CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21—372/8008/8010
`
`LABELING
`
`

`

`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
`
`----------------DOSAGE FORMS AND STRENGTHS-——-——--—-—-—--—
`0.25 mg/Sml (free base) single-use vial (3)
`0.075 mfg/1.5m] (free base) single-use vial (3)
`
`ALOXI” (palonosetron HCI) Injection for Intravenous Use
`Initial U.S. Approval: 2003
`
`------------------——RECENT MAJOR CHANGES—-—-——-—---—-—-—-——--
`Indications and Usage,
`Postoperative Nausea and Vomiting (1.2)
`Dosage and Administration,
`Recommended Dosing (2.1)
`Warnings and Precautions,
`QTc Intervals (5.2) - Deletion
`
`02/2008
`
`02/2008
`
`02/2008
`
`-------------------INDICATIONS AND USAGE--—-~--~—---—--——--——-—
`ALOXI is a serotonin subtype 3 (5-HT3) receptor antagonist indicated for:
`0
`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)
`Prevention of postoperative nausea and vomiting (PONV) for up
`to 24 hours following surgery. Efficacy beyond 24 hours has not
`been demonstrated (1.2)
`
`0
`
`I
`
`------------—DOSAGE AND ADMINISTRATION----—---—————-—--
`Chemotherapy-Induced Nausea and Vomiting (2.1)
`0
`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.
`
`'
`
`Postoperative Nausea and Vomiting (2.1)
`-
`Adult Dosage: a single 0.075 mg 1.V. dose administered over 10
`seconds immediately before the induction ofanesthesia.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`-----------------------CONTRAINDICATIONS——-——-—--—-—--—---————--
`ALOXIis contraindicatedin patients known to have hypersensitivity to the
`drug or any ofIts components (4)
`
`—-----------------—WARNINGS AND PRECAUTIONS—-——--——-——-———-—
`-
`Hypersensitivity reactions may occur in patients who have exhibited
`hypersensitivity to other selective S-HT; receptor antagonists (S. 1)
`
`-—-—---—-—-—---—---—---ADVERSE REACTIONS-----—-—---—--—-—-———--——-
`The most common adverse reactions in chemotherapy-induced nausea and
`vomiting (incidence 25%) are headache and constipation (6.1)
`
`The most common adverse reactions in postoperative nausea and vomiting
`(incidence 2 2%) are QT prolongation, bradycardia, headache, and
`constipation.
`
`To report SUSPECTED ADVERSE REACTIONS, contact MGI
`PHARMA at 1-800-562-5580 or FDA at l—800—FDA-1088 or
`\vww.fda.oov/medwatch.
`
`--—--«-—---—-—-—----DRUG INTERACTIONS------------------------
`
`The potential for clinically significant dmg 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 (8.4)
`-
`
`See I7 for PATIENT COUNSELING INFORMATION and FDA-
`approved Patient Labeling
`
`Revised: 02/2008
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Chemotherapy-Induced Nausea and Vomiting
`14.2 Postoperative Nausea and Vomiting
`16 HOW SUPPLIED/STORAGE AND HANDLING
`l7 PATIENT COUNSELING INFORMATION
`17.]
`Instructions for Patients
`17.2 FDA-Approved Patient Labeling
`
`* Sections or subsections omitted from the full prescribing information are
`not listed.
`
`1
`
`2
`
`Uldiw
`
`6
`
`OOH
`
`INDICATIONS AND USAGE'
`1.1
`Chemotherapy-Induced Nausea and Vomiting
`1.2
`Postoperative Nausea and Vomiting
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`2.2
`Instruch'ons for IV. Administration
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Hypersensitivity
`ADVERSE REACTIONS
`6.1
`Chemotherapy—Induced Nausea and Vomiting
`6.2
`Postoperative Nausea and Vomiting
`6.3
`Postmarketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy Teratogenic Effects
`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 OVERDOSE
`1] DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism ofAction
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`1.1 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
`1.2 Postoperative Nausea and Vomiting
`ALOXl is indicated for:
`o
`the prevention of postoperative nausea and vomiting (PONV) for
`up to 24 hours following surgery. Efficacy beyond 24 hours has
`not been demonstrated.
`
`-
`
`As with other antiemetics, routine prophylaxis is not
`recommended in patients in whom there is little expectation that nausea
`and/or vomiting will occur postoperatively. In patients where nausea
`and vomiting must be avoided during the postoperative period, ALOXI
`is recommended even where the incidence of postoperative nausea
`and/or vomiting is low.
