinical studies without any safety concerns. In case of overdose, the product should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of netupitant and palonosetron, emesis induced by a medicinal product may not be effective. Dialysis studies have not been performed. However, due to the large volume of distribution of palonosetron and netupitant, dialysis is unlikely to be an effective treatment for overdose. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5-HT3) antagonists; ATC code: A04AA55 Mechanism of action Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors. Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Chemotherapeutic substances produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. Delayed emesis has been associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses. Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after administration of 300 mg netupitant. Clinical efficacy and safety Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in two separate pivotal studies. Highly Emetogenic Chemotherapy (HEC) study In a multicenter, randomized, parallel, double-blind, controlled clinical study of 694 patients, the efficacy and safety of single doses of oral netupitant in combination with oral palonosetron was compared with a single oral dose of palonosetron in cancer patients receiving a chemotherapy regimen that included cisplatin (median dose = 75 mg/m2). The efficacy of Akynzeo was assessed in 135 patients who received a single oral dose (netupitant 300 mg and palonosetron 0.5 mg) and 136 patients who received oral palonosetron 0.5 mg alone. Treatment regimens for the Akynzeo and the palonosetron 0.5 mg arms are displayed in Table below. Oral Antiemetic treatment regimen –– HEC study
A summary of the key results from this study is shown in Table below. Proportion of patients receiving cisplatin chemotherapy responding by treatment group and phase
Delayed phase: 25 to 120 hours post-cisplatin treatment. Overall: 0 to 120 hours post-cisplatin treatment. Moderately Emetogenic Chemotherapy (MEC) study In a multicenter, randomized, parallel, double-blind, active-controlled, superiority study, the efficacy and safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron 0.5 mg in cancer patients scheduled to receive the first cycle of an anthracycline and cyclophosphamide regimen for the treatment of a solid malignant tumor. At the time of the study, anthracycline-cyclophosphamide containing chemotherapy regimens were considered to be moderately emetogenic. Recent guidance has updated these regimens to highly emetogenic. All patients received a single oral dose of dexamethasone Oral Antiemetic treatment regimen – MEC study
A total of 724 patients (99.9%) were treated with cyclophosphamide. All patients were additionally treated with either doxorubicin (68.0%) or epirubicin (32.0%). The primary efficacy endpoint was the CR rate in the delayed phase, 25-120 hours after the start of the chemotherapy administration. A summary of the key results from this study is shown in Table below. Proportion of patients receiving anthracycline and cyclophosphamide chemotherapy responding by treatment group and phase – cycle 1
Acute phase: 0 to 24 hours after anthracycline and cyclophosphamide regimen Delayed phase: 25 to 120 hours after anthracycline and cyclophosphamide regimen Overall: 0 to 120 hours after anthracycline and cyclophosphamide regimen Patients continued into the Multiple-Cycle extension for up to 7 additional cycles of chemotherapy. Antiemetic activity of Akynzeo was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles. The impact of nausea and vomiting on patients' daily lives was assessed using the Functional Living Index–Emesis (FLIE). The proportion of patients with Overall no impact on daily life was 6.3% higher (p value =0.005) in the Akynzeo group (78.5%) than in the palonosetron group (72.1%). Multiple-cycle safety study in patients receiving either Highly Emetogenic Chemotherapy or Moderately Emetogenic Chemotherapy In a separate study, a total of 413 patients undergoing initial and repeat cycles of chemotherapy (including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens), were randomized to receive either Akynzeo (n=309) or aprepitant and palonosetron (n=104). Safety and efficacy were maintained throughout all cycles. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Akynzeo in all subsets of the paediatric population in prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based and moderately emetogenic cancer chemotherapy (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Netupitant Absolute netupitant bioavailability data are not available in humans; based on data from two studies with intravenous netupitant, the bioavailability in humans is estimated to be greater than 60%. In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations followed a first order absorption process and reached Cmax in approximately 5 hours. There was a supra-proportional increase in Cmax and AUC parameters for doses from 10 mg to 300 mg. In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitant concentration (Cmax) was 486 ±268 ng/mL (mean ± SD) and median time to maximum concentration (Tmax) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. In