1.1 Prevention of Chemotherapy-Induced Nausea and Vomiting

ALOXI Capsules are indicated for:

• Moderately emetogenic cancer chemotherapy - prevention of acute nausea and vomiting associated with initial and repeat courses

2.1 Recommended Dosing

Dosage for Adults - one 0.5 mg capsule administered approximately one hour prior to the start of chemotherapy. ALOXI can be taken with or without food.

5.1 Hypersensitivity

Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists. Hypersensitivity
reactions have been very rarely reported post-marketing for intravenous palonosetron: dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria. No hypersensitivity reactions have been reported for oral palonosetron.

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 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 (7), Patient Counseling Information (17)].

6.1 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 induced by moderately emetogenic chemotherapy, 693 adult patients received oral palonosetron in doses ranging from 0.25 mg to 0.75 mg. Following is a listing of drug related adverse reactions reported by ≥ 2% of patients from two clinical trials.

The infrequently reported adverse reactions listed below, assessed by investigators as treatment-related or causality unknown/missing, occurred following administration of ALOXI Capsules to adult patients receiving concomitant cancer chemotherapy. Of these adverse events, fatigue (incidence 1%), was the only adverse event reported at an incidence of ≥1%. In general, adverse reactions were similar between oral and I.V. formulations.

Blood and Lymphatic System: <1%: anemia.

Cardiovascular: <1%: hypertension, transient arrhythmia, first degree atrioventricular block, second degree atrioventricular block, QTc prolongation.

Hearing and Labyrinth: <1%: motion sickness.

Eye: <1%: eye swelling.

Gastrointestinal System: <1%: gastritis, nausea, vomiting.

General: 1%: fatigue, <1%: chills, pyrexia.

Infections: <1%: sinusitis.

Liver: <1%: transient, asymptomatic increases in bilirubin.

Nutrition: <1%: anorexia.

Musculoskeletal: <1%: joint stiffness, myalgia, pain in extremity.

Nervous System: <1%: postural dizziness, dysgeusia.

Psychiatric: <1%: insomnia.

Respiratory System: <1%: dyspnea, epistaxis.

Skin: <1%: generalized pruritus, erythema, alopecia.

Very rare cases (<1/10,000) of hypersensitivity reactions have been reported for I.V. ALOXI from post-marketing experience.

8.1 Pregnancy

Teratogenic effects

Pregnancy Category B.
Reproduction studies have been performed in rats at oral doses up to 60 mg/kg/day (921 times the recommended human oral dose based on body surface area) and rabbits at oral doses up to 60 mg/kg/day (1841 times the recommended human oral dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.

8.2 Labor and Delivery

 Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

8.3 Nursing Mothers

It is not known whether palonosetron is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the total number of adult cancer patients in a pivotal study of oral palonosetron, 181 were 65 years of age and over. The number of geriatric patients receiving 0.5 mg palonosetron was insufficient to draw any efficacy or safety conclusions.

In a cross-study comparison, after a single oral dose (0.75 mg) the systemic exposure of palonosetron (AUC) was similar, but mean Cmax was 15% lower in healthy elderly subjects ≥65 years of age compared with the subjects < 65 years of age. No dose adjustment is required for geriatric
patients.

8.6 Renal Impairment

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure to intravenous ALOXI increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with mild to severe renal impairment. The pharmacokinetics of palonosetron have not been studied in subjects with end-stage renal disease.

8.7 Hepatic Impairment

Hepatic impairment does not significantly affect total body clearance of intravenous palonosetron compared to the healthy subjects. Dosage
adjustment is not necessary in patients with any degree of hepatic impairment.

8.8 Race

Oral pharmacokinetics of palonosetron were characterized in thirty-two healthy Japanese male subjects using solution over the dose range of 3-90 µg/kg. The apparent total body clearance was 26% higher in Japanese males than in white males based on a cross-study comparison; however, no dose adjustment is necessary. The pharmacokinetics of palonosetron in other races have not been adequately characterized.

8.9 Gender

Although a single dose of 0.5 mg ALOXI Capsule was associated with a 26- 35% higher systemic exposure in female subjects than in male subjects, dosage adjustment is not necessary based on gender.

12.1 Mechanism of Action

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5- HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.

12.2 Pharmacodynamics

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 (moxifloxicin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of intravenously administered palonosetron at single doses of 0.25 mg, 0.75 mg 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.

Clinical trials revealed that oral palonosetron had comparable effects on blood pressure, heart rate, and ECG parameters as intravenous palonosetron.

12.3 Pharmacokinetics

Absorption

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using buffered solution mean maximum palonosetron concentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose range of 3.0 to 80 µg/kg in healthy subjects.

In 36 healthy male and female subjects given a single oral dose of ALOXI Capsules 0.5 mg, maximum plasma palonosetron concentration (Cmax) was 0.81±1.66 ng/mL (mean ± SD) and time to maximum concentration (Tmax) was 5.1± 1.7 hours. In female subjects (n=18), the mean AUC was 35% higher and the mean Cmax was 26% higher than in male subjects (n=18).

In 12 cancer patients given a single oral dose of palonosetron 0.5 mg one hour prior to chemotherapy, Cmax was 0.93±0.34 ng/mL and Tmax was 5.1± 5.9 hours. The AUC was 30% higher in cancer patients than in healthy subjects. The mean PK parameters after a single oral dose of 0.5 mg palonosetron are compared between healthy subjects and cancer patients (Table 2).

1 a cross-study comparison

A high fat meal did not affect the Cmax and AUC of oral palonosetron. Therefore, ALOXI Capsules may be taken without regard to meals.

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
Following administration of a single oral 0.75 mg dose of [14C]- palonosetron to six healthy subjects, 85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. In healthy subjects given ALOXI Capsules 0.5 mg, the terminal elimination half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½ was 48 ± 19 hours. After a single- dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance was 66.5 ± 18.2 mL/h/kg.

Special Populations

[see USE IN SPECIFIC POPULATIONS (8.5-8.9)]

13.1 Carciogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30 and 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 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.