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英文药名：ALOXI(palonosetron HCI injection) 中文药名：盐酸帕洛诺司琼注射液 生产厂家：HELSINN HEALTHCARE SA
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for:
1.2 Postoperative Nausea and Vomiting ALOXI is indicated for:
As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low. 2 DOSAGE AND ADMINSTRATION 2.1 Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25mg I.V. dose administered over 30seconds. Dosing should occur 30minutes before the start of chemotherapy. Postoperative Nausea and Vomiting Dosage for Adults - a single 0.075mg I.V. dose administered over 10seconds immediately before the induction of anesthesia. 2.2 Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. 3 DOSAGE FORM AND STRENGTHS ALOXI is supplied as a single-use sterile, clear, colorless solution in glass vials that provide:
4 CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [seeAdverse Reactions (6.2)] 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Chemotherapy-Induced Nausea and Vomiting In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥2% of patients in these trials (Table1).
In other studies, 2subjects experienced severe constipation following a single palonosetron dose of 0.75mg, three times the recommended dose. One patient received a 10mcg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 0.75mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, <1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: <1%: allergic dermatitis, rash. Hearing and Vision: <1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1% diarrhea, <1% dyspepsia, abdominal pain, dry mouth, hiccups and flatulence. General: 1% weakness, <1% fatigue, fever, hot flash, flu-like syndrome. Liver: <1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, <1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: <1%: arthralgia. Nervous System: 1%: dizziness, <1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, <1%: euphoric mood. Urinary System: <1%: urinary retention. Vascular: <1%: vein discoloration, vein distention. 6.2 Postoperative Nausea and Vomiting The adverse reactions cited in Table2 were reported in ≥2% of adults receiving I.V. Aloxi 0.075mg immediately before induction of anesthesia in one phase2 and two phase3 randomized placebo-controlled trials. Rates of events between palonosetron and placebo groups were indistinguishable. Some events are known to be associated with, or may be exacerbated by concomitant perioperative and intraoperative medications administered in this surgical population. Please refer to Section12.2, thorough QTc study results, for definitive data demonstrating the lack of palonosetron effect on QT/QTc.
In these clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant perioperative and intraoperative medications including those associated with anesthesia: Cardiovascular: 1% electrocardiogram QTc prolongation, sinus bradycardia, tachycardia; <1%: blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema; ECG T wave amplitude decreased, platelet count decreased. The frequency of these adverse effects did not appear to be different from placebo. Dermatological: 1%: pruritus. Gastrointestinal System: 1%: flatatulence, <1%: dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia. General: <1%: chills. Liver: 1%: increases in AST and/or ALT, <1%: hepatic enzyme increased. Metabolic: <1%: hypokalemia, anorexia. Nervous System: <1%: dizziness. Respiratory: <1%: hypoventilation, laryngospasm. Urinary System: 1%: urinary retention. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25mg in the prevention of Chemotherapy Induced Nausea and Vomiting. 7 DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with latter mediated via multiple CYP enzymes. Further invitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25mg I.V. palonosetron and 20mg I.V. dexamethasone in healthy subjects no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25mg (I.V. bolus) was administered on day1 and oral aprepitant for 3days (125mg/80mg/80mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75mg) and steady state oral (10mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cytarabine, doxorubicin and mitomycin C) in murine tumor models. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60mg/kg/day (1894times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60mg/kg/day (3789times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. 8.3 Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in patients below the age of 18years have not been established. 8.5 Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥65years of age and younger patients (18 to 64years). Of the 1374adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥65years old, while 71 (5%) were ≥75years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520adult patients in Aloxi PONV clinical studies, 73 (5%) were ≥65years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, Aloxi efficacy in geriatric patients has not been adequately eva luated. 