Aloxi (Palonosetron hydrochloride) 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 (Palonosetron hydrochloride) is recommended even where the incidence of postoperative nausea and/or vomiting is low.

Chemotherapy-Induced Nausea and Vomiting
Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur 30 minutes before the start of chemotherapy.

Postoperative Nausea and Vomiting
Dosage for Adults - a single 0.075 mg I.V. dose administered over 10 seconds immediately before the induction of anesthesia.

Aloxi (Palonosetron hydrochloride) is supplied ready for intravenous injection. Aloxi (Palonosetron hydrochloride) should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of Aloxi (Palonosetron hydrochloride) .

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

Aloxi (Palonosetron hydrochloride) is supplied as a single-use sterile, clear, colorless solution in glass vials that provide:

Aloxi (Palonosetron hydrochloride) is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [ ()]

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.

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 (Palonosetron hydrochloride) and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 0.75 mg 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 (Palonosetron hydrochloride) to adult patients receiving concomitant cancer chemotherapy:

Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension,
Dermatological:
Hearing and Vision:
Gastrointestinal System: 1% diarrhea,
General: 1% weakness,
Liver:
Metabolic: 1%: hyperkalemia,
Musculoskeletal:
Nervous System: 1%: dizziness,
Psychiatric: 1%: anxiety,
Urinary System:
Vascular:
The adverse reactions cited in Table 2 were reported in ≥ 2% of adults receiving I.V. Aloxi (Palonosetron hydrochloride) 0.075 mg immediately before induction of anesthesia in one phase 2 and two phase 3 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 Section , 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 (Palonosetron hydrochloride) to adult patients receiving concomitant perioperative and intraoperative medications including those associated with anesthesia:

Cardiovascular: 1% electrocardiogram QTc prolongation, sinus bradycardia, tachycardia;
Dermatological: 1%: pruritus.

Gastrointestinal System: 1%: flatatulence,
General:
Liver: 1%: increases in AST and/or ALT,
Metabolic:
Nervous System:
Respiratory:
Urinary System: 1%: urinary retention.

The following adverse reactions have been identified during postapproval use of Aloxi (Palonosetron hydrochloride) . 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 (

Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with latter mediated via multiple CYP enzymes. Further 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 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects 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 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, C: 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, Aloxi (Palonosetron hydrochloride) 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.

Teratogenic Effects: Category B

Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/kg/day (3789 times 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.

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 (Palonosetron hydrochloride) 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 (Palonosetron hydrochloride) efficacy in geriatric patients has not been adequately evaluated.

There is no known antidote to Aloxi (Palonosetron hydrochloride) . Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. 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 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.

Aloxi (Palonosetron hydrochloride) is an antiemetic and antinauseant agent. It is a serotonin subtype 3 (5-HT) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3a)-2-[()-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1benz[]isoquinoline hydrochloride. The empirical formula is CHNO.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 (Palonosetron hydrochloride) injection is a sterile, clear, colorless, non pyrogenic, isotonic, buffered solution for intravenous administration. Aloxi (Palonosetron hydrochloride) injection is available as 5 mL single use vial or 1.5 mL single use vial. Each 5 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, 83 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration. The pH of the solution in the 5 mL and 1.5 mL vials is 4.5 to 5.5.

Palonosetron is a 5-HT 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-HT 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-HT 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-HT receptor has been demonstrated to selectively participate in the emetic response.

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 a 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.

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 (C) and area under the concentration-time curve (AUC) 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 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5.6 ± 5.5 ng/mL and mean AUC was 35.8 ± 20.9 ng•hr/mL.

Following I.V. administration of palonosetron 0.25 mg once every other day for 3 doses in 11 cancer the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42 ± 34%. Following I.V. 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%.

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 ± 2.5 L/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-HT receptor antagonist activity of palonosetron. 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 10 mcg/kg [C]-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 160 ± 35 mL/h/kg and renal clearance was 66.5 ± 18.2 mL/h/kg. Mean terminal elimination half-life is approximately 40 hours.

Special Populations

[ (- )]

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 3 trials and one Phase 2 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 Chemotherapy
Two Phase 3, double-blind trials involving 1132 patients compared single-dose I.V. Aloxi (Palonosetron hydrochloride) 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/m, cyclophosphamide  25 mg/m, epirubicin, irinotecan, and methotrexate > 250 mg/m. Concomitant corticosteroids were not administered prophylactically in study 1 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 Chemotherapy
A 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  1100 mg/m). 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 (Palonosetron hydrochloride) with single-dose I.V. ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥ 60 mg/m, cyclophosphamide > 1500 mg/m, 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 (Palonosetron hydrochloride) was evaluated during the acute phase (0-24 hours) [Table 3], delayed phase (24-120 hours) [Table 4], and overall phase (0-120 hours) [Table 5] post-chemotherapy in Phase 3 trials

These studies show that Aloxi (Palonosetron hydrochloride) 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-HT receptor antagonists has not been adequately demonstrated in the acute phase.

