Aloxi Capsules: Indications, Dosage, Precautions, Adverse Effects
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Aloxi Capsules - Product Information

Manufacture: Eisai Inc.
Country: Canada
Condition: Nausea/Vomiting, Chemotherapy Induced, Nausea/Vomiting, Postoperative
Class: 5HT3 receptor antagonists, Antiemetic/antivertigo agents
Form: Capsules
Ingredients: palonosetron hydrochloride, Mono-glycerides and di-glycerides of capryl/capric acid, glycerin, polyglyceryl oleate, water, and butylate hydroxyanisole

palonosetron hydrochloride

Summary Product Information

Route of Administration Dosage Form / Strength Non-medicinal Ingredients
Intravenous Solution for injection: 0.25 mg palonosetron (as palonosetron hydrochloride)/5 mL (0.05 mg/mL) Citrate buffer in water, disodium edetate, and mannitol.
Oral Capsule: 0.5 mg palonosetron (as palonosetron hydrochloride) Black printing ink, butylated hydroxyanisole, gelatin, glycerin, monoglycerides and diglycerides of capryl/capric acid, polyglyceryl oleate, sorbitol, titanium dioxide, water. May contain traces of medium chain triglyceride and lecithin.

Indications and Clinical Use

ALOXI injection is indicated in adults for:

  • the prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy
  • the prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high dose cisplatin

ALOXI capsules are indicated in adults for:

  • the prevention of acute nausea and vomiting associated with moderately emetogenic cancer chemotherapy

Geriatrics (≥65 years of age)

No overall differences in safety or effectiveness were observed between patients ≥65 years of age and younger patients (18 to 64 years).

Pediatrics (<18 years of age)

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

Contraindications

ALOXI (palonosetron hydrochloride) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

Warnings and Precautions

Carcinogenesis and Mutagenesis

Statistically significant increased incidences of a variety of different tumors affecting the adrenal, liver, mammary gland, and other tissues and organs were observed at high doses of palonosetron in a rat carcinogenicity study. In the mouse study the findings were not attributed to palonosetron treatment. Experimental evidence indicates that palonosetron is non-mutagenic.

Cardiac/QTc prolongation

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 all dose levels tested in the CINV pivotal clinical studies, cases of QTc prolongation were reported in the ALOXI treatment groups, although those cases were not considered clinically significant (see ADVERSE REACTIONS/Less Common Clinical Trial Adverse Reactions).

A thorough QT/QTc study with moxifloxacin as a positive control demonstrated a dose-dependent increase from baseline in maximum QTcI interval and increased numbers of patients with QTcI change of 30-60 msec in three palonosetron dose groups although the effect at doses up to 2.25 mg was below that of moxifloxacin. No clinically significant changes were shown on heart rate, atrioventricular (AV) conduction and cardiac repolarization (see ACTION AND CLINICAL PHARMACOLOGY/Pharmacodynamics).

Caution should be exercised in the concomitant use of ALOXI with medicinal products that increase the QT interval or in patients who have or are likely to develop prolongation of QT interval (e.g. congenital QT Syndrome, electrolyte imbalance).

Hepatic

Hepatic impairment does not significantly affect total body clearance of intravenous palonosetron compared to the healthy subjects. However, the terminal half-lives of palonosetron were increased in patients with moderate and severe degrees of hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY/Special Populations and Conditions/Hepatic Insufficiency). Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

Renal

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. The systemic exposure (AUC0-t) of palonosetron increased by approximately 45% in patients with severe renal impairment relative to healthy subjects. Longer terminal half-lives (estimated 115-300 hours) were also reported in some patients with severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY/Special Populations and Conditions/Renal Insufficiency). 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.

Sensitivity/Resistance

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, and urticaria. No hypersensitivity reactions have been reported for oral palonosetron.

Serotonin Syndrome/Neuroleptic Malignant Syndrome-like events

Cases of life-threatening serotonin syndrome or neuroleptic malignant syndrome-like events have been reported with 5-HT3 receptor antagonist antiemetics, particularly when given in combination with other serotonergic and/or neuroleptic drugs. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

As these syndromes may result in potentially life-threatening conditions, treatment should be discontinued if such events occur and supportive symptomatic treatment should be initiated. If concomitant treatment of ALOXI with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see DRUG INTERACTIONS).

