`-----------------------------CONTRAINDICATIONS------------------------------
`ALOXI is contraindicated in patients known to have hypersensitivity to the
`drug or any of its components (4)
`
`
`---------------------WARNINGS AND PRECAUTIONS-------------------------
`•
`Hypersensitivity reactions may occur in patients who have exhibited
`hypersensitivity to other 5-HT3 receptor antagonists (5.1)
`Administer with caution in patients who have or may develop
`prolongation of cardiac conduction intervals, particularly QTc (5.2)
`
`•
`
`Revised: 08/2007
`
`
`----------------------------ADVERSE REACTIONS--------------------------------
`The most common adverse reactions (incidence ≥5%) are headache and
`constipation (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact MGI
`PHARMA at 1-800-562-5580 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`---------------------------DRUG INTERACTIONS---------------------------------
`The potential for clinically significant drug interactions with palonosetron
`appears to be low (7)
`
`---------------___USE IN SPECIFIC POPULATIONS --------------------------
`Safety and effectiveness in patients below the age of 18 years have not been
`established.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`Approved Patient Labeling
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` *
`
` Sections or subsections omitted from the full prescribing information are
`not listed.
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ALOXI
`safely and effectively. See full prescribing information for ALOXI.
`
`ALOXI® (palonosetron HCl) Injection for Intravenous Use
`Initial U.S. Approval: 2003
`
`------------------------RECENT MAJOR CHANGES---------------------------
`Dosage and Administration, Recommended Dosing (2.1)
`08/2007
`
`-------------------------INDICATIONS AND USAGE---------------------------
`ALOXI is a serotonin subtype 3 (5-HT3) receptor antagonist indicated for:
`• Moderately emetogenic cancer chemotherapy -- prevention of acute
`and delayed nausea and vomiting associated with initial and repeat
`courses (1.1)
`Highly emetogenic cancer chemotherapy -- prevention of acute nausea
`and vomiting associated with initial and repeat courses (1.1)
`
`•
`
`
`--------------------DOSAGE AND ADMINISTRATION-----------------------
`Adult Dosage: a single 0.25 mg I.V. dose administered over 30 seconds.
`Dosing should occur approximately 30 minutes before the start of
`chemotherapy (2.1).
`
`-------------------DOSAGE FORMS AND STRENGTHS----------------------
`0.25 mg/5 mL (free base) single-use vial (3)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 1
`
`6
`
`7
`8
`
`
`
`
`
`
`
`
`2
`
`INDICATIONS AND USAGE
`1.1
`Prevention of Chemotherapy-Induced Nausea and Vomiting
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`2.2
`Instructions for IV Administration
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`5.2
`QTc Intervals
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`8.8
`Race
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Instructions for Patients
`17.2 FDA-Approved Patient Labeling
`
`

