Aloxi

Description for Aloxi

Aloxi (palonosetron hydrochloride) is an antiemetic and antinauseant agent. It is a serotonin-3 (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, nonpyrogenic, isotonic, buffered solution for intravenous administration. Aloxi 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.

Uses for Aloxi

ALOXI capsules are indicated in adults for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Dosage for Aloxi

The recommended dosage of ALOXI capsules in adults is 0.5 mg administered orally approximately one hour prior to the start of chemotherapy.

ALOXI can be taken with or without food [see CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

Capsules

0.5 mg palonosetron supplied in a light beige opaque soft gelatin capsule

Storage And Handling

ALOXI (palonosetron HCl) capsules are supplied as 0.5 mg palonosetron in light beige opaque soft gelatin capsules, five capsules per bottle, each bottle packaged in a small carton (NDC #69639-104-05).

Storage

• Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
• Protect from light.

Manufactured by Catalent Pharma Solutions, Somerset NJ and Philadelphia PA, USA, and Helsinn Birex Pharmaceuticals, Dublin, Ireland. Revised: Apr 2020

Side Effects for Aloxi

Serious or otherwise clinically significant adverse reactions reported in other sections of labeling:

• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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 associated with moderately emetogenic chemotherapy, 161 adult patients received a single oral dose of ALOXI 0. 5 mg. The most common adverse reactions reported in at least 2% of patients in two clinical trials were headache (4%) and constipation (1%). In other clinical trials, fatigue was also reported in 1% of patients.

Less common adverse reactions, reported in less than 1%, were:

• Blood and Lymphatic System: anemia.
• Cardiovascular: hypertension, transient arrhythmia, first degree atrioventricular block, second degree atrioventricular block, QTc prolongation.
• Hearing and Labyrinth: motion sickness.
• Eye: eye swelling.
• Gastrointestinal System: gastritis, nausea, vomiting.
• General: fatigue, chills, pyrexia.
• Infections: sinusitis.
• Liver: transient, asymptomatic increases in bilirubin.
• Nutrition: anorexia.
• Musculoskeletal: joint stiffness, myalgia, pain in extremity.
• Nervous System: postural dizziness, dysgeusia.
• Psychiatric: insomnia.
• Respiratory System: dyspnea, epistaxis.
• Skin: generalized pruritus, erythema, alopecia.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of palonosetron HCl. 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.

• Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticarial, anaphylaxis and anaphylactic shock with intravenous administration of palonosetron HCl [see WARNINGS AND PRECAUTIONS]

Drug Interactions for Aloxi

Serotonergic Drugs

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). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ALOXI and initiate supportive treatment [see WARNINGS AND PRECAUTIONS].

Warnings for Aloxi

Included as part of the "PRECAUTIONS" Section

Precautions for Aloxi

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of intravenous palonosetron HCl [see ADVERSE REACTIONS]. These reactions occurred in patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists. If hypersensitivity reactions occur, discontinue ALOXI and initiate appropriate medical treatment. Do not reinitiate ALOXI in patients who have previously experienced symptoms of hypersensitivity [see CONTRAINDICATIONS].

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 a 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].

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients with intravenous administration of palonosetron HCl. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur with administration of ALOXI capsules [see WARNINGS AND PRECAUTIONS].

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of ALOXI capsules 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].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron HCl at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 90 to 173 times the human exposure (AUC= 49.7 ng·h/mL) at the recommended oral dose of 0.5 mg. In a 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 a systemic exposure to palonosetron (Plasma AUC) of 82 and 185 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 HCl at oral doses up to 60 mg/kg/day (about 921 times the recommended human oral dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data on palonosetron HCl use in pregnant women to inform a drugassociated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron HCl during the period of organogenesis at doses up to 921 and 1,841 times the recommended human oral dose in rats and rabbits, respectively (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In animal reproduction studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron HCl at doses up to 60 mg/kg/day (921 times the recommended human oral dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (1,841 times the recommended human oral dose based on body surface area) during the period of organogenesis.

