POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Very rare cases (<1/10,000) of hypersensitivity reactions including anaphylaxis and anaphylactic shock and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. The most common adverse reactions in chemotherapy-induced nausea and vomiting in adults (incidence >=5%) are headache and constipation (6.1). The most common adverse reactions in postoperative nausea and vomiting (incidence >= 2%) are QT prolongation, bradycardia, headache, and constipation (6.2). To report SUSPECTED ADVERSE REACTIONS, contact EISAI at 1-888-422-4743 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Chemotherapy-Induced Nausea and Vomiting. Adults In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is listing of all adverse reactions reported by >= 2% of patients in these trials (Table 1).Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies >= 2% in any Treatment GroupEventALOXI 0.25 mg (N=633)Ondansetron 32 mg I.V.(N=410)Dolasetron 100 mg I.V. (N=194)Headache60 (9%)34 (8%)32 (16%)Constipation29 (5%)8 (2%)12 (6%)Diarrhea8 (1%)7 (2%)4 (2%)Dizziness8 (1%)9 (2%)4 (2%)Fatigue3 (< 1%)4 (1%)4 (2%)Abdominal Pain1 (< 1%)2 (< 1%)3 (2%)Insomnia1 (< 1%)3 (1%)3 (2%)In other studies, subjects experienced severe constipation following single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received 10 mcg/kg oral dose in post-operative nausea and vomiting study and one healthy subject received 0.75 mg I.V. dose in 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.PediatricsIn pediatric clinical trial for the prevention of chemotherapy-induced nausea and vomiting 163 cancer patients received single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron 30 minutes before beginning the first cycle of emetogenic chemotherapy. Patients had mean age of 8.4 years (range months to 16.9 years) and were 46% male; and 93% white.The following adverse reactions were reported for palonosetron:Nervous System: <1%: headache, dizziness, dyskinesia.General: <1%: infusion site pain.Dermatological: <1%: allergic dermatitis, skin disorder.In the trial, adverse reactions were evaluated in pediatric patients receiving palonosetron for up to chemotherapy cycles.. 6.2 Postoperative Nausea and Vomiting. The adverse reactions cited in Table were reported in >= 2% of adults receiving I.V. ALOXI 0.075 mg immediately before induction of anesthesia in one phase and two phase randomized placebo-controlled trials. Rates of events between palonosetron and placebo groups were similar. 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 Section 12.2, thorough QT/QTc study results, for data demonstrating the lack of palonosetron effect on QT/QTc.Table 2: Adverse Reactions from Postoperative Nausea and Vomiting Studies >= 2% in any Treatment GroupEventALOXI 0.075 mg (N=336)Placebo(N=369)Electrocardiogram QT prolongation16 (5%)11 (3%)Bradycardia13 (4%)16 (4%)Headache11 (3%)14 (4%)Constipation8 (2%)11(3%)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 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%: flatulence, 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Very rare cases (<1/10,000) of hypersensitivity reactions including anaphylaxis and anaphylactic shock and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30, and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced systemic exposure to palonosetron (Plasma AUC) of about 150 to 289 times the human exposure (AUC= 29.8 homcg/L) at the recommended intravenous dose of 0.25 mg. In 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30, and 60 mg/kg/day and 15, 45, and 90 mg/kg/day, respectively. The highest doses produced systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times 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 ex vivo 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 60 mg/kg/day (about 1894 times 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Palonosetron is 5-HT3 receptor antagonist with strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with 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 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 evaluated in double blind, randomized, parallel, placebo, and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of I.V. administered palonosetron at single doses of 0.25, 0.75, or 2.25 mg in 221 healthy subjects. The study demonstrated no significant effect on any ECG interval including QTc duration (cardiac repolarization) at doses up to 2.25 mg. 12.3 Pharmacokinetics. After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma concentrations is followed by 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 0.3-90 mcg/kg in healthy subjects and in cancer patients. Following single I.V. dose of palonosetron at mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (+-SD) maximum plasma concentration was estimated to be 5630 +- 5480 ng/L and mean AUC was 35.8 +- 20.9 homcg/L.Following I.V. administration of palonosetron 0.25 mg once every other day for doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day