`
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`Chemotherapy-Induced Nausea and Vomiting
`Dosage for Adults — a single 0.25 mg I.V. dose administered over 30
`seconds. Dosing should occur approximately 30 minutes before the
`start ofchemotherapy.
`Postoperative Nausea and Vomiting
`Dosage for Adults - a single 0.075 mg I.V. dose administered over 10
`seconds immediately before the induction of anesthesia.
`
`Instructions for I.V. Administration
`2.2
`ALOXI is supplied ready for intravenous injection. ALOXI should not
`be mixed with other drugs. Flush the infusion line with normal saline
`before and afier administration of ALOXI.
`
`Parenteral drug products should be inspected visually for particulate matter
`and discoloration before administration, whenever solution and
`container permit.
`
`.
`DOSAGE FORM AND STRENGTHS
`ALOXI is supplied as a single-use sterile, clear, colorless solution in
`glass vials that provide:
`0
`0.25 mg (free base) per 5 m1
`-
`0.075 mg (free base) per 1.5 ml.
`
`CONTRAINDICATIONS
`ALOXI is contraindicated in patients known to have hypersensitivity to
`the drug or any of its components. [see Adverse Reactions (6.2)]
`
`WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity
`Hypersensitivity reactions may occur in patients who have exhibited
`hypersensitivity to other 5-HT; receptor antagonists.
`
`ADVERSE REACTIONS
`Because clinical trials are conducted under widely varying conditions,
`adverse reaction rates observed in the clinical trials of a drug cannot be
`directly compared to rates in the clinical trials of another drug and may
`not reflect the rates observed in practice.
`
`6.1 Chemotherapy-Induced Nausea and Vomiting
`
`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 2% of patients in these trials (Table 1).
`
`Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and
`Vomitin- Studies 2 2% in an Treatment Groux
`Ondansetron
`
`Dolasetron
`
`
`
`
`Aloxi 0.25 mg
`100 mg I.V.
`32 mg I.V.
`(N=633)
`
`
`(N=410)
`(N=194)
`
`
`32 (16%)
`34 (8%)
`
`60 (9%)
`
`4 (2%)
`4 (2%)m“
`
`
`
`
`
`m———
`
`
`
`
`
`
`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 meg/kg oral dose in a post-
`operative nausea and vomiting study and one healthy subject received a 0.75
`mg I.V. 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: < l%: transient, asymptomatic increases in AST and/or ALT and
`bilirubin. These changes occurred predominantly in patients receiving highly
`cmetogenic 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 Postoperative Nausea and Vomiting
`
`The adverse reactions cited in Table 2 were reported in a 2% of adults
`receiving I.V. Aloxi 0.075 mg immediately before induction of anesthesia in
`one phase 2 and two phase ’3 randomized placebo—controlled trials. Rates of
`events between palonosetron and placebo groups were indistinguishable.
`Some events are known to be associated with, or may be exacerbated by
`concomitant perioperative and intraoperative medications administered in
`this surgical population. Please refer to Section 12.2, thorough QT/QTc
`study results, for definitive data demonstrating the lack of palonosetron effect
`on QT/QTc.
`
`

`

`Table 2: Adverse Reactions from Postoperative Nausea and Vomiting
`Studies 2 2% in an Treatment Grou -
`
`
`
`Placebon (N=336) (”=369)
`Aloxi 0.075 mg
`
`
`
`
`
`
`
`
`
`
`
`
`Electrocardiogram
`QT prolongation
`
`16 (5%)
`
`ll (3%)
`
`In these 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 perioperative and intraoperative medications including
`those associated with anesthesia:
`
`Cardiovascular: 1% Electrocardiogram QTc prolongation, sinus bradycardia,
`tachycardia; < 1%: blood pressure decreased, hypotension, hypertension,
`arrhythmia, ventricular extrasystoles, generalized edema; ECG T wave
`amplitude decreased, platelet count decreased. The frequency of these
`adverse effects did not appear to be different from placebo.
`
`Dermatological: 1%: pruritus.
`
`Gastrointestinal System: 1%: flatulence, < 1%: Dry mouth, upper abdominal
`pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility,
`anorexia.
`
`General: < 1%: chills.
`
`Liver: 1%: increases in AST and/or ALT< 1%: hepatic enzyme increased
`
`Metabolic: < 1%: hypokalemia, anorexia.
`
`Nervous System: < 1%: dizziness.
`
`Respiratory: < 1%: hypoventilation, laryngospasm.