a pooled analysis, females had a higher netupitant exposure compared to males; there was a 1.31-fold increase in Cmax, a 1.02 fold increase for AUC and a 1.36 fold increase in half-life. Netupitant AUC0-∞ and Cmax increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal. Palonosetron Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using buffered solution mean maximum palonosetron concentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose range of 3.0 to 80 mcg/kg in healthy subjects. In 36 healthy male and female subjects given a single oral dose of 0.5 mg palonosetron, maximum plasma concentration (Cmax) was 0.81 ± 1.66 ng/mL (mean ± SD) and time to maximum concentration (Tmax) was 5.1 ± 1.7 hours. In female subjects (n=18), the mean AUC was 35% higher and the mean Cmax was 26% higher than in male subjects (n=18). In 12 cancer patients given a single oral dose of palonosetron 0.5 mg one hour prior to chemotherapy, Cmax was 0.93 ± 0.34 ng/mL and Tmax was 5.1 ± 5.9 hours. The AUC was 30% higher in cancer patients than in healthy subjects. A high fat meal did not affect the Cmax and AUC of oral palonosetron. Distribution Netupitant After a single oral 300 mg dose administration in cancer patients, netupitant disposition was characterised by a two compartment model with an estimated median systemic clearance of 20.5 L/h and a large distribution volume in the central compartment (486 L). Human plasma protein binding of netupitant and its two major metabolites M1 and M3 is > 99% at concentrations ranging from 10 to 1500 ng/mL. The third major metabolite, M2, is > 97% bound to plasma proteins. Palonosetron Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins. Biotransformation Netupitant Three metabolites have been detected in human plasma at netupitant oral doses of 30 mg and higher (the desmethyl derivative, M1; the N-oxide derivative, M2; the OH-methyl derivative, M3). In vitro metabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are involved in the metabolism of netupitant. After administration of a single oral dose of 300 mg netupitant, mean plasma netupitant/plasma radioactivity ratios ranged from 0.13 to 0.49 over 96 h post-dose. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose, indicating that netupitant is being rapidly metabolized. Mean Cmax was approximately 11%, 47% and 16% of the parent for M1, M2 and M3 respectively; M2 had the lowest AUC relative to the parent (14%) whereas M1 and M3 AUC were approximately 29% and 33% of the parent, respectively. M1, M2 and M3 metabolites were all shown to be pharmacologically active in an animal pharmacodynamic model, where M3 was most potent and M2 least active. Palonosetron Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates. Elimination Netupitant Following administration of a single dose of Akynzeo, netupitant is eliminated from the body in a multi-exponential fashion, with an apparent mean elimination half-life of 88 hours in cancer patients. Renal clearance is not a significant elimination route for netupitant-related entities. The mean fraction of an oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95% and 70.7% of the radioactive dose was recovered in the urine and faeces, respectively. Approximately half the radioactivity administered orally as [14C]-netupitant was recovered from urine and faeces within 120 h of dosing. Elimination via both routes was estimated to be complete by Day 29-30 post-dose. Palonosetron Following administration of a single oral 0.75 mg dose of [14C]-palonosetron to six healthy subjects, 85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in faeces. The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. In healthy subjects given palonosetron capsules 0.5 mg, the terminal elimination half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½ was 48 ± 19 hours. After a single dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance was 66.5± 18.2 mL/h/kg. Special populations Hepatic Impairment Netupitant Maximum concentrations and total exposure of netupitant were increased in subjects with mild (n=8), moderate (n=8), and severe (n=2) hepatic impairment compared to matching healthy subjects, although there was pronounced individual variability in both hepatically-impaired and healthy subjects. Exposure to netupitant (Cmax, AUC0-t and AUC0-∞) compared to matching healthy subjects was 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically-impaired subjects, respectively. As such, no dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Limited data exist in patients with severe hepatic impairment (Child Pugh score ≥9). Palonosetron Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetron is increased in the subjects with severe hepatic impairment, this does not warrant dose reduction. Renal impairment Netupitant No specific studies were performed to evaluate netupitant in patients with renal impairment. In the ADME trial, less than 5% of all netupitant-related material was excreted in urine and less than 1% of the netupitant dose was eliminated unchanged in the urine and therefore any accumulation of netupitant or metabolites after a single dose would be negligible. Furthermore, the population PK study showed no correlation between PK parameters of netupitant and markers of renal dysfunction. Palonosetron Mild to moderate renal impairment does not significantly affect palonosetron PK parameters. Total systemic exposure to intravenous palonosetron increased by approximately 28% in patients with severe impairment relative to healthy subjects. In a population PK study, patients with a reduced creatinine clearance (CLCR) also had a reduced palonosetron clearance, but this reduction would not result in a significant change in palonosetron exposure. Therefore, Akynzeo can be administered without dosage adjustment in patients with renal impairment. Neither netupitant nor palonosetron have been evaluated in patients with end-stage renal disease. 