These studies show that Aloxi (Palonosetron hydrochloride) 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 (Palonosetron hydrochloride) 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.

In one multicenter, randomized, stratified, double-blind, parallel-group, phase 3 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 1 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 Study 1 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 0 to 72 hour time period after surgery.

Of the 138 patients treated with 0.075 mg palonosetron in Study 1 and evaluated 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 74 years, with a 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:

The primary hypothesis in Study 1 was that at least one of the three palonosetron doses were superior to placebo.

Results for Complete Response in Study 1 for 0.075 mg Aloxi (Palonosetron hydrochloride) versus placebo are described in the following table.

Aloxi (Palonosetron hydrochloride) 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that Aloxi (Palonosetron hydrochloride) 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.

A phase 2 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 μg/kg) were evaluated in a 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 1 μg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004. Palonosetron 1 μg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.

NDC # 62856-797-01, Aloxi (Palonosetron hydrochloride) Injection 0.25 mg/5 mL (free base) single-use vial individually packaged in a carton.

NDC # 62856-798-01, Aloxi (Palonosetron hydrochloride) Injection 0.075 mg/1.5 mL (free base) single-use vial packaged in a carton containing 5 vials.

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Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [ ()].

Patients should be instructed to read the patient insert.

Patient Information
Aloxi (Palonosetron hydrochloride) (Ah-lock-see)
Read the Patient Information that comes with Aloxi (Palonosetron hydrochloride) before your treatment with Aloxi (Palonosetron hydrochloride) and each time you get Aloxi (Palonosetron hydrochloride) . There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have questions about Aloxi (Palonosetron hydrochloride) , ask your doctor or pharmacist.

What is Aloxi (Palonosetron hydrochloride) ?
Aloxi (Palonosetron hydrochloride) is a medicine called an "antiemetic." Aloxi (Palonosetron hydrochloride) is used in adults to help prevent the nausea and vomiting that happens:

What is Aloxi (Palonosetron hydrochloride) used for?
Aloxi (Palonosetron hydrochloride) is used to prevent nausea and vomiting that may happen:

Who should not take Aloxi (Palonosetron hydrochloride) ?
Do not take Aloxi (Palonosetron hydrochloride) if you are allergic to any of the ingredients in Aloxi (Palonosetron hydrochloride) . The active ingredient is palonosetron hydrochloride. See the end of this leaflet for a complete list of ingredients in Aloxi (Palonosetron hydrochloride) . Aloxi (Palonosetron hydrochloride) has not been studied in children under 18 years of age.

What should I tell my doctor before using Aloxi (Palonosetron hydrochloride) ?
Tell your doctor about all of your medical conditions, including if you:

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements.

How should I use Aloxi (Palonosetron hydrochloride) ?
Aloxi (Palonosetron hydrochloride) is given in your vein by I.V. (intravenous) injection. It is only given to you by a healthcare provider in a hospital or clinic. Aloxi (Palonosetron hydrochloride) is usually injected into your vein about 30 minutes before you get your anti-cancer medicine (chemotherapy) or immediately before anesthesia for surgery.

What are the possible side effects of Aloxi (Palonosetron hydrochloride) ?
The most common side effects of Aloxi (Palonosetron hydrochloride) are
These are not all the side effects from Aloxi (Palonosetron hydrochloride) . For more information ask your doctor or pharmacist.

General information about Aloxi (Palonosetron hydrochloride)
Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. Aloxi (Palonosetron hydrochloride) was prescribed for your medical condition.

This leaflet summarizes the most important information about Aloxi (Palonosetron hydrochloride) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Aloxi (Palonosetron hydrochloride) that is written for health professionals. You can also visit the Aloxi (Palonosetron hydrochloride) web site at www.Aloxi (Palonosetron hydrochloride) .com.

What are the ingredients in Aloxi (Palonosetron hydrochloride) ?
Active ingredient: palonosetron hydrochloride

Inactive ingredients: 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, Ireland

HELSINN, Mfd for Helsinn Healthcare SA, Switzerland

Eisai, Inc. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677 under license of Helsinn Healthcare SA, Switzerland

Aloxi (Palonosetron hydrochloride) is a registered trademark of Helsinn Healthcare, SA, Lugano, Switzerland

©2008 Eisai Inc., Woodcliff Lake, NJ 07677 U.S.A. 201227 9/08

NDC 62856-797-01

NDC 62856-798-01