`
`Urinary System: 1%: urinary retention.
`
`6.3 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 of ALOXI 0.25 mg in the prevention of
`chemotherapy—induced nausea and vomiting.
`
`7
`
`DRUG INTERACTIONS
`Palonosetron is eliminated fiom 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, CYPZB6, 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.
`
`Coadministration of 0.25 mg I.V. palonosetron and 20 mg 1.V.
`dexamethasone in healthy subjects revealed no pharmacokinetic drug-
`interactions between palonosetron and dexamethasone.
`
`In an interaction study in healthy subjects where palonosetron 0.25 mg
`(I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125
`mg/80 mg/80mg), the pharmacokinetics of palonosetron were not
`significantly altered (AUC: no change, Cmax: 15% increase).
`
`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 pharrnacokinetic 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.] 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 patientsundergoing 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
`tumorigeriicity shown for palonosetron in the rat carcinogenicity study, a
`decision should be made whether to discontinue nursing or to discontinue the
`dnrg, taking into account the importance ofthe dmg 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 phannacokinetics between cancer patients 2 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 2 65 years old, while 71
`(5%) were 2 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.
`
`Of the 1520 adult patients in Aloxi PONV clinical studies, 73 (5%)
`were 265 years old. No overall differences in safety were observed between
`older and younger subjects in these studies, though the possibility of
`heightened sensitivity in some older individuals cannot be excluded. No
`differences in efficacy were observed in geriatric patients for the CINV
`indication and none are expected for geriatric PONV patients. However,
`Aloxi efficacy in geriatric patients has not been adequately evaluated.
`
`8.6 Renal Impairment
`Mild to moderate renal impairment does not significantly affect
`palonosetron phannaeokinetic 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
`palonosedon compared to the healthy subjects. Dosage adjustment is not
`necessary in patients with any degree of hepatic impairment.
`8.8 Race
`1ntravenous palonosetron pharmacokinetics was characterized in
`twenty-four healthy Japanese subjects over the dose range of 3 — 90 meg/kg.
`
`

`

`Total body clearance was 25% higher in Japanese subjects compared to
`Whites, however, no dose adjustment is required. The phannacokinetics 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 meg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study.
`This is approximately 25 times the recommended dose of0.25 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 (palonosetron hydrochloride) is an antiemetic and antinauseant
`agent. It is a serotonin subtype 3 (S-HTJ) receptor antagonist with a strong
`binding affinity for this receptor. Chemically, palonosetron hydrochloride is:
`(3a§)—2-[(§)- l-Azabicyclo [2.2.2]oct~3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo—
`leenz[de]isoquinoline hydrochloride. The empirical formula is
`CwHuNzOl‘ICi, with a molecular weight of 332.87. Palonosetron
`hydrochloride exists as a single isomer and has the following structural
`formula:
`
`N
`
`O
`
`”I
`
`I?)K
`H M
`
`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. ALOXI injection is
`available as 5 mL single use vial or 1.5 mL single use vial. Each 5 mL vial
`contains 0.25 mg palonosetron base as hydrochloride, 207.5 mg mannitol,
`disodium edetate and citrate buffer in water for intravenous administration.
`Each 1.5 mL vial contains 0.075 mg palonosetron base as
`hydrochloride, 83 mg mannitol, disodium edetate and citrate buffer in water
`for intravenous administration.
`The pH ofthe solution in the 5 mL and 1.5 mL vials 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 ofthe small
`intestine and that the released serotonin then activates 5-I-I'I‘3 receptors
`located on vagal afferents to initiate the vomiting reflex.
`
`Postoperative nausea and vomiting is influenced by multiple patient,
`surgical and anesthesia related factors and is triggered by release of 5-HT in
`a cascade of neuronal events involving both the central nervous system and
`the gastrointestinal tract. The S-HT; receptor has been demonstrated to
`selectively participate in the emetic response.
`
`12.2 Pharmacodynamics
`The effect ofpalonosetron on blood pressure, heart rate, and ECG
`. parameters including QTc were comparable to ondansetron and dolasetron in
`CINV clinical trials.
`In PONV clinical trials the effect ofpalonosetron on
`
`the QTc interval was no different from placebo. 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 I.V. administered palonosetron at single doses of 0.25, 0.75 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.