5.3 Preclinical safety data Palonosetron Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use. Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion channels involved in ventricular de- and re-polarisation and prolong action potential duration. Degeneration of seminiferous epithelium was associated with palonosetron following a one month oral repeat dose toxicity study in rats. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Only limited data from animal studies are available regarding the placental transfer (see section 4.6). Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 15 times the human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours, endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not in mice. The underlying mechanisms are not fully understood, but because of the high doses employed and since the medicinal product is intended for single application in humans, these findings are not considered relevant for clinical use. Netupitant and combination with palonosetron Effects in non-clinical studies based on safety pharmacology and single and repeated dose toxicity were observed only at exposures considered in excess of the maximum human exposure, indicating little relevance to clinical use. Phospholipidosis (foamy macrophages) has been observed with the administration of netupitant after repeated administration in rats and dogs. The effects were reversible or partially reversible after the recovery period. The significance of these findings in humans is unknown. Non-clinical studies indicate that netupitant and its metabolites and the combination with palonosetron only at very high concentrations may block ion channels involved in ventricular de- and re-polarisation and prolong action potential duration. Reproductive studies in animals with netupitant do not indicate direct or indirect harmful effects with respect to fertility, parturition or postnatal development. An increased incidence of positional foetal abnormalities of the limbs and paws, fused sternebrae and agenesis of accessory lung lobe were observed following daily administration of netupitant in rabbits at 10 mg/kg/day and higher during the period of organogenesis. In a pilot dose range finding study in rabbits, cleft palate, microphtalmia and aphakia were observed in four foetuses from one litter in the 30 mg/kg/day group. The relevance of these findings in humans is unknown. No data from animal studies with netupitant are available regarding placental transfer and lactation. Netupitant is not mutagenic. 6. Pharmaceutical particulars 6.1 List of excipients Hard capsule content: Netupitant tablets Microcrystalline cellulose (E460) Sucrose lauric acid esters Povidone K-30 Croscarmellose sodium Colloidal hydrated silica Sodium stearyl fumarate Magnesium stearate Palonosetron soft capsule Capsule content Glycerol monocaprylocaproate (type I) Glycerol Polyglyceryl oleate Purified water Butylhydroxyanisole (E320) Capsule shell Gelatin Glycerol Sorbitol 1,4 sorbitan Titanium dioxide (E171) Hard capsule shell: Gelatin Titanium dioxide (E171) Yellow iron oxide (E172) Red iron oxide (E172) Printing ink Shellac glaze (partially esterified) Black iron oxide (E172) Propylene glycol (E1520) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Alu/alu blister containing one hard capsule. Pack size of one capsule. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Helsinn Birex Pharmaceuticals Ltd Damastown Mulhuddart Dublin 15 Ireland. 8. Marketing authorisation number(s) EU/1/15/1001/001 9. Date of first authorisation/renewal of the authorisation 27/05/2015 10. Date of revision of the text 11/11/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 欧盟批准Akynzeo用于预防化疗诱发的恶心及呕吐 欧盟委员会批准Helsinn旗下Akynzeo(奈妥吡坦-帕洛诺司琼)在欧盟用于预防与高度呕吐的含铂类药物癌症化疗及中度呕吐性癌症化疗相关的急性与延迟性恶心和呕吐。该决定是在人用医药产品委员会(CHMP)积极意见被采纳之后做出的,其适用于欧盟所有28个成员国,以及爱尔兰、列支敦士登和挪威。 Akynzeo是一种新型口服固定剂量的复方制剂,由一种高度选择性NK1受体拮抗剂及5-HT3受体拮抗剂帕洛诺司琼组成,用于化疗诱发的恶心与呕吐(CINV) 预防。 CINV是化疗最常见的一种副作用。其管理在过去几十年已经得到改善,但尽管存在有效治疗药物及明确的止吐指南,但许多患者仍遭受CINV的痛苦,特别是化疗后的延迟期。研究显示,患者通常接受与CINV治疗指南不一致的止吐药物方案,这也呼吁多种途径的止吐预防。 Akynzeo提供了一种由两种止吐药组成的单一口服胶囊复方药物。一种NK1受体拮抗剂、一种5-HT3受体拮抗剂及地塞米松的方案满足了指南对高度呕吐性及以蒽环霉素环磷酰胺为基础化疗后最优止吐剂治疗的建议。 Helsinn集团首席执行官Braglia评论称:Helsinn宣布欧盟批准Akynzeo是自豪的,这一批准将允许我们为欧洲的癌症患者提供一种改善的CINV预防选择。Akynzeo将在化疗治疗后的急性及延迟期的恶心及呕吐预防中起着重要的作用,这可能为患者导致更多的治疗选择。 |
AKYNZEO(netupitant/palonosetron hard capsules)简介:
英文药名:AKYNZEO(netupitant/palonosetron hard capsules)
中文药名:奈妥吡坦/帕洛诺司琼复方硬胶囊
生产厂家:中外制药药品简介新型复方止吐药物——Akynzeo(奈妥吡坦-帕洛诺司琼)复方硬胶囊获 ... 责任编辑:admin |
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