英文药名：Aloxi（Palonosetron  hydrochloride)capsule

中文药名：盐酸帕洛诺司琼胶囊

生产厂家：Helsinn Birex制药
药品介绍
2008年8月23日美国FDA批准第二代5-HT3受体拮抗剂Aloxi(palonosetron HCl，盐酸帕洛诺司琼胶囊)用于预防化疗引起的急性恶心呕吐。
药理作用
5-羟色胺3(5-HT3)受体存在于外周和中枢催吐化学感受区的迷走神经末梢，细胞毒素剂释放来自于肠嗜铬细胞的5-HT3，随后5-HT3结合到迷走神经的传入回路(激活作用)，从而诱发呕吐。本品为5-HT3受体抑制药，对5-HT3受体有高选择性拮抗作用，可阻断呕吐反射中枢外周神经元的突触前5-HT3受体的兴奋，并且直接影响中枢神经系统内5-HT3受体传递的迷走神经传入后区的作用，阻断肠道中迷走神经末梢，阻止信号传递到5-HT3受体触发区，减少呕吐和恶心的发生率，但对已发生的恶心、呕吐效果较差。本品半衰期较长，故对化疗诱发的急、慢性呕吐均有效。
药动学
本品生物利用度为80%～90%，达峰时间为2～3h，t1/2为40h，血浆蛋白结合率为60%～90%，量效关系不呈线性。约50%在肝内代谢，代谢物为6-S-羟基帕洛诺司琼和N-O-帕洛诺司琼，两者皆无临床活性。约80%的本品在144h内经肾排出，其中有40%属于原形药物，代谢产物约占50%。尚不清楚本品是否经乳汁分泌。
适应证
用于预防化疗诱发的呕吐及手术后的恶心和呕吐。
禁忌证
1.有本品过敏史者禁用。
2.不推荐儿童使用本品。
注意事项
1.对于18岁以下的患者，尚未确定临床疗效和安全性。
2.本品的妊娠安全性分级为B级。
3.药物对哺乳的影响尚不明确。
4.本品不宜与其他药物混合使用。
5.本品半衰期长，给药7天内无需补给。
6.给药前后应将输注管路用0.9%氯化钠注射液清洗。
7.正在服用利尿药的患者，在使用本品的过程中，应将血钾水平控制在正常范围内。
8.本品对已经发生的恶心、呕吐无作用。
9.慎用：以下患者慎用。
(1)使用其他5-羟色胺3受体拮抗药过敏或发生其他严重不良反应者。
(2)心血管疾病的患者。
(3)有使心脏传导间期延长的危险因素(如低钾血症、低血镁症、原发性QT综合征、抗心律失常或其他可引起QT间期延长的药物、既往使用过蒽环类抗生素)的患者。
不良反应
1.胃肠道：常见便秘；少见腹泻、腹痛、消化不良和口干。
2.中枢神经系统：可见头痛；罕见头昏、失眠、疲乏或无力、焦虑。
3.心血管系统：偶见低血压、心动过缓或非持续性心动过速；罕见高血压、心肌缺血、QT间期延长和期前收缩。
4.泌尿生殖系统：偶见尿潴留。
5.肌肉骨骼系统：罕见关节痛。
6.肝脏：罕见血清氨基转移酶升高。
7.眼：罕见眼刺激和弱视。
8.过敏反应：罕见过敏性皮炎或非特异性皮疹。
9.其他：罕见疲乏、运动病和耳鸣。
10.代谢/内分泌系统：有高钾血症的报道。
用法用量
1.口服：预防腹腔镜手术后的恶心和呕吐，手术前1～2h口服1μg/kg，可有效预防术后恶心和呕吐(主要是妇女)。此剂量可降低呕吐的发生率和术后24h对止吐药的需求。但增加剂量，有效率并不升高。
2.静注：
(1)预防化疗诱发的呕吐 化疗前约30min给药，单剂250μg，30s注射完。
(2)预防子宫切除术后的恶心和呕吐 手术结束前20～30min，注射30μg/kg(30s注射完)。此剂量可降低呕吐的发生率和术后24h对止吐药的需求。这个剂量也可延长出现第1次呕吐的时间。低剂量则效果不佳。肝、肾功能不全时无需调整剂量。
药物相应作用
与其他可延长QT间期的药物合用，可加重QT间期延长的症状。
Aloxi 500 microgrammes soft capsules
1. Name of the medicinal product
Aloxi 500 micrograms soft capsules
2. Qualitative and quantitative composition
Each capsule contains 500 micrograms palonosetron (as hydrochloride).