to Day was 42+-34%. Following I.V. administration of palonosetron 0.25 mg once daily for days in 12 healthy subjects, the mean (+-SD) increase in plasma palonosetron concentration from Day to Day 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.DistributionPalonosetron has volume of distribution of approximately 8.3 +- 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.MetabolismPalonosetron 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 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.EliminationAfter single intravenous dose of 10 mcg/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. In healthy subjects, the total body clearance of palonosetron was 0.160 +- 0.035 L/h/kg and renal clearance was 0.067+- 0.018 L/h/kg. Mean terminal elimination half-life is approximately 40 hours.Specific PopulationsPediatric Patients Single-dose I.V. ALOXI pharmacokinetic data was obtained from subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg. When the dose was increased from 10 mcg/kg to 20 mcg/kg dose-proportional increase in mean AUC was observed. Following single dose intravenous infusion of ALOXI 20 mcg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients 6 years than in older patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hours across age groups after administration of 20 mcg/kg.The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg.Table 3: Pharmacokinetics Parameters in Pediatric Cancer Patients Following Intravenous Infusion of ALOXI at 20 mcg/kg over 15 minPediatric Age GroupPK Parameter a<2 y2 to <6 y6 to <12 y12 to <17 yN=12N=42N=38N=44CT b, ng/L9025 (197)9414 (252)16275 (203)11831 (176)N=5N=7N=10AUC0-, h.mcg/L103.5 (40.4)98.7 (47.7)124.5 (19.1)N=6N=14N=13N=19Clearance c, L/h/kg0.31 (34.7)0.23 (51.3)0.19 (46.8)0.16 (27.8)Vss c, L/kg6.08 (36.5)5.29 (57.8)6.26 (40.0)6.20 (29.0)a Geometric Mean (CV) except for t1/2 which is median values.b CT is the plasma palonosetron concentration at the end of the 15 minute infusion.c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 97.5% Confidence IntervalALOXI minus Comparator c. 97.5% Confidence IntervalALOXI minus Comparator c. 97.5% Confidence IntervalALOXI minus Comparator c. 14.1 Chemotherapy-Induced Nausea and Vomiting in Adults. 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 Phase trials and one Phase 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 120 hours after administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed.Moderately Emetogenic ChemotherapyTwo Phase 3, double-blind trials involving 1132 patients compared single-dose I.V. ALOXI with either single-dose I.V. ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin <= 50 mg/m2, cyclophosphamide 1500 mg/m2, doxorubicin 25 mg/m2, epirubicin, irinotecan, and methotrexate 250 mg/m2. Concomitant corticosteroids were not administered prophylactically in study and were only used by 4-6% of patients in study 2. The majority of patients in these studies were women (77%), White (65%) and naive to previous chemotherapy (54%). The mean age was 55 years. Highly Emetogenic ChemotherapyA Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose I.V. palonosetron from 0.3 to 90 mcg/kg (equivalent to 0.1 mg to mg fixed dose) in 161 chemotherapy-naive adult cancer patients receiving highly-emetogenic chemotherapy (either cisplatin >= 70 mg/m2 or cyclophosphamide 1100 mg/m2). Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.A Phase 3, double-blind trial involving 667 patients compared single-dose I.V. ALOXI with single-dose I.V. ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin >= 60 mg/m2, cyclophosphamide 1500 mg/m2, and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, 60% White, and 59% naive to previous chemotherapy. The mean age was 52 years. Efficacy Results The antiemetic activity of ALOXI was evaluated during the acute phase (0-24 hours) [Table 4], delayed phase (24-120 hours) [Table 5], and overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase trials.Table 4: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response RatesChemotherapyStudyTreatmentGroupN a% with CompleteResponsep-value b97.5% Confidence IntervalALOXI minus Comparator ModeratelyEmetogenic1 ALOXI 0.25 mg 189810.009Ondansetron 32 mg I.V.185692ALOXI 0.25 mg18963NSDolasetron 100 mg I.V.19153Highly Emetogenic3ALOXI 0.25 mg22359NSDifference in Complete Response RatesOndansetron 32 mg I.V.22157a Intent-to-treat cohortb 2-sided Fishers exact test. Significance level at =0.025.c These studies were designed to show non-inferiority. lower bound greater than -15% demonstrates non-inferiority between ALOXI and comparator.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 study 3, 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. Table 5: Prevention of Delayed Nausea and Vomiting (24-120 hours): Complete Response Rates ChemotherapyStudyTreatmentGroupN a% with Complete Responsep-value b97.5% Confidence IntervalALOXI minus Comparator cModeratelyEmetogenic1ALOXI 0.25 mg18974<0.001Ondansetron 32 mg I.V.185552ALOXI 0.25 mg189540.004Dolasetron 100 mg I.V.19139Difference in Complete Response Ratesa Intent-to-treat cohortb 2-sided Fishers exact test. Significance level at =0.025.c These studies were designed to show non-inferiority. lower bound greater than -15% demonstrates non-inferiority between ALOXI and comparator.