Special Populations

Pregnant women

There are 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.

Nursing women

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.

Pediatrics (<18 years of age):

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

Adverse Reactions

Adverse Drug Reaction Overview

Aloxi injection

The most common adverse reactions reported in the 633 patients treated for the prevention of chemotherapy-induced nausea and vomiting with a single dose of 0.25 mg in the ALOXI I.V. pivotal Phase 3 program were headache (9%) and constipation (5%). Dizziness and diarrhea were reported at a rate of 1%.

Aloxi capsules

Similarly, the most common adverse reactions reported in the 161 patients who received oral palonosetron 0.5 mg were headache (4%) and constipation (0.6%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Aloxi injection

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron, including 633 patients received a single dose of palonosetron 0.25 mg. The duration for monitoring adverse events was 14 days after study drug administration for all patients. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥1% of patients in these trials (Table 1). Adverse events known to be caused by chemotherapy such as blood and lymphatic system disorder were not reported as adverse reactions.

Table 1: Adverse Reactions1 from Chemotherapy-Induced Nausea and Vomiting Studies* with Frequency ≥1% in any Treatment Group - ALOXI I.V.
Adverse Reaction1 ALOXI
0.25 mg I.V.
(N=633)
Ondansetron
32 mg I.V.
(N=410)
Dolasetron
100 mg I.V.
(N=194)
Any adverse reaction 131 (21%) 77 (19%) 61 (31%)
Headache 60 (9%) 34 (8%) 32 (16%)
Constipation 29 (5%) 8 (2%) 12 (6%)
Diarrhea 8 (1%) 7 (2%) 4 (2%)
Dizziness 8 (1%) 9 (2%) 4 (2%)
Fatigue 3 (<1%) 4 (<1%) 4 (2%)
Abdominal Pain 1 (<1%) 2 (<1%) 3 (2%)
Appetite decreased 1 (<1%) 1 (<1%) 2 (1%)
Insomnia 1 (<1%) 3 (<1%) 3 (2%)
Back pain 0 (0%) 1 (<1%) 2 (1%)
Dermatitis 0 (0%) 0 (0%) 2 (1%)

1 Adverse events assessed by investigators as ‘definitively, possibly, or probably’ related to study medications.

Aloxi capsules

In a clinical trial for the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy, a total of 161 adult patients received oral palonosetron 0.5 mg. Following is a listing of drug related adverse reactions reported by ≥ 1% of patients from the clinical trial.

Table 2: Adverse Reactions from the Chemotherapy-Induced Nausea and Vomiting Study*with Frequency ≥ 1% - ALOXI Capsules
Adverse Reaction1 0.5 mg oral
(N=161)
0.25 mg I.V.
(N=163)
Any adverse reaction 13 (8%) 26 (16%)
Headache 6 (4%) 14 (9%)
Constipation 1 (<1%) 5 (3%)

1 Adverse events assessed by investigators as ‘definitively, possibly, or probably’ related to study medications.

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

Aloxi injection

In clinical trials, the following infrequently (<1%) reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following a single dose of administration of 0.25 mg ALOXI I.V. to adult patients receiving concomitant cancer chemotherapy:

Cardiac Disorders: non-sustained tachycardia, bradycardia, hypotension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles, QT prolongation

Ear and Labyrinth Disorders: motion sickness, tinnitus

Eye Disorders: eye irritation, amblyopia

Gastrointestinal Disorders: dyspepsia, abdominal pain, dry mouth, hiccups, flatulence

General Disorders and Administration Site Conditions: weakness, fatigue, fever, hot flash, flu-like syndrome, asthenia

Hepatobiliary Disorders: transient, asymptomatic increases in AST and/or ALT and bilirubin

Metabolism and Nutrition Disorders: hyperkalemia, hypocalcaemia, electrolyte fluctuations, hyperglycemia, metabolic disorders nos, metabolic acidosis, glycosuria, anorexia