Lactation

Risk Summary

There are no data on the presence of palonosetron in human milk, the effects of palonosetron on the breastfed infant, or the effects of palonosetron on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALOXI and any potential adverse effect on the breastfed infant from palonosetron or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use

Of the total number of adult cancer patients of oral palonosetron HCl, 181 were 65 years of age and over. The number of geriatric patients receiving the 0.5 mg recommended dose of ALOXI capsules was insufficient to draw any efficacy or safety conclusions.

Overdose Information for Aloxi

There is no known antidote to palonosetron. Overdose should be managed with supportive care.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single oral dose of palonosetron HCl at 500 mg/kg in rats and 100 mg/kg in dogs (7,673 and 5,115 times the recommended human oral dose, respectively, based on body surface area) was lethal. The major signs of toxicity included convulsions, labored breathing, and salivation.

Contraindications for Aloxi

ALOXI is contraindicated in patients known to have hypersensitivity to palonosetron [see WARNINGS AND PRECAUTIONS].

Clinical Pharmacology for Aloxi

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.

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 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.

Pharmacokinetics

After intravenous dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma 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 0.3–90 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 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9 h•mcg/L.

Following I.V. administration of palonosetron 0.25 mg once every other day for 3 doses in 11 cancer patients, 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-HT₃ receptor antagonist activity of palonosetron. In vitro 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 [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 Populations

Pediatric Patients

Single-dose I.V. ALOXI pharmacokinetic data was obtained from a 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 a 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 min

PK Parameter a	Pediatric Age Group
	< 2 y N=12	2 to < 6 y N=42	6 to < 12 y N=38	12 to < 17 y N=44
CT b, ng/L	9025 (197)	9414 (252)	16275 (203)	11831 (176)
		N=5	N=7	N=10
AUC0-∞, h•mcg/L		103.5 (40.4)	98.7 (47.7)	124.5 (19.1)
	N=6	N=14	N=13	N=19
Clearance c, L/h/kg	0.31 (34.7)	0.23 (51.3)	0.19 (46.8)	0.16 (27.8)
Vss c, L/kg	6.08 (36.5)	5.29 (57.8)	6.26 (40.0)	6.20 (29.0)
a Geometric Mean (CV) except for t½ 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

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 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 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 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 naïve 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 < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naïve 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% naïve 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 3 trials.

Table 4: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates

Chemotherapy	Study	Treatment Group	Na	% with Complete Response	p-value b	97.5% Confidence Interval ALOXI minus Comparator c
Moderately Emetogenic	1	ALOXI 0.25 mg	189	81	0.009
		Ondansetron 32 mg I.V.	185	69
	2	ALOXI 0.25 mg	189	63	NS
		Dolasetron 100 mg I.V.	191	53
Highly Emetogenic	3	ALOXI 0.25 mg	223	59	NS
		Ondansetron 32 mg I.V.	221	57
a Intent-to-treat cohort b 2-sided Fisher's exact test. Significance level at &apha;=0.025. c These studies were designed to show non-inferiority. A 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

Chemotherapy	Study	Treatment Group	Na	% with Complete Response	p-value b	97.5% Confidence Interval ALOXI minus Comparator c
Moderately Emetogenic	1	ALOXI 0.25 mg	189	74	< 0.001
		Ondansetron 32 mg I.V.	185	55
	2	ALOXI 0.25 mg	189	54	0.004
		Dolasetron 100 mg I.V.	191	39
a Intent-to-treat cohort b 2-sided Fisher's exact test. Significance level at &apha;=0.025. c These studies were designed to show non-inferiority. A 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

Chemotherapy	Study	Treatment Group	N a	% with Complete Response	p-value b	97.5% Confidence Interval ALOXI minus Comparator c
Moderately Emetogenic	1	ALOXI 0.25 mg	189	6950	< 0.001
		Ondansetron 32 mg I.V.	185
	2	ALOXI 0.25 mg	189	46	0.021
		Dolasetron 100 mg I.V.	191	34
a Intent-to-treat cohort b 2-sided Fisher's exact test. Significance level at &apha;=0.025. c These studies were designed to show non-inferiority. A 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.

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 a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of ALOXI 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 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 4 and 8 hours after the first dose of ondansetron, with a 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 Results

As shown in Table 7, intravenous ALOXI 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval.