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. Table 6: Prevention of Overall Nausea and Vomiting (0-120 hours): Complete Response Rates ChemotherapyStudyTreatmentGroupN a% with Complete Responsep-value b97.5% Confidence IntervalALOXI minus Comparator cModeratelyEmetogenic1ALOXI 0.25 mg18969<0.001Ondansetron 32 mg I.V.185502ALOXI 0.25 mg189460.021Dolasetron 100 mg I.V.19134Difference in Complete Response Ratesa Intent-to-treat cohortb 2-sided Fishers exact test. Significance level at =0.025.c These studies were designed to show non-inferiority. lower bound greater than -15% demonstrates non inferiority between ALOXI and comparator.These studies show that ALOXI was effective in the prevention of nausea and vomiting throughout the 120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy. 14.2 Chemotherapy-Induced Nausea and Vomiting in Pediatrics. One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients. The total population (N 327) had mean age of 8.3 years (range months to 16.9 years) and were 53% male; and 96% white. Patients were randomized and received 20 mcg/kg (maximum 1.5 mg) intravenous infusion of ALOXI 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions and hours after the dose of palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions and hours after the first dose of ondansetron, with maximum total dose of 32 mg). Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m2), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.Efficacy ResultsAs shown in Table 7, intravenous ALOXI 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the to 24 hour time interval.Table 7: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response RatesI.V. ALOXI20 mcg/kg(N=165)I.V. Ondansetron0.15 mg/kg 3 (N=162)Difference [97.5% Confidence Interval]: I.V. ALOXI minus I.V. Ondansetron Comparator59.4%58.6%0.36% [-11.7%, 12.4%] To adjust for multiplicity of treatment groups, lower-bound of 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.In patients that received ALOXI at lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.. 14.3 Postoperative Nausea and Vomiting. In one multicenter, randomized, stratified, double-blind, parallel-group, phase clinical study (Study 1), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. Study was 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 Study patients were randomized to receive palonosetron 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia. The antiemetic activity of palonosetron was evaluated during the to 72 hour time period after surgery. Of the 138 patients treated with 0.075 mg palonosetron in Study and evaluated for efficacy, 96% were women; 66% had 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 74 years, with mean age of 37.9 years. Three patients were greater than 65 years 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 24-72 hours postoperatively. Secondary efficacy endpoints included: Complete Response (CR) 0-48 and 0-72 hours Complete Control (CC) defined as CR and no more than mild nausea Severity of nausea (none, mild, moderate, severe) The primary hypothesis in Study was that at least one of the three palonosetron doses were superior to placebo. Results for Complete Response in Study for 0.075 mg palonosetron versus placebo are described in the following table.Table 8: Prevention of Postoperative Nausea and Vomiting: Complete Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo Treatmentn/N (%)Palonosetron Vs Placebop-valueCo-primary Endpoints CR 0-24 hours Palonosetron59/138 (42.8%)16.8% 0.004 Placebo35/135 (25.9%) CR 24-72 hours Palonosetron67/138 (48.6%)7.8% 0.188 Placebo55/135 (40.7%) To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p<0.017. Difference (%): palonosetron 0.075 mg minus placeboPalonosetron 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that palonosetron 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.A phase randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate 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 30 ug/kg) were evaluated in total of 381 intent-to-treat patients. The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery. The lowest effective dose was palonosetron ug/kg (approximately 0.075 mg) which had CR rate of 44% versus 19% for placebo, p=0.004. Palonosetron ug/kg also significantly reduced the severity of nausea versus placebo, p=0.009.. Complete Response (CR) 0-48 and 0-72 hours Complete Control (CC) defined as CR and no more than mild nausea Severity of nausea (none, mild, moderate, severe).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components [see Adverse Reactions (6.2)]. ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components (4).

