5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of intravenous palonosetron HCl [see Adverse Reactions (6.2)].  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 (4)].

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 (7.1)].

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 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.

6.2 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 (5.1)]

7.1 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 (5.2)].

8.1 Pregnancy

Risk Summary

There are no available data on palonosetron HCl use in pregnant women to inform a drug-associated 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.

8.2 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.

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 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.

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

Cardiac Electrophysiology

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.

At a dose of 4.5 times the recommended dose, ALOXI capsules do not prolong the QT interval to any clinically relevant extent.

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

12.3 Pharmacokinetics

Absorption

Following oral administration, palonosetron is well absorbed with 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 to 80 mcg/kg in healthy subjects.

The mean pharmacokinetic parameters after a single oral dose of 0.5 mg ALOXI are compared across studies in healthy subjects and cancer patients (Table 1). The AUC was 30% higher in cancer patients than in healthy subjects.

Table 1: Pharmacokinetic Parameters1 of Palonosetron after a Single Oral Dose of 0.5 mg ALOXI in Healthy Subjects and Cancer Patients

1 a cross-study comparison

Effect of Food

A high fat meal did not affect the Cmax and AUC of oral palonosetron [see Dosage and Administration (2)].

Distribution

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

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.

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.

Excretion

Palonosetron is partially renally eliminated from the body.

Specific Populations

Geriatric Patients

In a cross-study comparison, after a single oral 0.75 mg dose of ALOXI capsules (1.5 times the recommended dose), the systemic exposure of palonosetron (AUC) was similar, but mean Cmax was 15% lower in healthy elderly subjects 65 years of age and older compared to subjects less than 65 years of age. This decrease in exposure is not considered to be clinically meaningful.

Male and Female Patients

In female subjects (n=18), the mean AUC was 35% higher and the mean Cmax was 26% higher than in male subjects (n=18).  This increase in exposure in female subjects is not considered clinically meaningful.

Patients with Renal Impairment

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure to palonosetron following administration of intravenous palonosetron HCl increased by approximately 28% in patients with severe renal impairment relative to healthy subjects. This increase is not considered clinically meaningful.

Patients with Hepatic Impairment

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects.

Racial or Ethnic Groups

The pharmacokinetics of palonosetron were characterized in 32 healthy Japanese male subjects administered an oral solution of palonosetron HCl over a dose range of 3 to 90 mcg/kg. The apparent total body clearance was 26% higher in Japanese males than in white males based on a cross-study comparison; however, this increase is not considered to be clinically meaningful.

Drug Interaction Studies

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.

Metoclopramide

A study in healthy subjects involving a single 0.75 mg intravenous dose of palonosetron HCl and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

Chemotherapeutic Agents, Corticosteroids, Analgesics, Drugs for Functional Gastrointestinal Disorders, Antiemetics/Antinauseants

In controlled clinical trials, ALOXI capsules have been safely administered with chemotherapeutic agents, systemic corticosteroids, analgesics, and drugs for gastrointestinal disorders including functional gastrointestinal disorders, acid-related disorders, and antiemetics/antinauseants.

Antacids

Concomitant administration of an antacid (Maalox® liquid 30 mL) had no effect on the oral absorption or pharmacokinetics of a single oral dose of 0.75 mg palonosetron HCl in healthy subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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