`
`12.3 Pharmacokinetics
`Afier 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 (Cm) and
`area under the concentration-time curve (AUCM) are generally dose-
`proportional over the dose range of 03—90 meg/kg in healthy subjects and in
`cancer patients. Following single I.V. dose ofpalonosetron at 3 meg/kg (or
`0.21 mg/70 kg) to six cancer patients, mean (iSD) maximum plasma
`concentration was estimated to be 5.6 i 5.5 ng/mL and mean AUC was 35.8
`i 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 42i34%. Following
`I.V. administration of palonosetron 0.25 mg once daily for 3 days in [2
`healthy subjects, the mean (iSD) increase in plasma palonosetron
`concentration from Day 1 to Day 3 was 1 10¢45%.
`
`After intravenous dosing of palonosetron in patients undergoing
`surgery (abdominal surgery or vaginal hysterectomy), the phannacokinetic
`characteristics ofpalonosetron were similar to those observed in cancer
`patients.
`
`Distribution
`
`Palonosetron has a volume of distribution of approximately 8.3 i
`2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.
`M_etaltofl$m
`Palonosetron is eliminated by multiple routes with approximately 50%
`metabolized to formtwo primary metabolites: N-oxide-palonosetron and 6—S-
`. hydroxy—palonosetron. These metabolites each have less than 1% of the 5-
`HT; receptor antagonist activity ofpalonosetron. In vitro metabolism studies
`have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYPl A2
`are involved in the metabolism of palonosetron. However, clinical
`phannacokinetic parameters are not significantly different between poor and
`extensive metabolizers ofCYP2D6 substrates.
`
`Elimination
`
`-
`
`After a single intravenous dose of 10 meg/kg [”C]-palonosetron,
`approximately 80% ofthe 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 i 35
`mL/h/kg and renal clearance was 66.5i 18.2 mL/h/‘kg. Mean terminal
`elimination half-life is approximately 40 hours.
`
`Special Populations
`[See USE IN SPECIFIC POPULA TIONS (8.5 — 8.8)
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a lO4—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 Am'es tesL 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 ofmale and
`female rats.
`
`14 CLINICAL STUDIES
`
`14.1 Chemotherapy Induced Nausea and Vomiting
`
`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
`episodes and no rescue medication) and other efficacy parameters were
`assessed through at least 120 hours afier 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 l.V. ALOXl with either single-dose l.V. ondansetron (study 1) or
`dclasetron (study 2) given 30 minutes prior to moderately emetogenic
`chemotherapy including carboplatin, cisplatin S 50 mg/ml,
`cyclophosphamide < 1500 mg/m’, doxorubicin > 25 mg/m2, epirubicin,
`in'notecan, and methotrexate > 250 mg/m’. Concomitant corticosteroids were
`not administered prophylactically in study 1 and were only used by 4-6% of
`patients in study 2. The majority ofpatients in these studies were women
`(77%), White (65%) and naive 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 l.V. palonosetron from 0.3 to 90 meg/kg (equivalent to < 0.1 mg
`to 6 mg fixed dose) in 161 chemotherapy-naive adult cancer patients
`receiving highly-emetogenic chemotherapy (either cisplatin 2 70 mg/m2 or
`cyclophosphamide > 1100 mg/mz). 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 l.V. ALOXI with single-dose l.V. ondansetron (study 3) given 30
`minutes prior to highly emetogenic chemotherapy including cisplatin Z 60
`mg/m’, cyclophosphamide > 1500 mg/m’, and dacarbazine. Corticosteroids
`were co-administered prophylactically before chemotherapy in 67% of
`patients. Of the 667 patients, 51% were women, 60% White, and 59% naive
`to previous chemotherapy. The mean age was 52 years.
`
`Efficacy Results
`The antiemetic activity of ALOXl was evaluated during the acute phase
`(0-24 hours) [Table 3], delayed phase (24—120 hours) [Table 4], and overall
`phase (0-120 hours) [Table 5] post-chemotherapy in Phase 3 trials.
`
`Table 3: Prevention of Acute Nausea and Vomiting (0-24 hours):
`Com Ilete Res - onse Rates
`
`
`
`¢
`
`97.5% Confidence Interval
`ALOXI minus Comparator
`
`[2mm
`
`Treatment Group
`
`VawithCompleteResponse
`
`Chemotherapy
`
`Moderately
`Emetogenic
`
`Emetogenic
`
`
`
`a Intent-to—trent cohort
`b Z-sided Fisher's exact test. Significance level at a=0.025.
`c These studies were designed to show non-inferiority. A lower bound greater than -l$% demonstrates
`nonvinferiority 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.
`
`Table 4: Prevention of Delayed Nausea and Vomiting (24-120 hours):
`Corn - lete Res onse Rates
`
`
`Chcmothcrapy
`
`Moderately
`Emetogenic
`
`"IawithComplete
`
`Response
`
`97.5% Confidence Interval
`ALOXI minus Comparator‘
`
`mm:
`
`
`
`Ondnnsctron
`
`'
`
`[154.17%]
`
`10 1520151015
`5
`I
`-I0 -5
`Difltmtt inCunplrtr Rupert“ Rik:
`
`Dolasetron
`
`n lntent-to-rrent cohort
`b 2-sirlcd Fisher's exact test. Significance level nt @0025.
`c These studies were designed to show non—inferiority. A lower bound greater than —l 5% demonstrates non-
`infcriority between ALOXI and comparator.
`
`These studies show that ALOXl was effective in the prevention of
`delayed nausea and vomiting associated with initial and repeat courses of
`moderately emetogenic chemotherapy.
`
`

`

`Table 6: Prevention of Postoperative Nausea and Vomiting: Complete
`Res nonse CR , Stud 1, Palonosetron 0.075 m- Vs Placebo
`Palonosetron Vs Placebo
`
`
`.-
`
`
`C ,05—24'h'o'urs
`
`
`
`
`
`R-24-72 Iiou'rs-
`
`;
`
`Table 5: Prevention of Overall Nausea and Vomiting (0-120 hours):
`Com lete Res . onse Rates
`
`Chemotherapy
`
`Moderately
`Emelogenit:
`
`
`
`%withCompleteRosonse
`
`97.5% Contidenee Interval
`ALOXI minus Comparator’
`
`[mu-u
`
`[075147.]
`
`4060 5101511153155
`Dill'oaxeiiComfldeliaponsellztu
`
`
`
`a Intent-town cohort
`b 2-sided Fisher‘s exrrcl (i=1. Signil’uznec level at ot=0.025.
`e These studies were designed to show non-inferiority. A lower bound greater than ~15": demonstrates non-
`inferiority between ALOXl 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.
`
`14.2 Postoperative Nausea and Vomiting
`
`In one multicenter, randomized, stratified, double-blind, parallel-group,
`phase 3 clinical study (Study 1), palonosetron was compared with placebo for
`the prevention of PONV in 546 patients undergoing abdominal and
`gynecological surgery. All patients received general anesthesia. Study 1 was
`a pivotal study conducted predominantly in the US in the out-patient setting
`for patients undergoing elective gynecologic or abdominal laparoscopic
`surgery and stratified at randomization for the following risk factors: gender,
`non-smoking status, history of post operative nausea and vomiting and/or
`motion sickness.
`
`In Study 1 patients were randomized to receive palonosetron 0.025 mg,
`0.050 mg or 0.075 mg or placebo, each given intravenously immediately
`prior to induction of anesthesia. The antiemetic activity of palonosetron was
`evaluated during the 0 to 72 hour time period after surgery.
`
`Of the 138 patients treated with 0.075 mg palonosetron in Study 1 and
`evaluated for efficacy, 96% were women; 66% had a history of PONV or
`motion sickness; 85% were non—smokers. As for race, 63% were White,
`20% were Black, 15% were Hispanic, and 1% were Asian. The age of
`patients ranged from 21 to 74 years, with a mean age of 37.9 years. Three
`patients were greater than 65 years ofage.
`
`Co-primary efficacy measures were Complete Response (CR) defined
`as no emetic episode and no use of rescue medication in the 0-24 and in the
`24-72 hours postoperatively.
`Secondary efficacy endpoints included:
`0
`Complete Response (CR) 0-48 and 0-72 hours
`I
`Complete Control (CC) defined as CR and no more than mild
`nausea
`
`-
`
`Severity of nausea (none, mild, moderate, severe)
`
`The primary hypothesis in Study 1 was that at least one of the three
`palonosetron doses were superior to placebo.
`Results for Complete Response in Study 1 for 0.075 mg palonosetron
`versus placebo are described in the following table.
`
`—-I—
`* To reach statistical significance for each co-primary endpoint, the required
`significance limit for the lowest p-value was p<0.017.
`ADifference (%): palonosetron 0.075 mg minus placebo
`
`Palonosetron 0.075 mg reduced the severity of nausea compared to
`placebo. Analyses of other secondary endpoints indicate that palonosetron
`0.075 mg was numerically better than placebo, however, statistical
`significance was not formally demonstrated.
`
`A phase 2 randomized, double-blind, multicenter, placebo-controlled,
`dose rangin