DESCRIPTION SECTION.

11 DESCRIPTION. ALOXI (palonosetron hydrochloride) is an antiemetic and antinauseant agent. It is serotonin-3 (5-HT3) receptor antagonist with 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 molecular weight of 332.87. Palonosetron hydrochloride exists as single isomer and has the following structural formula:Palonosetron hydrochloride is 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 sterile, clear, colorless, nonpyrogenic, isotonic, buffered solution for intravenous administration. ALOXI injection is available as mL single use vial or 1.5 mL single use vial. Each mL vial contains 0.25 mg palonosetron base as 0.28 mg palonosetron hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration. Each 1.5 mL vial contains 0.075 mg palonosetron base as 0.084 mg palonosetron hydrochloride, 62.25 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration. The pH of the solution in the mL and 1.5 mL vials is 4.5 to 5.5.. The structural formula for serotonin-3 (5-HT3) is receptor antagonist with 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 molecular weight of 332.87.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Chemotherapy-Induced Nausea and Vomiting (2.1)AgeDoseInfusion TimeAdults 0.25 mg 1Infuse over 0 e o nd beginning approx. 30 min before the start of chemoPediatrics(1 month to lessthan 17 years)20 micrograms perkilogram (max 1.5mg) 1Infuse over 5 i nut es beginning approx. 30 min before the start of chemoNote different dosing units in pediatrics Postoperative Nausea and Vomiting (2.1) Adult Dosage: single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia. Adult Dosage: single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia. 2.1 Recommended Dosing. Chemotherapy-Induced Nausea and VomitingAgeDoseInfusion TimeAdults 0.25 mg 1 Infuse over 0 e o nd beginning approx. 30 min before the start of chemo Pediatrics(1 month to lessthan 17 years)20 micrograms perkilogram (max 1.5mg) 1Infuse over 5 i nut es beginning approx. 30 min before the start of chemoNote different dosing units in pediatricsPostoperative Nausea and VomitingDosage for Adults a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia. 2.2 Instructions for Intravenous Administration. ALOXI is supplied ready for intravenous administration at concentration of 0.05 mg/mL (50 mcg/ mL). ALOXI should not be mixed with other drugs. The infusion line should be flushed 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. ALOXI is supplied as single-use sterile, clear, colorless solution in glass vials that provide:0.25 mg (free base) per mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.075 mg (free base) per 1.5 mL (concentration: 0.05 mg/mL, 50 mcg/mL). 0.25 mg (free base) per mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.075 mg (free base) per 1.5 mL (concentration: 0.05 mg/mL, 50 mcg/mL). 0.25 mg/5mL (free base) single-use vial (3)0.075 mg/1.5mL (free base) single-use vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro 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.Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.2)].Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day and oral aprepitant for days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg 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, cyclophosphamide, cytarabine, doxorubicin, and mitomycin C) in murine tumor models.. The potential for clinically significant drug interactions with palonosetron appears to be low (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients >= 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were >= 65 years old, while 71 (5%) were >= 75 years 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 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were >=65 years 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 evaluated.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. NDC 62856-797-01, ALOXI Injection 0.25 mg/5 mL (free base) single-use vial individually packaged in carton.NDC 62856-798-01, ALOXI Injection 0.075 mg/1.5 mL (free base) single-use vial packaged in carton containing vials. StorageStore at controlled temperature of 20-25C (68F-77F). Excursions permitted to 15-30C (59-86F). Protect from freezing. Protect from light.. Store at controlled temperature of 20-25C (68F-77F). Excursions permitted to 15-30C (59-86F). Protect from freezing. Protect from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ALOXI is serotonin-3 (5-HT3) receptor antagonist indicated in adults for:Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses (1.1) Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses (1.1) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated (1.3) ALOXI is indicated in pediatric patients aged month to less than 17 years for:Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (1.2). Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses (1.1) Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses (1.1) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated (1.3) Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (1.2). 1.1 Chemotherapy-Induced Nausea and Vomiting in Adults. ALOXI is indicated for:Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses. Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses. 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged Month to Less than 17 Years. ALOXI is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.. 1.3 Postoperative Nausea and Vomiting in Adults. ALOXI is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated.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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labelling (Patient Information).Instructions for PatientsPatients should be advised to report to their physician all of their medical conditions, including any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6.3) ]. Advise patients of the possibility of serotonin syndrome, especially with concomitant use of ALOXI and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [see Warnings and Precautions (5.2)].Patients should be instructed to read the Patient Information.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Palonosetron is 5-HT3 receptor antagonist with strong binding affinity for this receptor and little or no affinity for other receptors. Cancer chemotherapy may be associated with 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30, and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced systemic exposure to palonosetron (Plasma AUC) of about 150 to 289 times the human exposure (AUC= 29.8 homcg/L) at the recommended intravenous dose of 0.25 mg. In 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30, and 60 mg/kg/day and 15, 45, and 90 mg/kg/day, respectively. The highest doses produced systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times 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 ex vivo 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 60 mg/kg/day (about 1894 times 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.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is not known whether ALOXI is present 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 [see Nonclinical Toxicology (13.1) ], decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at dose of 90 mcg/kg (equivalent to mg fixed dose) as part of dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had 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. single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 62856-797-01Aloxi0.25 mg/ mL (0.05 mg/ mL)Rx Only. PRINCIPAL DISPLAY PANELNDC 62856-797-01Aloxi0.25 mg/ mL (0.05 mg/ mL)Rx Only.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Chemotherapy-Induced Nausea and VomitingSafety and effectiveness of ALOXI have been established in pediatric patients aged month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. Use is supported by clinical trial where 165 pediatric patients aged months to <17 years were randomized to receive single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [see Clinical Studies (14.2) ]. While this study demonstrated that pediatric patients require higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [see Adverse Reactions (6.1) ].Safety and effectiveness of ALOXI in neonates (less than month of age) have not been established.Postoperative Nausea and Vomiting StudiesSafety and efficacy have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed.Pediatric Study 1, dose finding study, was conducted to compare two doses of palonosetron, mcg/kg (max 0.075 mg) versus mcg/kg (max 0.25 mg). total of 150 pediatric surgical patients participated, age range month to <17 years. No dose response was observed.Pediatric Study 2, multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared I.V. palonosetron (1 mcg/kg, max 0.075 mg) versus I.V. ondansetron. total of 670 pediatric surgical patients participated, age 30 days to <17 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults (Table 2).

PHARMACODYNAMICS SECTION.

