英文药名：Aloxi（Palonosetron for injection） 中文药名：盐酸帕洛诺司琼注射液 生产厂家：RIEMSER  药品介绍 药品英文名 Palonosetron 药品别名 盐酸帕罗司琼、Palonosetron Hydrochloride、Aloxi、Onicit、RS-25259-197 药物剂型 帕洛诺司琼注射剂：250μg/5ml。15～30℃避光保存，避免冷冻。 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. 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 250 micrograms solution for injection 1. Name of the medicinal product Aloxi 250 micrograms solution for injection. 2. Qualitative and quantitative composition Each ml of solution contains 50 micrograms palonosetron (as hydrochloride). Each vial of 5 ml of solution contains 250 micrograms palonosetron (as hydrochloride). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection. Clear, colourless solution. 4. Clinical particulars 4.1 Therapeutic indications Aloxi is indicated in adults for: • the prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy, • 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. This medicinal product should be administered by a healthcare professional under appropriate medical supervision. Posology Adults 250 micrograms palonosetron administered as a single intravenous bolus approximately 30 minutes before the start of chemotherapy. Aloxi should be injected over 30 seconds. The efficacy of Aloxi in the prevention of nausea and vomiting induced by highly emetogenic chemotherapy may be enhanced by the addition of a corticosteroid administered prior to 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 intravenous use. 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 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. This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium- free'. 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 agents 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. Therefore, 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 250 micrograms (total 633 patients) the most frequently observed adverse reactions, at least possibly related to Aloxi, were headache (9 %) and constipation (5 %). 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). Very rare (<1/10,000) adverse reactions were reported post-marketing. Within each frequency grouping, adverse reactions are presented below in order of decreasing seriousness. System organ class Common ARs (≥1/100 to<1/10) Uncommon ARs (≥1/1,000 to <1/100) Very rare ARs° (<1/10,000) Immune system disorders     Hypersensitivity, anaphylaxis, anaphylactic/ anaphylactoid reactions and shock Metabolism and nutrition disorders   Hyperkalaemia, metabolic disorders, hypocalcaemia, hypokalaemia, anorexia, hyperglycaemia, appetite decreased   Psychiatric disorders   Anxiety, euphoric mood   Nervous system disorders Headache Dizziness Somnolence, insomnia, paraesthesia, hypersomnia, peripheral sensory neuropathy   Eye disorders   Eye irritation, amblyopia   Ear and labyrinth disorders   Motion sickness, tinnitus   Cardiac disorders   Tachycardia, bradycardia, extrasystoles, myocardial ischaemia, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles   Vascular disorders   Hypotension, hypertension, vein discolouration, vein distended   Respiratory, thoracic and mediastinal disorders   Hiccups   Gastrointestinal disorders Constipation Diarrhoea Dyspepsia, abdominal pain, abdominal pain upper, dry mouth, flatulence   Hepatobiliary disorders   Hyperbilirubinaemia   Skin and subcutaneous tissue disorders   Dermatitis allergic, pruritic rash   Musculoskeletal and connective tissue disorders   Arthralgia   Renal and urinary disorders   Urinary retention, glycosuria   General disorders and administration site conditions   Asthenia, pyrexia, fatigue, feeling hot, influenza like illness Injection site reaction* Investigations   Elevated transaminases-, electrocardiogram QT prolonged   ° From post-marketing experience * Includes the following: burning, induration, discomfort and pain 4.9 Overdose No case of overdose has been reported. Doses of up to 6 mg have been used in clinical studies. 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 two randomised, double-blind studies with a total of 1,132 patients receiving moderately emetogenic chemotherapy that included cisplatin ≤50 mg/m2, carboplatin, cyclophosphamide ≤1,500 mg/m2 and doxorubicin >25 mg/m2, palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg (half-life 4 hours) or dolasetron 100 mg (half-life 7.3 hours) administered intravenously on Day 1, without dexamethasone. In a randomised, double-blind study with a total of 667 patients receiving highly emetogenic chemotherapy that included cisplatin ≥ 60 mg/m2, cyclophosphamide > 1,500 mg/m2 and dacarbazine, palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg administered intravenously on Day 1. Dexamethasone was administered prophylactically before chemotherapy in 67 % of patients. The pivotal studies were not designed to assess efficacy of palonosetron in delayed onset nausea and vomiting. The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours. Results for the studies on moderately emetogenic chemotherapy and for the study on highly emetogenic chemotherapy are summarised in the following tables. Palonosetron was non-inferior versus the comparators in the acute phase of emesis both in moderately and highly emetogenic setting. Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlled clinical studies, 875 patients enrolled in the three phase 3 trials continued in an open label safety study and were treated with palonosetron 750 micrograms for up to 9 additional cycles of chemotherapy. The overall safety was maintained during all cycles. Table 1: Percentage of patients a responding by treatment group and phase in the Moderately Emetogenic Chemotherapy study versus ondansetron Aloxi 250 micrograms (n= 189) Ondansetron 32 milligrams (n= 185)     Delta     % % %   Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b 0 – 24 hours 81.0 68.6 12.4 [1.8 %, 22.8 %] 24 – 120 hours 74.1 55.1 19.0 [7.5 %, 30.3 %] 0 – 120 hours 69.3 50.3 19.0 [7.4 %, 30.7 %] Complete Control (Complete Response and No More Than Mild Nausea) p-value c 0 – 24 hours 76.2 65.4 10.8 NS 24 – 120 hours 66.7 50.3 16.4 0.001 0 – 120 hours 63.0 44.9 18.1 0.001 No Nausea (Likert Scale) p-value c 0 – 24 hours 60.3 56.8 3.5 NS 24 – 120 hours 51.9 39.5 12.4 NS 0 – 120 hours 45.0 36.2 8.8 NS a Intent-to-treat cohort. b The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates non-inferiority between Aloxi and comparator. c Chi-square test. Significance level at α=0.05. Table 2: Percentage of patients a responding by treatment group and phase in the Moderately Emetogenic Chemotherapy study versus dolasetron Aloxi 250 micrograms (n= 185) Dolasetron 100 milligrams (n= 191)     Delta     % % %   Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b 0 – 24 hours 63.0 52.9 10.1 [-1.7 %, 21.9 %] 24 – 120 hours 54.0 38.7 15.3 [3.4 %, 27.1 %] 0 – 120 hours 46.0 34.0 12.0 [0.3 %, 23.7 %] Complete Control (Complete Response and No More Than Mild Nausea) p-value c 0 – 24 hours 57.1 47.6 9.5 NS 24 – 120 hours 48.1 36.1 12.0 0.018 0 – 120 hours 41.8 30.9 10.9 0.027 No Nausea (Likert Scale) p-value c 0 – 24 hours 48.7 41.4 7.3 NS 24 – 120 hours 41.8 26.2 15.6 0.001 0 – 120 hours 33.9 22.5 11.4 0.014 a Intent-to-treat cohort. b The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates non-inferiority between Aloxi and comparator. c Chi-square test. Significance level at α=0.05. Table 3: Percentage of patients a responding by treatment group and phase in the Highly Emetogenic Chemotherapy study versus ondansetron Aloxi 250 micrograms (n= 223) Ondansetron 32 milligrams (n= 221)     Delta     % % %   Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b 0 – 24 hours 59.2 57.0 2.2 [-8.8 %, 13.1 %] 24 – 120 hours 45.3 38.9 6.4 [-4.6 %, 17.3 %] 0 – 120 hours 40.8 33.0 7.8 [-2.9 %, 18.5 %] Complete Control (Complete Response and No More Than Mild Nausea) p-value c 0 – 24 hours 56.5 51.6 4.9 NS 24 – 120 hours 40.8 35.3 5.5 NS 0 – 120 hours 37.7 29.0 8.7 NS No Nausea (Likert Scale) p-value c 0 – 24 hours 53.8 49.3 4.5 NS 24 – 120 hours 35.4 32.1 3.3 NS 0 – 120 hours 33.6 32.1 1.5 NS a Intent-to-treat cohort. b The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates non-inferiority between Aloxi and comparator. c Chi-square test. Significance level at α=0.05. The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in CINV clinical studies. 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 repolarisation. 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 intravenous administration, an initial decline in plasma concentrations is followed by slow elimination from the body with a mean terminal elimination half-life of approximately 40 hours. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generally dose-proportional over the dose range of 0.3–90 μg/kg in healthy subjects and in cancer patients. Following intravenous administration of palonosetron 0.25 mg once every other day for 3 doses in 11 testicular cancer patients, the mean (± SD) increase in plasma concentration from Day 1 to Day 5 was 42 ± 34 %. After intravenous administration of palonosetron 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (± SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110 ± 45 %. Pharmacokinetic simulations indicate that the overall exposure (AUC0-∞) of 0.25 mg intravenous palonosetron administered once daily for 3 consecutive days was similar to a single intravenous dose of 0.75 mg, although Cmax of the 0.75 mg single dose was higher. 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 After a single intravenous dose of 10 micrograms/kg [14C]-palonosetron, approximately 80 % of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40 % of the administered dose, as unchanged active substance. After a single intravenous bolus administration in healthy subjects the total body clearance of palonosetron was 173 ± 73 ml/min and renal clearance was 53 ± 29 ml/min. The low total body clearance and large volume of distribution resulted in a terminal elimination half-life in plasma of approximately 40 hours. Ten percent of patients have a mean terminal elimination half-life greater than 100 hours. Pharmacokinetics in special populations Elderly Age does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary in elderly patients. Gender Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary based on gender. Paediatric population 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 dosage 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 30 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 Mannitol Disodium edetate Sodium citrate Citric acid monohydrate Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 5 years. Upon opening of the vial, use immediately and discard any unused solution. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Type I glass vial with chlorobutyl siliconised rubber stopper and aluminium cap. Available in packs of 1 vial containing 5 ml of solution. 6.6 Special precautions for disposal and other handling Single use only, any unused solution should be discarded. Any unused 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/1/04/306/001 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 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu