PRODUCT MONOGRAPH
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`PrALOXI®
`
`(palonosetron injection)
`as palonosetron hydrochloride
`
`0.05 mg/mL palonosetron
`
`PrALOXI®
`
`(palonosetron capsules)
`as palonosetron hydrochloride
`
`0.5 mg palonosetron
`
`Anti-emetic (5-HT3 receptor antagonist)
`
`
`
`Date of Preparation:
`March 12, 2012
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`Eisai Limited
`2630 Skymark Avenue
`Mississauga, Ontario
`L4W 5A4
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`ALOXI® is a registered trademark of Helsinn Healthcare SA used under license by Eisai
`Limited.
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`ALOXI® (palonosetron hydrochloride)
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`Helsinn Healthcare Exhibit 2056
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`

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`Table of Contents
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`PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3
`SUMMARY PRODUCT INFORMATION ........................................................................3
`INDICATIONS AND CLINICAL USE ..............................................................................3
`CONTRAINDICATIONS ...................................................................................................4
`WARNINGS AND PRECAUTIONS ..................................................................................4
`ADVERSE REACTIONS ....................................................................................................5
`DRUG INTERACTIONS ....................................................................................................8
`DOSAGE AND ADMINISTRATION ................................................................................9
`OVERDOSAGE ................................................................................................................10
`ACTION AND CLINICAL PHARMACOLOGY ............................................................10
`STORAGE AND STABILITY ..........................................................................................13
`DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................14
`
`PART II: SCIENTIFIC INFORMATION ...............................................................................15
`PHARMACEUTICAL INFORMATION ..........................................................................15
`CLINICAL TRIALS ..........................................................................................................16
`DETAILED PHARMACOLOGY .....................................................................................20
`TOXICOLOGY .................................................................................................................22
`REFERENCES ..................................................................................................................25
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`PART III: CONSUMER INFORMATION ..............................................................................27
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`PART III: CONSUMER INFORMATION ..............................................................................29
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`SUMMARY PRODUCT INFORMATION
`
`
`Route of
`Administration
`Intravenous
`
`Oral
`
`Dosage Form / Strength
`
`Solution for injection:
`0.25 mg palonosetron (as
`palonosetron
`hydrochloride)/5 mL
`(0.05 mg/mL)
`Capsule:
`0.5 mg palonosetron (as
`palonosetron
`hydrochloride)
`
`ALOXI®
`palonosetron hydrochloride
`
`PART I: HEALTH PROFESSIONAL INFORMATION
`
`Clinically Relevant Non-medicinal
`Ingredients
`None
`
`For a complete listing see Dosage Forms,
`Composition and Packaging section.
`
`None
`
`For a complete listing see Dosage Forms,
`Composition and Packaging section.
`
`
`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.
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`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 (see TOXICOLOGY/Carcinogenicity). Experimental evidence indicates
`that palonosetron is non-mutagenic (see TOXICOLOGY/Genotoxicity).
`
`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 (see DETAILED
`PHARMACOLOGY). 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
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`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.
`
`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%).
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`Clinical Trial Adverse Drug Reactions
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`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.
`
`
`Adverse Reaction1
`
`Table 1: Adverse Reactions1 from Chemotherapy-Induced Nausea and Vomiting Studies* with Frequency
`≥ 1% in any Treatment Group – ALOXI I.V.
`ALOXI
`Ondansetron
`Dolasetron
`0.25 mg I.V.
`32 mg I.V.
`100 mg I.V.
`(N=633)
`(N=410)
`(N=194)
`61 (31%)
`131 (21%)
`77 (19%)
`Any adverse reaction
`32 (16%)
`60 (9%)
`34 (8%)
`Headache
`12 (6%)
`29 (5%)
`8 (2%)
`Constipation
`4 (2%)
`8 (1%)
`7 (2%)
`Diarrhea
`4 (2%)
`8 (1%)
`9 (2%)
`Dizziness
`4 (2%)
`3 (<1%)
`4 (<1%)
`Fatigue
`3 (2%)
`1 (<1%)
`2 (<1%)
`Abdominal Pain
`2 (1%)
`1 (<1%)
`1 (<1%)
`Appetite decreased
`3 (2%)
`1 (<1%)
`3 (<1%)
`Insomnia
`2 (1%)
`0 (0%)
`1 (<1%)
`Back pain
`2 (1%)
`0 (0%)
`0 (0%)
`Dermatitis
`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.
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`Table 2: Adverse Reactions from the Chemotherapy-Induced Nausea and
`Vomiting Study*with Frequency ≥ 1% – ALOXI Capsules
`Adverse Reaction1
`0.5 mg oral
`0.25 mg I.V.
`(N=161)
`(N=163)
`13 (8%)
`26 (16%)
`Any adverse reaction
`6 (4%)
`14 (9%)
`Headache
`1 (<1%)
`5 (3%)
`Constipation
`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
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`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
`
`ALOXI Injection
`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.
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`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.
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`Coadministration of a single dose of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in
`healthy subjects revealed no pharmacokinetic drug interactions between palonosetron and
`dexamethasone.
`
`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
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`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.
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`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 (see Part II SCIENTIFIC
`INFORMATION/Detailed Pharmacology).
`
`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 (see Part II SCIENTIFIC INFORMATION/Detailed Pharmacology).
`
`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 (see CLINICAL TRIALS).
`
`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.
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`Parenteral drug products should be inspected visually for particulate matter and discoloration
`before administration, whenever solution and container permit.
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`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.
`
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`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.
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`Pharmacokinetics
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`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
`Healthy subjects (n=36)
`0.81 ± 0.17
`5.1 ± 1.7
`38.2 ± 11.7
`37 ± 12
`
`Cancer patients (n=12)
`0.93 ± 0.34
`5.1 ± 5.9
`49.7 ± 12.2
`48 ± 19
`
`PK Parameters
`Cmax (ng/mL)
`Tmax (h)
`AUC∞ (ng•h/mL)
`t1/2 (h)
`1 a cross-study comparison
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`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).
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`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.
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`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 20-25ºC; excursions permitted from 15-30ºC. Protect from light.
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`ALOXI® (palonosetron hydrochloride)
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`ALOXI Capsules
`Store at 20-25ºC; excursions permitted from 15-30ºC.
`
`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.
`
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`ALOXI® (palonosetron hydrochloride)
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`PART II: SCIENTIFIC INFORMATION
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`PHARMACEUTICAL INFORMATION
`
`Drug Substance
`
`Proper name: palonosetron hydrochloride
`
`Chemical name: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-
`oxo-1Hbenz[de]isoquinoline hydrochloride
`
`
`Molecular formula and molecular mass: C19H24N2O·HCl
`
`
`
`332.87
`
`Structural formula:
`
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`Physicochemical properties: 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.
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`CLINICAL TRIALS
`
`ALOXI Injection
`Efficacy of single-dose (0.25 mg, 0.75 mg) palonosetron I.V. injection in preventing acute and
`delayed nausea and vomiting induced by moderately or highly emetogenic chemotherapy was
`studied in three Phase 3 trials. In these 3-arm double blind studies, efficacy was based on
`demonstrating non-inferiority of a single dose of ALOXI I.V. compared to ondansetron I.V. or
`dolasetron I.V. Non-inferiority criteria were met if the lower boundary of the two-sided 97.5%
`confidence interval for the difference in the complete response rate of palonosetron minus
`ondansetron or dolasetron was above -15% (non-inferiority margin 15%).
`
`The primary endpoint was Complete Response (no emetic episode and no rescue medication)
`during the first 24 hours (acute phase) after chemotherapy. Secondary endpoints included
`Complete Response at further time periods (24-120 hours, delayed phase) and Complete Control
`(complete response and no more than mild nausea).
`
`Moderately Emetogenic Chemotherapy
`Two Phase 3, double-blind trials involving 1132 patients compared single-dose ALOXI I.V. with
`either single-dose I.V. ondansetron (Study 1) or I.V. 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, epirub