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 evaluated in double blind, randomized, parallel, placebo, and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of I.V. administered palonosetron at single doses of 0.25, 0.75, or 2.25 mg in 221 healthy subjects. The study demonstrated no significant effect on any ECG interval including QTc duration (cardiac repolarization) at doses up to 2.25 mg.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma concentrations is followed by 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 0.3-90 mcg/kg in healthy subjects and in cancer patients. Following single I.V. dose of palonosetron at mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (+-SD) maximum plasma concentration was estimated to be 5630 +- 5480 ng/L and mean AUC was 35.8 +- 20.9 homcg/L.Following I.V. administration of palonosetron 0.25 mg once every other day for doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day to Day was 42+-34%. Following I.V. administration of palonosetron 0.25 mg once daily for days in 12 healthy subjects, the mean (+-SD) increase in plasma palonosetron concentration from Day to Day 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.DistributionPalonosetron has volume of distribution of approximately 8.3 +- 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.MetabolismPalonosetron 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 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.EliminationAfter single intravenous dose of 10 mcg/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. In healthy subjects, the total body clearance of palonosetron was 0.160 +- 0.035 L/h/kg and renal clearance was 0.067+- 0.018 L/h/kg. Mean terminal elimination half-life is approximately 40 hours.Specific PopulationsPediatric Patients Single-dose I.V. ALOXI pharmacokinetic data was obtained from subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg. When the dose was increased from 10 mcg/kg to 20 mcg/kg dose-proportional increase in mean AUC was observed. Following single dose intravenous infusion of ALOXI 20 mcg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients 6 years than in older patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hours across age groups after administration of 20 mcg/kg.The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg.Table 3: Pharmacokinetics Parameters in Pediatric Cancer Patients Following Intravenous Infusion of ALOXI at 20 mcg/kg over 15 minPediatric Age GroupPK Parameter a<2 y2 to <6 y6 to <12 y12 to <17 yN=12N=42N=38N=44CT b, ng/L9025 (197)9414 (252)16275 (203)11831 (176)N=5N=7N=10AUC0-, h.mcg/L103.5 (40.4)98.7 (47.7)124.5 (19.1)N=6N=14N=13N=19Clearance c, L/h/kg0.31 (34.7)0.23 (51.3)0.19 (46.8)0.16 (27.8)Vss c, L/kg6.08 (36.5)5.29 (57.8)6.26 (40.0)6.20 (29.0)a Geometric Mean (CV) except for t1/2 which is median values.b CT is the plasma palonosetron concentration at the end of the 15 minute infusion.c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Category BRisk SummaryAdequate and well controlled studies with ALOXI have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively. Because animal reproduction studies are not always predictive of human response, ALOXI should be used during pregnancy only if clearly needed.Animal DataIn animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.

RECENT MAJOR CHANGES SECTION.

Indication (1.2)Dosage and Administration, Pediatric Cancer Patients (2.1)Warnings and Precautions, Serotonin Syndrome (5.2)05/201405/201409/2014.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationALOXI(R) (Ah-lock-see)(palonosetron HCl) Injection for Intravenous UseRead this Patient Information before you receive ALOXI and each time you receive ALOXI. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.What is ALOXIALOXI is prescription medicine called an antiemetic.ALOXI is used in adults to help prevent the nausea and vomiting that happens: right away or later with certain anti-cancer medicines (chemotherapy) up to 24 hours while recovering from anesthesia after surgeryALOXI is used in children month old to less than 17 years of age to help prevent the nausea and vomiting that happens right away with certain anti-cancer medicines (chemotherapy).It is not known if ALOXI is safe and effective in children less than month old to help prevent nausea and vomiting after chemotherapy. It is not known if ALOXI is safe and effective in children for the prevention of nausea and vomiting while recovering from anesthesia after surgery. Who should not receive ALOXIDo not receive ALOXI if you are allergic to palonosetron hydrochloride or any of the ingredients in ALOXI. See the end of this leaflet for complete list of ingredients in ALOXI.What should tell my doctor before receiving ALOXIBefore receiving ALOXI, tell your doctor about all of your medical conditions, including if you:have had an allergic reaction to another medicine for nausea or vomiting are pregnant or plan to become pregnant. It is not known if ALOXI will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ALOXI passes into your breast milk. You and your doctor should decide if you will receive ALOXI if you breastfeed.Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive ALOXIALOXI will be given to you in your vein by intravenous (I.V.) injection. ALOXI is usually given about 30 minutes before you receive your anti-cancer medicine (chemotherapy) or right before anesthesia for surgery.What are the possible side effects of ALOXIALOXI can cause allergic reactions that can sometimes be serious. Tell your doctor or nurse right away if you have any of the following symptoms of serious allergic reaction with ALOXI: hives swollen face breathing trouble chest painThe most common side effects of ALOXI in adults are headache and constipation.These are not all the possible side effects from ALOXI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ALOXIMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your doctor or pharmacist for information about ALOXI that is written for health professionals.What are the ingredients in ALOXIActive ingredient: palonosetron hydrochloride n ct v i g re ien s mannitol, disodium edetate, and citrate buffer in water Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Medicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, IrelandHELSINN, Mfd for Helsinn Healthcare SA, Switzerland Distributed by Eisai Inc., Woodcliff Lake, NJ 07677 under license of Helsinn Healthcare SA, SwitzerlandMarketed by Eisai Inc., Woodcliff Lake, NJ 07677 and Helsinn Therapeutics (U.S.), Inc. Iselin, NJ 08830, under license of Helsinn Healthcare SA, SwitzerlandALOXI(R) is registered trademark of Helsinn Healthcare, SA, Lugano, Switzerland(C)2013 Eisai Inc., Woodcliff Lake, NJ 07677 U.S.A. 201227 For more information, go to www.ALOXI.com.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2015. right away or later with certain anti-cancer medicines (chemotherapy) up to 24 hours while recovering from anesthesia after surgery. It is not known if ALOXI is safe and effective in children less than month old to help prevent nausea and vomiting after chemotherapy. It is not known if ALOXI is safe and effective in children for the prevention of nausea and vomiting while recovering from anesthesia after surgery.. have had an allergic reaction to another medicine for nausea or vomiting are pregnant or plan to become pregnant. It is not known if ALOXI will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ALOXI passes into your breast milk. You and your doctor should decide if you will receive ALOXI if you breastfeed.. ALOXI will be given to you in your vein by intravenous (I.V.) injection. ALOXI is usually given about 30 minutes before you receive your anti-cancer medicine (chemotherapy) or right before anesthesia for surgery.. hives swollen face breathing trouble chest pain.

SPL UNCLASSIFIED SECTION.

1.1 Chemotherapy-Induced Nausea and Vomiting in Adults. ALOXI is indicated for:Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses. Moderately emetogenic cancer chemotherapy -- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy -- prevention of acute nausea and vomiting associated with initial and repeat courses.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Chemotherapy-Induced Nausea and VomitingPediatric use: Safety and effectiveness in neonates (less than month of age) have not been established (8.4) Postoperative Nausea and VomitingSafety and Effectiveness in patients below the age of 18 years have not been established (8.4) 8.1 Pregnancy Pregnancy Category BRisk SummaryAdequate and well controlled studies with ALOXI have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively. Because animal reproduction studies are not always predictive of human response, ALOXI should be used during pregnancy only if clearly needed.Animal DataIn animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.. 8.3 Nursing Mothers. It is not known whether ALOXI is present 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 [see Nonclinical Toxicology (13.1) ], 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. Chemotherapy-Induced Nausea and VomitingSafety and effectiveness of ALOXI have been established in pediatric patients aged month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. Use is supported by clinical trial where 165 pediatric patients aged months to <17 years were randomized to receive single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [see Clinical Studies (14.2) ]. While this study demonstrated that pediatric patients require higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [see Adverse Reactions (6.1) ].Safety and effectiveness of ALOXI in neonates (less than month of age) have not been established.Postoperative Nausea and Vomiting StudiesSafety and efficacy have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed.Pediatric Study 1, dose finding study, was conducted to compare two doses of palonosetron, mcg/kg (max 0.075 mg) versus mcg/kg (max 0.25 mg). total of 150 pediatric surgical patients participated, age range month to <17 years. No dose response was observed.Pediatric Study 2, multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared I.V. palonosetron (1 mcg/kg, max 0.075 mg) versus I.V. ondansetron. total of 670 pediatric surgical patients participated, age 30 days to <17 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults (Table 2).. 8.5 Geriatric Use. Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients >= 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were >= 65 years old, while 71 (5%) were >= 75 years 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 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were >=65 years 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 evaluated.. 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 - 90 mcg/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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other selective 5-HT3 receptor antagonists (5.1) Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs (5.2). Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other selective 5-HT3 receptor antagonists (5.1) Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs (5.2). 5.1 Hypersensitivity. Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists. 5.2 Serotonin Syndrome. The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in post-anesthesia care unit or an infusion center.Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ALOXI and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue ALOXI and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if ALOXI is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17) ].