Excipient(s):
Each capsule contains 14.21 milligrams sorbitol.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Soft capsule.
Light beige, opaque, oval, soft gelatine capsules, imprinted with black logo “AlO”, filled with a clear yellowish solution.
4. Clinical particulars
4.1 Therapeutic indications
Aloxi is indicated in adults for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.
4.2 Posology and method of administration
Aloxi should be used only before chemotherapy administration.
Posology
Adults
500 micrograms palonosetron administered orally approximately one hour before the start of chemotherapy.
Elderly population
No dose adjustment is necessary for the elderly.
Paediatric population
The safety and efficacy in children have not been established. Currently available data are described in section 5.1 and section 5.2, but no recommendation on posology can be made.
Hepatic impairment
No dose adjustment is necessary for patients with impaired hepatic function.
Renal impairment
No dose adjustment is necessary for patients with impaired renal function.
No data are available for patients with end stage renal disease undergoing haemodialysis.
Method of administration
For oral use.
Aloxi can be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
As palonosetron may increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored following administration. Two cases of constipation with faecal impaction requiring hospitalisation have been reported in association with palonosetron 750 micrograms.
At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QT corrected (QTc) interval. A specific thorough QT/QTc study was conducted in healthy volunteers for definitive data demonstrating the effect of palonosetron on QT/QTc. (see section 5.1).
However, as for other 5-HT3 antagonists, caution should be exercised in the use of palonosetron in patients who have or are likely to develop prolongation of the QT interval. These conditions include patients with a personal or family history of QT prolongation, electrolyte abnormalities, congestive heart failure, bradyarrhythmias, conduction disturbances and in patients taking anti-arrhythmic agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypomagnesemia should be corrected prior to 5-HT3-antagonist administration.
Aloxi should not be used to prevent or treat nausea and vomiting in the days following chemotherapy if not associated with another chemotherapy administration.
Aloxi contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product. Aloxi capsules may also contain a trace of lecithin derived from soya. Therefore, patients with known hypersensitivity to peanut or soya, should be monitored closely for signs of an allergic reaction.
4.5 Interaction with other medicinal products and other forms of interaction
Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based on in vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinically relevant concentrations.
Chemotherapeutic medicinal products
In preclinical studies, palonosetron did not inhibit the antitumour activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C).
Metoclopramide
In a clinical study, no significant pharmacokinetic interaction was shown between a single intravenous dose of palonosetron and steady state concentration of oral metoclopramide, which is a CYP2D6 inhibitor.
CYP2D6 inducers and inhibitors
In a population pharmacokinetic analysis, it has been shown that there was no significant effect on palonosetron clearance when co-administered with CYP2D6 inducers (dexamethasone and rifampicin) and inhibitors (including amiodarone, celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine, haloperidol, paroxetine, quinidine, ranitidine, ritonavir, sertraline or terbinafine).
Corticosteroids
Palonosetron has been administered safely with corticosteroids.
Other medicinal products
Palonosetron has been administered safely with analgesics, antiemetic/antinauseants, antispasmodics and anticholinergic medicinal products.
4.6 Fertility, pregnancy and lactation
Pregnancy
For Palonosetron, no clinical data on exposed pregnancies are available. 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 5.3). There is no experience of palonosetron in human pregnancy so palonosetron should not be used in pregnant women unless it is considered essential by the physician.
Breast-feeding
As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be discontinued during therapy.
Fertility
There are no data concerning the effect of palonosetron on fertility.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned when driving or operating machines.
4.8 Undesirable effects
In clinical studies at a dose of 500 micrograms (total 161 patients) the most frequently observed adverse reaction, at least possibly related to Aloxi, was headache (3.7 %).
In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably related to Aloxi. These were classified as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to <1/100).