Table 7: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates

I.V. ALOXI 20 mcg/kg (N=165)	I.V. Ondansetron 0.15 mg/kg x 3 (N=162)	Difference [97.5% Confidence Interval]*: I.V. ALOXI minus I.V. Ondansetron Comparator
59.4%	58.6%	0.36% [-11.7%, 12.4%]
* To adjust for multiplicity of treatment groups, a lower-bound of a 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.

In patients that received ALOXI at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.

Postoperative Nausea And Vomiting

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:

• 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 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 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

Treatment	n/N (%)	Palonosetron Vs Placebo
		Δ	p-value*
Co-primary Endpoints
CR 0-24 hours
Palonosetron	59/138 (42.8%)	16.8%	0.004
Placebo	35/135 (25.9%)
CR 24-72 hours
Palonosetron	67/138 (48.6%)	7.8%	0.188
Placebo	55/135 (40.7%)
* To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p < 0.017. Δ Difference (%): palonosetron 0.075 mg minus placebo

Palonosetron 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 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.

Patient Information for Aloxi

ALOXI^®
(Ah-lock-see)
(palonosetron HCl) capsules, for oral use

Read this Patient Information before you start taking ALOXI and each time you refill your prescription for 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 ALOXI?

ALOXI is a prescription medicine called an “antiemetic.”

ALOXI is a prescription medicine used in adults to help prevent the nausea and vomiting that happens with certain anticancer medicines (chemotherapy).

It is not known if ALOXI is safe and effective in people under the age of 18 years.

Who should not take ALOXI?

Do not take ALOXI if you are allergic to palonosetron or any of the ingredients in ALOXI. See the end of this leaflet for a complete list of ingredients in ALOXI.

What should I tell my doctor before taking ALOXI?

Before taking 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 or if it will affect your baby or your breast milk. Talk to your doctor about the best way to feed your baby if you take ALOXI.

Tell your doctor about all of the medicines you take, including prescriptions and over-the-counter medicines, vitamins and herbal supplements.

ALOXI and certain other medicines can affect each other, causing serious side effects.

How should I take ALOXI?

• Take ALOXI exactly as prescribed by your doctor.
• Take one ALOXI Capsule by mouth about one hour before you get your anti-cancer medicine (chemotherapy).
• ALOXI can be taken with or without food.
• If you take too much ALOXI, tell your doctor right away.

What are the possible side effects of ALOXI? ALOXI may cause serious side effects, including:

• Serious allergic reactions, such as anaphylaxis. Get emergency medical help right away if you get any of the following symptoms.
  • hives
  • swollen face
  • breathing trouble
  • chest pain
• Serotonin Syndrome. A possible life threatening problem called serotonin syndrome can happen with medicines called 5-HT₃ receptor antagonists, including ALOXI, especially when used with medicines used to treat depression and migraine headaches called serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs) and certain other medicines. Tell your doctor or nurse right away if you have any of the following symptoms of serotonin syndrome:
  • agitation, seeing things that are not there (hallucinations), confusion, or coma
  • fast heartbeat or unusual and frequent changes in your blood pressure
  • dizziness, sweating, flushing, or fever
  • tremors, stiff muscles, muscle twitching, overactive reflexes, or loss of coordination
  • seizures
  • nausea, vomiting, or diarrhea

The most common side effects in adults who take ALOXI capsules include: headache and constipation.

These are not all the possible side effects of ALOXI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088.

General information the safe and effective use of ALOXI.

Medicines are sometimes prescribed for conditions other than those listed in a Patient Information Leaflet. Do not use ALOXI or a condition for which it was not prescribed. Do not give ALOXI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about ALOXI that is written for health professionals. For more information call 1-844-357-4668, or go to www.ALOXI.com.

How should I store ALOXI?

• Store ALOXI at room temperature between of 68°F to 77°F (20°C to 25°C).
• Keep ALOXI away from light.

Keep ALOXI out of the reach of children.

What are the ingredients in ALOXI?

Active ingredient: palonosetron hydrochloride

Inactive ingredients: Mono-glycerides and di-glycerides of capryl/capric acid, glycerin, polyglyceryl oleate, water, and butylated hydroxyanisole

This Patient Information has been approved by the U.S. Food and Drug Administration