`

`
`
`Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and
`Vomiting Studies ≥ 2% in any Treatment Group
`Ondansetron
`32 mg IV
`(N=410)
`
`Event
`
`Aloxi 0.25 mg
`(N=633)
`
`
`
`Dolasetron
`100 mg IV
`(N=194)
`
`Headache
`Constipation
`
`Diarrhea
`
`Dizziness
`
`Fatigue
`
`Abdominal Pain
`
`Insomnia
`
`60 (9%)
`
`29 (5%)
`
`8 (1%)
`
`8 (1%)
`
`3 (< 1%)
`
`1 (< 1%)
`
`1 (< 1%)
`
`34 (8%)
`
`8 (2%)
`
`7 (2%)
`
`9 (2%)
`
`4 (1%)
`
`2 (< 1%)
`
`3 (1%)
`
`32 (16%)
`
`12 (6%)
`
`4 (2%)
`
`4 (2%)
`
`4 (2%)
`
`3 (2%)
`
`3 (2%)
`
`
`In other studies, 2 subjects experienced severe constipation following a
`
`single palonosetron dose of approximately 0.75 mg, three times the
`recommended dose. One patient received a 10 mcg/kg oral dose in a post-
`operative nausea and vomiting study and one healthy subject received a 0.75
`mg IV dose in a pharmacokinetic study.
`
`In clinical trials, the following infrequently reported adverse reactions,
`
`assessed by investigators as treatment-related or causality unknown, occurred
`following administration of ALOXI to adult patients receiving concomitant
`cancer chemotherapy:
`
`Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension,
`< 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia,
`sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In
`many cases, the relationship to ALOXI was unclear.
`
`Dermatological: < 1%: allergic dermatitis, rash.
`
`Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and
`amblyopia.
`
`Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry
`mouth, hiccups and flatulence.
`
`General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.
`
`Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and
`bilirubin. These changes occurred predominantly in patients receiving highly
`emetogenic chemotherapy.
`
`Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia,
`metabolic acidosis, glycosuria, appetite decrease, anorexia.
`
`Musculoskeletal: < 1%: arthralgia.
`
`Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia,
`paresthesia.
`
`Psychiatric: 1%: anxiety, < 1%: euphoric mood.
`
`Urinary System: < 1%: urinary retention.
`
`Vascular: < 1%: vein discoloration, vein distention.
`
`6.2 Postmarketing Experience
`
`The following adverse reactions have been identified during
`postapproval 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.
`
`Very rare cases (<1/10,000) of hypersensitivity reactions and injection
`
`site reactions (burning, induration, discomfort and pain) were reported from
`postmarketing experience.
`
`Aloxi® (palonosetron HCl) injection
`FULL PRESCRIBING INFORMATION
`
` 1
`
`
`
`INDICATIONS AND USAGE
`1.1 Prevention of Chemotherapy-Induced Nausea and Vomiting
`ALOXI is indicated for:
`• Moderately emetogenic cancer chemotherapy -- prevention of
`acute and delayed nausea and vomiting associated with initial and
`repeat courses
`Highly emetogenic cancer chemotherapy -- prevention of acute
`nausea and vomiting associated with initial and repeat courses
`
`•
`
`
`
` 2
`
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`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
`
`
`2.2 Instructions for Administration
`
`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.
`
`
`
` 3
`
`DOSAGE FORM AND STRENGTHS
`ALOXI is supplied as a single-use sterile, clear, colorless solution in
`
`glass vials that provides 0.25 mg (free base) per 5 mL.
`
` 4
`
`
`
`CONTRAINDICATIONS
`ALOXI is contraindicated in patients known to have hypersensitivity to
`the drug or any of its components. [see Adverse Reactions (6.2)]
`
`
` 5
`
` WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`Hypersensitivity reactions may occur in patients who have exhibited
`
`hypersensitivity to other 5-HT3 receptor antagonists.
`
`5.2 QTc Intervals
`
`
`Although palonosetron has been safely administered to 192 patients
`with pre-existing cardiac impairment in the Phase 3 studies, ALOXI should
`be administered with caution in patients who have or may develop
`prolongation of cardiac conduction intervals, particularly QTc. These
`include patients with hypokalemia or hypomagnesemia, patients taking
`diuretics with potential for inducing electrolyte abnormalities, patients with
`congenital QT syndrome, patients taking anti-arrhythmic drugs or other drugs
`which lead to QT prolongation, and cumulative high dose anthracycline
`therapy.
`
`In 3 pivotal trials, ECGs were obtained at baseline and 24 hours after
`
`subjects received palonosetron or a comparator drug. In a subset of patients
`ECGs were also obtained 15 minutes following dosing. The percentage of
`patients (< 1%) with changes in QT and QTc intervals (either absolute values
`of > 500 msec or changes of > 60 msec from baseline) was similar to that
`seen with the comparator drugs.
`
` 6
`
`
`
`ADVERSE REACTIONS
`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 reported in practice.
`
`In clinical trials for the prevention of nausea and vomiting induced by
`
`moderately or highly emetogenic chemotherapy, 1374 adult patients received
`palonosetron. Adverse reactions were similar in frequency and severity with
`ALOXI and ondansetron or dolasetron. Following is a listing of all adverse
`reactions reported by ≥ 2% of patients in these trials (Table 1).
`
`
`
`
`
`
`
`
`
`

`

`
`Total body clearance was 25% higher in Japanese subjects compared to
`Whites, however, no dose adjustment is required. The pharmacokinetics of
`palonosetron in Blacks has not been adequately characterized.
`
`10 OVERDOSAGE
`
`There is no known antidote to ALOXI. Overdose should be managed
`with supportive care.
`
`Fifty adult cancer patients were administered palonosetron at a dose of
`
`90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study.
`This is approximately 25 times the recommended dose of 0.25 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. A single intravenous dose of palonosetron at 30
`mg/kg (947 and 474 times the human dose for rats and mice, respectively,
`based on body surface area) was lethal to rats and mice. The major signs of
`toxicity were convulsions, gasping, pallor, cyanosis and collapse.
`
`11 DESCRIPTION
`
`ALOXI is an antiemetic and antinauseant agent. It is a serotonin
`subtype 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, non-pyrogenic, isotonic,
`
`buffered solution for intravenous administration. Each 5 mL vial of ALOXI
`Injection contains 0.25 mg palonosetron base as hydrochloride, 207.5 mg
`mannitol, disodium edetate and citrate buffer in water for intravenous
`administration. The pH of the solution is 4.5 to 5.5.
`
`12 CLINICAL PHARMACOLOGY
`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
`
`The effect of palonosetron on blood pressure, heart rate, and ECG
`
`parameters including QTc were comparable to ondansetron and dolasetron in
`clinical trials. 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. In clinical trials, the dose-response
`relationship to the QTc interval has not been fully evaluated.
`
`
`12.3 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
`
`Aloxi® (palonosetron HCl) injection
`7
`DRUG INTERACTIONS
`
`Palonosetron is eliminated from the body through both renal excretion
`and metabolic pathways with the latter mediated via multiple CYP enzymes.
`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.
`
`A study in healthy volunteers involving single-dose IV palonosetron
`
`(0.75 mg) and steady state oral metoclopramide (10 mg four times daily)
`demonstrated no significant pharmacokinetic interaction.
`
`In controlled clinical trials, ALOXI injection has been safely
`
`administered with corticosteroids, analgesics, antiemetics/antinauseants,
`antispasmodics and anticholinergic agents.
`
`Palonosetron did not inhibit the antitumor activity of the five
`
`chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine,
`doxorubicin and mitomycin C) in murine tumor models.
`
`
`
` 8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Teratogenic Effects: Category B
`Teratology studies have been performed in rats at oral doses up to 60
`
`mg/kg/day (1894 times the recommended human intravenous dose based on
`body surface area) and rabbits at oral doses up to 60 mg/kg/day (3789 times
`the recommended human intravenous 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
`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. No dose
`adjustment or special monitoring are required for geriatric patients.
`
`
`8.6 Renal Impairment
`Mild to moderate renal impairment does not significantly affect
`
`palonosetron pharmacokinetic parameters. Total systemic exposure
`increased by approximately 28% in severe renal impairment relative to
`healthy subjects. Dosage adjustment is not necessary in patients with any
`degree of renal impairment.
`
`
`8.7 Hepatic Impairment
`Hepatic impairment does not significantly affect total body clearance of
`
`palonosetron compared to the healthy subjects. Dosage adjustment is not
`necessary in patients with any degree of hepatic impairment.
`
`
`8.8 Race
`Intravenous palonosetron pharmacokinetics was characterized in
`
`twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg.
`
`
`
`

`

`
`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 IV ALOXI with either single-dose IV 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 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 IV 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 IV ALOXI with single-dose IV 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 2], delayed phase (24-120 hours) [Table 3], and overall
`phase (0-120 hours) [Table 4] post-chemotherapy in Phase 3 trials.
`
`Table 2: Prevention of Acute Nausea and Vomiting (0-24 hours):
`Complete Response Rates
`
`
`97.5% Confidence Interval
`ALOXI minus Comparator c
`
`
`
`[ 2%, 23% ]
`
`[
`
`[ -2%, 22% ]
`
`[
`
`]
`
`]
`
`p-value b
`
`% with Complete
`
`Response
`
`N a
`
`Treatment
`
`Group
`
`Study
`
`Chemotherapy
`
`Moderately
`Emetogenic
`
`1
`
`ALOXI
`0.25 mg
`
`189
`
`81
`
`0.009
`
`Ondansetron
`32 mg IV
`
`185
`
`69
`
`2
`
`ALOXI
`0.25 mg
`
`189
`
`63
`
`NS
`
`[
`
`[ -9%, 13% ]
`]
`
`Dolasetron
`100 mg IV
`
`191
`
`53
`
`-10 -5
`0
`5
`10 15 20 25 30 35
`Difference in Complete Response Rates
`
`
`
`Highly
`Emetogenic
`
`3
`
`ALOXI
`0.25 mg
`
`223
`
`59
`
`NS
`
`Ondansetron
`32 mg IV
`
`221
`
`57
`
`a Intent-to-treat cohort
`b 2-sided Fisher’s exact test. Significance level at α=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.
`
`Aloxi® (palonosetron HCl) injection
`cancer patients. Following single IV 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 5.6 ± 5.5 ng/mL and mean AUC was 35.8
`± 20.9 ng•hr/mL. Following IV 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 IV 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%.
`
`
`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 160 ± 35 mL/h/kg and renal clearance was 66.5± 18.2
`mL/h/kg. Mean terminal elimination half-life was approximately 40
`hours.
`
`Special Populations
`[See USE IN SPECIFIC POPULATIONS (8.5 – 8.8)]
`
`
`
`13 NONCLINICAL TOXICOLOGY
`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 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 150 to
`289 times the human exposure (AUC= 29.8 ng•h/ mL) at the recommended
`intravenous dose of 0.25 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 137 and 308 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 1894 times the
`
`recommended human intravenous dose based on body surface area) was
`found to have no effect on fertility and reproductive performance of male and
`female rats.
`
`14 CLINICAL STUDIES
`
`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
`
`
`
`
`
`
`
`

`

`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`See FDA-Approved Patient Labeling (17.2)
`
`17.1 Instructions for Patients
`
`
`
`
`
`
`
`•
`
`•
`
`•
`
`Patients should be advised to report to their physician all of their
`medical conditions, especially if they have heart problems
`including a problem called “congenital QT syndrome” or they are
`taking medicines that have caused or may cause severe heart beat
`changes such as diuretics, anti-arrhythmics or anthracycline. [see
`Warnings and Precautions (5.2)].
`Patients should be advised to report to their physician any pain,
`redness, or swelling in and around the infusion site [see Adverse
`Reactions (6.2)].
`Patients should be instructed to read the patient insert.
`
`17.2 FDA-Approved Patient Labeling
`
`
`______________________________________________________________
`
`
`
`
`
`
`
`Aloxi® (palonosetron HCl) injection
`
`Table 3: Prevention of Delayed Nausea and Vomiting (24-120 hours):
`Complete Response Rates
`
`
`97.5% Confidence Interval
`ALOXI minus Comparator c
`
`[ 8%, 30% ]
`
`]
`
`[
`
`p-value b
`
`% with Complete
`
`Response
`
`N a
`
`Treatment
`
`Group
`
`Study
`
`Chemotherapy
`
`Moderately
`Emetogenic
`
`1
`
`ALOXI
`0.25 mg
`
`189
`
`74
`
`<0.001
`
`Ondansetron
`32 mg IV
`
`185
`
`55
`
`[ 3%, 27% ]
`
`]
`
`[
`
`2
`
`ALOXI
`0.25 mg
`
`189
`
`54
`
`0.004
`
`-10 -5
`0
`5
`10 15 20 25 30 35
`Difference in Complete Response Rates
`
`Dolasetron
`100 mg IV
`
`191
`
`39
`
`a Intent-to-treat cohort
`b 2-sided Fisher’s exact test. Significance level at α=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 4: Prevention of Overall Nausea and Vomiting (0-120 hours):
`Complete Response Rates
`
`
`97.5% Confidence Interval
`ALOXI minus Comparator c
`
`[ 7%, 31% ]
`
`]
`
`[
`
`p-value b
`
`% with Complete
`
`Response
`
`N a
`
`Treatment
`
`Group
`
`Study
`
`Chemotherapy
`
`Moderately
`Emetogenic
`
`1
`
`ALOXI
`0.25 mg
`
`189
`
`69
`
`<0.001
`
`Ondansetron
`32 mg IV
`
`185
`
`50
`
`2
`
`ALOXI
`0.25 mg
`
`189
`
`46
`
`0.021
`
`Dolasetron
`100 mg IV
`
`191
`
`34
`
`[ 0%, 24% ]
`
`]
`
`[
`
`-10 -5
`0
`5
`10 15 20 25 30 35
`Difference in Complete Response Rates
`
`a Intent-to-treat cohort
`b 2-sided Fisher’s exact test. Significance level at α=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.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`NDC # 58063-797-25, 0.25 mg/5 mL (free base) single-use vial
`individually packaged in a carton
`
`Storage
`•
`
`Store at controlled temperature of 20–25°C (68°F–77°F).
`Excursions permitted to 15–30 °C (59-86°F).
`Protect from freezing.
`Protect from light.
`
`•
`•
`
`
`
`
`
`
`
`
`