System Organ Class	Common ARs	Uncommon ARs
Psychiatric disorders		Insomnia
Nervous system disorders	Headache
Eye disorders		Eye swelling
Cardiac disorders		Atrioventricular block first degree, atrioventricular block second degree
Respiratory, thoracic and mediastinal disorders		Dyspnoea
Gastrointestinal disorders		Constipation, nausea
Musculoskeletal and connective tissue disorders		Myalgia
Investigations		Blood bilirubin increased

In post marketing very rare cases (<1/10,000) of hypersensitivity reactions occurred with palonosetron solution for injection for intravenous use.
4.9 Overdose
No case of overdose has been reported.
Doses of up to 6 mg have been used in clinical trials. The highest dose group showed a similar incidence of adverse reactions compared to the other dose groups and no dose response effects were observed. In the unlikely event of overdose with Aloxi, this should be managed with supportive care. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for Aloxi overdose.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT3) antagonists, ATC code: A04AA05
Palonosetron is a selective high-affinity receptor antagonist of the 5HT3 receptor.
In a multicentre, randomised, double-blind active control clinical trial of 635 patients set to receive moderately emetogenic cancer chemotherapy. A single-dose of 250 mcg, 500 mcg, or 750 mcg oral palonosetron capsules given one hour prior to moderately emetogenic chemotherapy was compared to a single-dose of 250 mcg intravenous Aloxi given 30 minutes prior to chemotherapy. Patients were randomised to either dexamethasone or placebo in addition to their assigned treatment. The majority of patients in the study were women (73 %), white (69 %), and naïve to previous chemotherapy (59 %). The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours.
Efficacy was based on demonstrating non-inferiority of oral palonosetron doses compared to the approved intravenous formulation. Non-inferiority criteria were met if the lower bound of the two-sided 98.3 % confidence interval for the difference in complete response rates of oral palonosetron dose minus approved intravenous formulation was larger than -15 %. The non-inferiority margin was 15 %.
As shown in Table 1, oral Aloxi capsules 500 micrograms demonstrated non-inferiority to the active comparator during the 0 to 24 hour and 0 to 120 hour time intervals; however, for the 24 to 120 hour time period, non-inferiority was not shown.
Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlled clinical trials, 217 patients were enrolled in a multicentre, open label safety study and were treated with palonosetron capsules 750 micrograms for up to 4 cycles of chemotherapy in a total of 654 chemotherapy cycles. Approximately 74 % of patients also received single dose oral or intravenous dexamethasone 30 minutes before chemotherapy. Complete Response was not formally evaluated for the repeat cycle application. However, in general the antiemetic effect for the 0-24 hour interval was similar throughout the consecutively repeated cycles and the overall safety was maintained during all cycles.
Table 1: Proportion of patientsa responding by treatment group and phase

Aloxi Oral 500 micrograms (n=160)	Aloxi Intravenous 250 micrograms (n=162)	Delta
	%	%	%
Complete Response (No Emesis and No Rescue Medication)				98.3 % CIb
0-24 hours	76.3	70.4	5.9	[-6.5 %, 18.2 %]
24-120 hours	62.5	65.4	-2.9	[-16.3 %, 10.5 %]
0-120 hours	58.8	59.3	-0.5	[-14.2 %, 13.2 %]
Complete Control (Complete Response and No More Than Mild Nausea)				p-valuec
0-24 hours	74.4	68.5	5.9	NS
24-120 hours	56.3	62.3	-6.0	NS
0-120 hours	52.5	56.2	-3.7	NS
No Nausea (Likert Scale)				p-valuec
0-24 hours	58.8	57.4	1.4	NS
24-120 hours	49.4	47.5	1.9	NS
0-120 hours	45.6	42.6	3.0	NS

a Intent-to-treat cohort
b The study was designed to show non-inferiority. A lower bound greater that -15 % demonstrates non-inferiority between Aloxi oral and comparator Aloxi intravenous
c Chi-square test. Significance levels at alpha 0.0167 (adjusted for multiple comparisons).
In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarisation and to prolong action potential duration.
The effect of palonosetron on QTc interval was evaluated in a double blind, randomised, parallel, placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of IV administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in 221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as any other ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heart rate, atrioventricular (AV) conduction and cardiac repolarization.