8.6 Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. 8.7 Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. 8.8 Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3- 90mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. 10 OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90mcg/kg (equivalent to 6mg fixed dose) as part of a dose ranging study. This is approximately 25times the recommended dose of 0.25mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30mg/kg (947 and 474times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. 11 DESCRIPTION ALOXI (palonosetron hydrochloride) is an antiemetic and antinauseant agent. It is a serotonin subtype3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C19H24N2O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer and has the following structural formula:
Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol. ALOXI injection is a sterile, clear, colorless, non pyrogenic, isotonic, buffered solution for intravenous administration. ALOXI injection is available as 5mL single use vial or 1.5mL single use vial. Each 5mL vial contains 0.25mg palonosetron base as 0.28mg palonosetron hydrochloride, 207.5mg mannitol, disodium edetate and citrate buffer in water for intravenous administration. Each 1.5mL vial contains 0.075mg palonosetron base as 0.084mg palonosetron hydrochloride, 83mg mannitol, disodium edetate and citrate buffer in water for intravenous administration. The pH of the solution in the 5mL and 1.5mL vials is 4.5 to 5.5. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response. 12.2 Pharmacodynamics The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in CINV clinical trials. In PONV clinical trials the effect of palonosetron on the QTc interval was no different from placebo. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration. The effect of palonosetron on QTc interval was eva luated in a double blind, randomized, parallel, placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to eva luate the ECG effects of I.V. administered palonosetron at single doses of 0.25, 0.75 or 2.25mg in 221healthy subjects. The study demonstrated no significant effect on any ECG interval including QTc duration (cardiac repolarization) at doses up to 2.25mg. 12.3 Pharmacokinetics After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generally dose-proportional over the dose range of 0.3-90mcg/kg in healthy subjects and in cancer patients. Following single I.V. dose of palonosetron at 3mcg/kg (or 0.21mg/70kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5.6 ±5.5ng/mL and mean AUC was 35.8 ±20.9ng•hr/mL. Following I.V. administration of palonosetron 0.25mg once every other day for 3doses in 11cancer the mean increase in plasma palonosetron concentration from Day1 to Day5 was 42 ±34%. Following I.V. administration of palonosetron 0.25mg once daily for 3days in 12healthy subjects, the mean ±SD) increase in plasma palonosetron concentration from Day1 to Day3 was 110 ±45%. After intravenous dosing of palonosetron in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients. Distribution Palonosetron has a volume of distribution of approximately 8.3 ±2.5L/kg. Approximately 62% of palonosetron is bound to plasma proteins. Metabolism 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. Invitro 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 After a single intravenous dose of 10mcg/kg [14C]-palonosetron, approximately 80% of the dose was recovered within 144hours in the urine with palonosetron representing approximately 40% of the administered dose. In healthy subjects, the total body clearance of palonosetron was 160 ±35mL/h/kg and renal clearance was 66.5 ±18.2mL/h/kg. Mean terminal elimination half-life is approximately 40hours. Special Populations [SeeUSE IN SPECIFIC POPULATIONS (8.5- 8.8)] 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30 and 60mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289times the human exposure (AUC= 29.8ng•h/mL) at the recommended intravenous dose of 0.25mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30 and 60mg/kg/day and 15, 45 and 90mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma. Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the exvivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test. Palonosetron at oral doses up to 60mg/kg/day (about 1894times the recommended human intravenous dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats. 14 CLINICAL STUDIES 14.1 Chemotherapy-Induced Nausea and Vomiting Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting induced by both moderately and highly emetogenic chemotherapy was studied in three Phase3 trials and one Phase2 trial. In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120hours after administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed. Moderately Emetogenic Chemotherapy Two Phase3, double-blind trials involving 1132patients compared single-dose I.V. ALOXI with either single-dose I.V. ondansetron (study1) or dolasetron (study2) given 30minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤50mg/m2, cyclophosphamide <1500mg/m2, doxorubicin >25mg/m2, epirubicin, irinotecan, and methotrexate >250mg/m2. Concomitant corticosteroids were not administered prophylactically in study1 and were only used by 4-6% of patients in study2. The majority of patients in these studies were women (77%), White (65%) and naive to previous chemotherapy (54%). The mean age was 55years. Highly Emetogenic Chemotherapy A Phase2, double-blind, dose-ranging study eva luated the efficacy of single-dose I.V. palonosetron from 0.3 to 90mcg/kg (equivalent to <0.1mg to 6mg fixed dose) in 161chemotherapy-naive adult cancer patients receiving highly-emetogenic chemotherapy (either cisplatin ≥70mg/m2 or cyclophosphamide >1100mg/m2). Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 0.25mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy. A Phase3, double-blind trial involving 667patients compared single-dose I.V. ALOXI with single-dose I.V. ondansetron (study3) given 30minutes prior to highly emetogenic chemotherapy including cisplatin ≥60mg/m2, cyclophosphamide >1500mg/m2, and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667patients, 51% were women, 60% White, and 59% naive to previous chemotherapy. The mean age was 52years. Efficacy Results The antiemetic activity of ALOXI was eva luated during the acute phase (0-24hours) [Table3], delayed phase (24-120hours) [Table4], and overall phase (0-120hours) [Table5] post-chemotherapy in Phase3 trials
These studies show that ALOXI was effective in the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. In study3, efficacy was greater when prophylactic corticosteroids were administered concomitantly. Clinical superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute phase.
These studies show that ALOXI was effective in the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy.
These studies show that ALOXI was effective in the prevention of nausea and vomiting throughout the 120hours (5days) following initial and repeat courses of moderately emetogenic cancer chemotherapy. 14.2 Postoperative Nausea and Vomiting In one multicenter, randomized, stratified, double-blind, parallel-group, phase3 clinical study (Study1), palonosetron was compared with placebo for the prevention of PONV in 546patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. Study1 was a pivotal study conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of post operative nausea and vomiting and/or motion sickness. In Study1 patients were randomized to receive palonosetron 0.025mg, 0.050mg or 0.075mg or placebo, each given intravenously immediately prior to induction of anesthesia. The antiemetic activity of palonosetron was eva luated during the 0 to 72hour time period after surgery. Of the 138patients treated with 0.075mg palonosetron in Study1 and eva luated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers. As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian. The age of patients ranged from 21 to 74years, with a mean age of 37.9years. Three patients were greater than 65years of age. Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 and in the 24-72hours postoperatively. Secondary efficacy endpoints included:
The primary hypothesis in Study1 was that at least one of the three palonosetron doses were superior to placebo. Results for Complete Response in Study1 for 0.075mg ALOXI versus placebo are described in the following table.
ALOXI 0.075mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that ALOXI 0.075mg was numerically better than placebo, however, statistical significance was not formally demonstrated. A phase2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to eva luate I.V. palonosetron for the prevention of post-operative nausea and vomiting following abdominal or vaginal hysterectomy. Five I.V. palonosetron doses (0.1, 0.3, 1.0, 3.0 and 30μg/kg) were eva luated in a total of 381intent-to-treat patients. The primary efficacy measure was the proportion of patients with CR in the first 24hours after recovery from surgery. The lowest effective dose was palonosetron 1μg/kg (approximately 0.075mg) which had a CR rate of 44% versus 19% for placebo, p=0.004. Palonosetron 1μg/kg also significantly reduced the severity of nausea versus placebo, p=0.009. 16HOW SUPPLIED/STORAGE AND HANDLING NDC # 62856-797-01, ALOXI Injection 0.25mg/5mL (free base) single-use vial individually packaged in a carton. NDC # 62856-798-01, ALOXI Injection 0.075mg/1.5mL (free base) single-use vial packaged in a carton containing 5vials. Storage Store at controlled temperature of 20-25°C (68°F-77°F). Excursions permitted to 15-30°C (59-86°F). Protect from freezing. Protect from light.
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