`

`17.2 FDA-Approved Patient Labeling
`
`Patient Information
`ALOXI™ (Ah-lock-see)
`Palonosetron HCI injection
`
`Read the Patient Information that comes with ALOXI before your treatment with ALOXI and each
`time you get 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. If you have questions
`about ALOXI, ask your doctor or pharmacist.
`
`What is ALOXI?
`ALOXI is a medicine called an “antiemetic.” ALOXI is used in adults to help prevent the nausea
`and vomiting that happens:
`right away with certain anti-cancer medicines (chemotherapy)
`•
`• or later with certain anti-cancer medicines
`
`
`What is ALOXI used for?
`ALOXI is used to prevent nausea and vomiting that may happen:
`soon after taking certain anti-cancer medicines
`•
`•
`later after taking certain anti-cancer medicines
`
`
`Who should not take ALOXI?
`Do not take ALOXI if you are allergic to any of the ingredients in ALOXI. The active
`ingredient is palonosetron hydrochloride. See the end of this leaflet for a complete list of
`ingredients in ALOXI.
`
`ALOXI has not been studied in children under 18 years of age.
`
`What should I tell my doctor before using ALOXI?
`Tell your doctor about all of your medical conditions, including if you:
`• have heart problems including a problem called “congenital QT syndrome”
`• have low potassium in your blood
`• have low magnesium in your blood
`• are pregnant. It is not known if ALOXI may harm your unborn baby. You and your doctor
`should decide if ALOXI is right for you.
`• are breastfeeding. It is not known if ALOXI passes into your milk and if it can harm your
`baby. You should choose to either take ALOXI or breastfeed, but not both.
`
`
`Tell your doctor about all of the medicines you take including prescription and
`nonprescription medicines, vitamins and herbal supplements. ALOXI should be given with
`caution in patients who may be taking other medicines that have caused, or may cause, severe
`heart beat changes.
`Especially, tell your doctor if you take:
`“water pills” (diuretics)
`•
`• medicine to control your heartbeat (anti-arrhythmics)
`• anthracycline (an anti-cancer medicine)
`
`
`How should I use ALOXI?
`ALOXI is given in your vein by IV (intravenous) injection. It is only given to you by a healthcare
`provider in a hospital or clinic. ALOXI is usually injected into your vein about 30 minutes before
`you get your anti-cancer medicine (chemotherapy).
`
`
`
`

`

`What are the possible side effects of ALOXI?
`ALOXI should be given with caution in patients who have or may develop severe heart beat
`changes from QT prolongation. This can happen in people who have certain heart or other
`medical problems or who take certain medicines.
`
`The most common side effects of ALOXI are headache and constipation. Diarrhea and
`dizziness have also been observed.
`
`These are not all the side effects from ALOXI. For more information ask your doctor or
`pharmacist.
`
`General information about ALOXI
`Medicines are sometimes prescribed for conditions other than those listed in patient information
`leaflets. ALOXI was prescribed for your medical condition.
`
`This leaflet summarizes the most important information about ALOXI. If you would like more
`information, talk with your doctor. You can ask your doctor or pharmacist for information about
`ALOXI that is written for health professionals. You can also visit the ALOXI web site at
`www.ALOXI.com. Or visit www.ManageCINV.com. This is a web site for patients with nausea and
`vomiting from anti-cancer medicines.
`
`What are the ingredients in ALOXI?
`Active ingredient: palonosetron hydrochloride
`Inactive ingredients: mannitol, disodium edetate, and citrate buffer in water
`
`Rx Only
`
`Mfd by Cardinal Health, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn
`Birex Pharmaceuticals, Dublin, Ireland
`
`HELSINN, Mfd for Helsinn Healthcare SA, Switzerland
`
`MGI PHARMA, INC. Distributed and marketed by MGI PHARMA, INC. Bloomington, MN. 55437 under license of Helsinn
`Healthcare SA, Switzerland.
`
`ALOXI® is a registered trademark of Helsinn Healthcare, SA, Lugano, Switzerland
`
`©2006 MGI PHARMA, INC. Bloomington, MN. 55437 U.S.A. 445091002 2/06
`
`
`