Musculoskeletal and Connective Tissue Disorders: arthralgia

Nervous System Disorders: somnolence, hypersomnia, paresthesia, peripheral sensory neuropathy

Psychiatric Disorders: anxiety, euphoric mood

Renal and Urinary Disorders: urinary retention

Vascular Disorders: vein discoloration, vein distention, hypertension,

Skin and Subcutaneous Tissue Disorders: allergic dermatitis, rash

Aloxi capsules

The infrequently (<1%) reported adverse reactions listed below, assessed by investigators as treatment-related or causality unknown/missing, occurred following administration of a single dose of 0.5 mg ALOXI Capsules to adult patients receiving concomitant cancer chemotherapy. In general, adverse reactions were similar between oral and I.V. formulations.

Cardiac Disorders: transient arrhythmia, first degree atrioventricular block, second degree atrioventricular block

Ear and Labyrinth Disorders: motion sickness

Eye Disorders: eye swelling

Gastrointestinal Disorders: gastritis, nausea

General Disorders and Administration Site Conditions: fatigue, chills

Investigations: blood bilirubin increased

Musculoskeletal and Connective Tissue Disorders: joint stiffness, myalgia, pain in extremity

Nervous System Disorders: dysgeusia

Psychiatric Disorders: insomnia

Respiratory, Thoracic and Mediastinal Disorders: dyspnea

Skin and Subcutaneous Tissue Disorders: generalized pruritus, erythema

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post-approval use of ALOXI. 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 and injection site reactions (burning, induration, discomfort and pain), convulsive events, and syncope.

Drug Interactions

Overview

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.

Drug-Drug Interactions

A 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.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

Coadministration of a single dose of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects r

In an interaction study in healthy subjects where a single dose of palonosetron 0.25 mg (I.V. bolus) was administered on Day 1 and oral aprepitant for 3 days (125mg/80mg/80mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase).

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

Prolonged nausea, vomiting and abdominal cramps were reported in patients co-administered with ALOXI 0.25 mg I.V. and atropine prior to chemotherapy. The combination should be avoided.

In clinical trials, palonosetron has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants and antispasmodic agents.

Serotonin Syndrome/Neuroleptic Malignant Syndrome-like Events

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with 5-HT3 receptor antagonist antiemetic treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, lithium, sibutramine, fentanyl and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine or St. John's Wort [Hypericum perforatum], and with drugs which impair metabolism of serotonin (such as MAOIs, including linezolid [an antibiotic which is a reversible non-selective MAOI], and methylene blue; See WARNINGS AND PRECAUTIONS.)

Dosage and Administration

Dosing Considerations

ALOXI should be used only on the day of chemotherapy. Drug accumulation was observed in subjects administered ALOXI on consecutive days or once every two days for three doses. There is limited safety data available regarding repeated dosing of ALOXI.

No dose adjustment is required for geriatric patients and patients with renal or hepatic impairment.

ALOXI has been shown to have similar safety profiles between initial and repeat courses of chemotherapy.

Recommended dose and dosage adjustment

Aloxi injection

Dosage for Adults – a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.

The efficacy of ALOXI in the prevention of acute nausea and vomiting induced by highly emetogenic chemotherapy was demonstrated mainly in patients who were co-administered prophylactic corticosteroids.

Aloxi capsules

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.

Administration

Aloxi injection

ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line 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.

Overdosage

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

Fifty adult cancer patients were administered palonosetron at an oral dose of 90 µg/kg (equivalent to 6 mg fixed dose in a 70 kg individual) as part of a dose ranging study. This is approximately 12 times the recommended oral dose of 0.5 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre immediately.

Action and Clinical Pharmacology

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.

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 (moxifloxacin) 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. However, a dose-dependent increase in maximum QTcI value on Day 1 (6.4, 7.5, 9.0 msec, although the maximum increase was below that of moxifloxacin at 12.9 msec) from baseline and the percentage of subjects with an increased QTcI at the 30 - 60 msec range (0%, 2.2%, 11%) were revealed in the three palonosetron dosing groups.