Paediatric population
Prevention of Chemotherapy Induced Nausea and Vomiting (CINV):
The safety and efficacy of Palonosetron i.v at single doses of 3µg/kg and 10µg/kg was investigated in a clinical study in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11 years (31 patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was the proportion of patients with a complete response (CR, defined as no emetic episode and no rescue medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after palonosetron 10 µg/kg compared to palonosetron 3µg/kg was 54.1% and 37.1% respectively. Pharmacokinetic information is provided in section 5.2.
Prevention of Post Operative Nausea and Vomiting (PONV):
The safety and efficacy of Palonosetron i.v at single doses of 1µg/kg and 3µg/kg was compared in a clinical study in 150 patients in the following age groups, >28 days to 23 months (7 patients), 2 to 11 years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective surgery. No safety concerns were raised in either treatment group. The proportion of patients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 µg/kg or 3 µg/kg (88% vs 84%).
Please see section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
Absorption
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 µg/kg in healthy subjects.
In 36 healthy male and female subjects given a single oral dose of palonosetron capsules 500 micrograms, maximum plasma palonosetron concentration (Cmax) was 0.81 ± 0.17 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 capsules 500 micrograms 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. Therefore, Aloxi capsules may be taken without regard to meals.
Distribution
Palonosetron at the recommended dose is widely distributed in the body with a volume of distribution of approximately 6.9 to 7.9 l/kg. Approximately 62 % of palonosetron is bound to plasma proteins.
Biotransformation
Palonosetron is eliminated by dual route, about 40 % eliminated through the kidney and with approximately 50 % metabolised to form two primary metabolites, which have less than 1 % of the 5HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have shown that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolisers of CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinically relevant concentrations.
Elimination
Following administration of a single oral 750 micrograms 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 feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40 % of the administered dose. In healthy subjects given palonosetron capsules 500 micrograms, 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.
Pharmacokinetics in special populations
Elderly
Age does not affect the pharmacokinetics of palonosetron. No dose adjustment is necessary in elderly patients.
Gender
Gender does not affect the pharmacokinetics of palonosetron. No dose adjustment is necessary based on gender.
Paediatric patients
Across all age groups, (>28 days to 23 months (11 patients), 2 to 11 years (30 patients), and 12 to 17 years of age (29 patients)) of CINV paediatric patients, exposure to palonosetron was generally dose proportional for the 3μg/kg and 10μg/kg dose levels. Both clearance and volume of distribution appear to increase with increasing age largely due to the expected increase in body weight among the age groups. Mean terminal elimination half-life values ranged from 21-37 hours and did not change with dose or age. There was no effect of gender on clearance, volume of distribution or half-life. Please see section 4.2 for information on paediatric use.
Renal impairment
Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Severe renal impairment reduces renal clearance, however total body clearance in these patients is similar to healthy subjects. No dose adjustment is necessary in patients with renal insufficiency. No pharmacokinetic data in haemodialysis patients are available.
Hepatic impairment
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.
5.3 Preclinical safety data
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.
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 Aloxi is intended for single application in humans, these findings are not considered relevant for clinical use.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content:
Mono/diglycerides of caprylic/capric acid
Polyglycerol oleate
Glycerol
Purified water
Butylhydroxyanisole (BHA)
Capsule shell:
Gelatin
Sorbitol (E420)
Glycerol
Titanium dioxide (E171)
Printing Ink:
Iron oxide black (E172)
Polyvinyl acetate phthalate
Macrogol 400
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
Polyamide/aluminium/PVC blister containing one or five soft capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Helsinn Birex Pharmaceuticals Limited.
Damastown
Mulhuddart
Dublin 15
Ireland
8. Marketing authorisation number(s)
EU/1/04/306/002
EU/1/04/306/003
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 22 March 2005
Date of latest renewal: 23 March 2010
10. Date of revision of the text
Date of revision May 2013.
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
---------------------------------------------------------------
产地国家: 美国
原产地英文商品名:
ALOXI capsules 0.5MG/CAP 5CAP/BOX
原产地英文药品名:
PALONOSETRON HCL
原产地英文化合物名称:
(3aS)-2-(3S)-1-Azabicyclo[2.2.2]oct-3-yl-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one monohydrochloride
中文参考商品译名:
ALOXI胶囊  500毫克/胶囊 5胶囊/盒
中文参考药品译名:
盐酸帕洛诺司琼
生产厂家中文参考译名:
Helsinn Birex制药