Pharmacokinetics

Absorption

Aloxi injection

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 µg/kg in healthy subjects and in cancer patients. Following administration of a single I.V. dose of palonosetron at 3 µg/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 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%.

Aloxi capsules

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using buffered solution in healthy volunteers, 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. Mean time to maximum concentration ranged from 3.8 to 5.7 hours after oral dosing.

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 ± 0.17 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 revealed in two studies (Table 3).

Table 3: Mean PK parameters1 (± SD) of Palonosetron After a Single Dose of 0.5 mg ALOXI Capsules in Healthy Subjects and Cancer Patients
PK Parameters Healthy subjects (n=36) Cancer patients (n=12)
Cmax (ng/mL) 0.81 ± 0.17 0.93 ± 0.34
Tmax (h) 5.1 ± 1.7 5.1 ± 5.9
AUC (ng·h/mL) 38.2 ± 11.7 49.7 ± 12.2
t½ (h) 37 ± 12 48 ± 19

1a 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 (over palonosetron concentration range of 5.15 – 412 ng/mL) is bound to plasma proteins.

Metabolism

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron (account for 12.9% of the I.V. dose; 13.5% of the oral dose) and 6-S-hydroxy-palonosetron (account for 11.5% of the I.V. dose; 17.2% of the oral dose). 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

Aloxi injection

After a single intravenous dose of 10 µg/kg [14C]-palonosetron to healthy subjects, approximately 80% of the dose was recovered within 144 hours in the urine. The amount of unchanged palonosetron excreted in urine represents approximately 42% 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 following a single I.V. dose of approximately 0.75 mg. Mean terminal elimination half-life was approximately 37 hours.

Aloxi capsules

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. In healthy subjects given ALOXI Capsules 0.5 mg, the terminal elimination half-life (t½) of palonosetron was approximately 37 hours (mean ± SD), and in cancer patients, t½ was ~48 hours (see Table 3).

Special Populations and Conditions

Geriatrics

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.

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.

Gender

Aloxi capsules

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.

Race

Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 µg/kg. Total body clearance was 25% higher and systemic exposure (AUC0-∞) was 35% lower in Japanese male subjects compared to Caucasian males based on a cross-study comparison.

Similarly, 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 Caucasian males based on a cross-study comparison.

No dose adjustment is necessary in Japanese subjects. The pharmacokinetics of palonosetron in other races have not been adequately characterized.

Hepatic insufficiency

Hepatic impairment does not significantly affect total body clearance of a single dose of intravenous palonosetron compared to the healthy subjects. The half-lives of palonosetron increased by 43% and 52% in patients with moderate and severe hepatic impairments (56 and 60 hours, respectively) compared to those of healthy subjects (39 hours). Systemic exposure decreased in patients with mild (by 27%) or severe (by 22%) hepatic impairment.

Renal insufficiency

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. The systemic exposure (AUC0-t) to a single dose of intravenous ALOXI increased by approximately 45% in subjects with severe renal impairment relative to healthy subjects. Longer terminal half-lives (estimated 115-300 hours) were reported in 3 out of 7 patients with severe renal impairment compared to ~39 hours in healthy volunteers. The pharmacokinetics of palonosetron have not been studied in subjects with end-stage renal disease.

Storage and Stability

Aloxi Injection

Store at 20-25°C; excursions permitted from 15-30°C. Protect from light.

Aloxi Capsules

Store at 20-25°C; excursions permitted from 15-30°C.

Dosage Forms, Composition and Packaging

Aloxi Injection

ALOXI (palonosetron hydrochloride), 0.25 mg (free base) in 5 mL, is supplied as a single-use sterile, clear, colourless solution in glass vials.

Inactive ingredients: mannitol, disodium edetate, and citrate buffer in water.

Aloxi Capsules

ALOXI (palonosetron hydrochloride) Capsules, 0.5 mg (free base), are supplied as light beige opaque soft gelatin capsules.

Inactive ingredients: monoglycerides and diglycerides of capryl/capric acid, gelatin, sorbitol, glycerin, water, polyglyceryl oleate, titanium dioxide, butylated hydroxyanisole, and black printing ink. May contain traces of medium chain triglyceride and lecithin.