`-------------------DOSAGE FORMS AND STRENGTHS----------------------
`0.25 mg/5mL (free base) single-use vial (3)
`
`
`0.075 mg/1.5mL (free base) single-use vial (3)
`
`-----------------------------CONTRAINDICATIONS------------------------------
`ALOXI is contraindicated in patients known to have hypersensitivity to the
`drug or any of its components (4)
`
`
`
`---------------------WARNINGS AND PRECAUTIONS------------------------­
`
`Hypersensitivity reactions, including anaphylaxis, have been reported
`
`with or without known hypersensitivity to other selective 5-HT3
`
`receptor antagonists (5.1)
`
`
`
`
`Revised: 07/2013
`
`
`
`----------------------------ADVERSE REACTIONS--------------------------------
`
`The most common adverse reactions in chemotherapy-induced nausea and
`
`vomiting (incidence ≥5%) are headache and constipation (6.1)
`
`The most common adverse reactions in postoperative nausea and vomiting
`
`(incidence ≥ 2%) are QT prolongation, bradycardia, headache, and
`
`constipation.
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact EISAI at 1­
`888-422-4743 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 (8.4)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved Patient Labeling
`
`
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`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
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1
`Instructions for Patients
`
` 17.2 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—-----------------------
`Warnings and Precautions, Hypersensitivity (5.1)
`07/2013
`
`-------------------------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)
`Prevention of postoperative nausea and vomiting (PONV) for up to 24
`hours following surgery. Efficacy beyond 24 hours has not been
`demonstrated (1.2)
`
`
`
`
`
`
`
`
`--------------------DOSAGE AND ADMINISTRATION----------------------­
`
`Chemotherapy-Induced Nausea and Vomiting (2.1)
`
`
`
`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 I.V. dose administered over 10
`
`
`
`seconds immediately before the induction of anesthesia.
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`
`
`2
`
`
`6
`
`
`7
`
`8
`
`INDICATIONS AND USAGE
`1.1
`Chemotherapy-Induced Nausea and Vomiting
`1.2
`Postoperative Nausea and Vomiting
`
`DOSAGE AND ADMINISTRATION
`
`
`Recommended Dosing
`2.1
`
`2.2
`Instructions for I.V. Administration
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`CONTRAINDICATIONS
`4
`
`5 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
`
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`
`
`
`
`
`Reference ID: 3448951
`
`

`

`
`
`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
`
`ALOXI is indicated for:
`
`Prevention of postoperative nausea and vomiting (PONV) for up
`
`
`to 24 hours following surgery. Efficacy beyond 24 hours has not
`been demonstrated.
`
`
`
`
`
`
`
`
`2
`
`
`
`3
`
`
`
`4
`
`
`
`
`
`
`6
`
`
`
`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 of chemotherapy.
`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.
`
`2.2 Instructions for I.V. 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.
`
`DOSAGE FORM AND STRENGTHS
`ALOXI is supplied as a single-use sterile, clear, colorless solution in
`glass vials that provide:
`
`
`
`
`0.25 mg (free base) per 5 mL
`
`
`
`
`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)]
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
` Hypersensitivity
`5.1
`Hypersensitivity reactions, including anaphylaxis, have been reported
`with or without known hypersensitivity to other 5-HT3 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% of patients in these trials (Table 1).
`
`
`
`Reference ID: 3448951
`
`
`
`
`
`Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and
`Vomiting Studies ≥ 2% in any Treatment Group
`Ondansetron
`
`Dolasetron
`
`
`
`
`Event
`
`Headache
`
`Constipation
`
`Diarrhea
`
`Dizziness
`
`Fatigue
`
`
`Abdominal Pain
`
`Insomnia
`
` Aloxi 0.25 mg
`
`
`(N=633)
`
`
`
` 32 mg I.V.
`
`100 mg I.V.
`
`
`
`60 (9%)
`
`
`29 (5%)
`
`
`8 (1%)
`
`
`8 (1%)
`
`3 (< 1%)
`
`1 (< 1%)
`
`1 (< 1%)
`
`(N=410)
`
`
`34 (8%)
`
`
`8 (2%)
`
`
`7 (2%)
`
`
`9 (2%)
`
`
`4 (1%)
`
`2 (< 1%)
`
`3 (1%)
`
`(N=194)
`
`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 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: < 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 Postoperative Nausea and Vomiting
`
`The adverse reactions cited in Table 2 were reported in ≥ 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% in any Treatment Group
`
`Event
`
`
`Electrocardiogram
`
`QT prolongation
`
`Bradycardia
`Headache
`
`Constipation
`
`
`
`
`Aloxi 0.075 mg
`
`(N=336)
`
`
`16 (5%)
`
`13 (4%)
`
`11 (3%)
`
`
`8 (2%)
`
`
`Placebo
`
`(N=369)
`
`
`11 (3%)
`
`16 (4%)
`
`14 (4%)
`
`
`11(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 including
`
`anaphylaxis and anaphylactic shock 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 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.
`
`
`
`Coadministration 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 palonosetron 0.25 mg
`(I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125
`
`mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not
`significantly altered (AUC: no change, Cmax: 15% increase).
`
`
`
`
`Reference ID: 3448951
`
`
`
`
`
`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.
`
`
`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.
`
`
`Of the 1520 adult patients in Aloxi PONV clinical studies, 73 (5%)
`
`were ≥65 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 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.
`
`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 (palonosetron hydrochloride) 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. 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 0.28 mg palonosetron 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 0.084 mg
`
`
`palonosetron hydrochloride, 83 mg mannitol, disodium edetate and citrate
`
`
`buffer in water for intravenous administration.
`
`
`
`The pH of the 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 of the small
`
`intestine and that the released serotonin then activates 5-HT3 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 5-HT3 receptor has been demonstrated to
`
`selectively participate in the emetic response.
`
`
`
`
`
`
`12.2 Pharmacodynamics
`
`
`The effect of palonosetron 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 of palonosetron 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
`
`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
`
`
`cancer patients. Following single I.V. 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 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%.
`
`
`After intravenous dosing of palonosetron in patients undergoing
`
`surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic
`
`characteristics of palonosetron were similar to those observed in cancer
`
`patients.
`
`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 is 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
`
`
`Reference ID: 3448951
`
`

`

`
`
`Table 3: Prevention of Acute Nausea and Vomiting (0-24 hours):
`Complete Response Rates
`
`
`
`
`
`97.5% Confidence Interval
` ALOXI minus Comparator c
`
`
`
`
`
`
`
`
`
`
`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 I.V.
`
`
`185
`
`69
`
`2 ALOXI
`
`0.25 mg
`
`
`189
`
`63
`
`NS
`
`
`Dolasetron
`100 mg I.V.
`
`
`191
`
`53
`
`[ 2%, 23% ]
`]
`
`[
`
`[ -2%, 22% ]
`]
`
`[
`
`Highly
`
`Emetogenic
`
`
`3 ALOXI
`
`0.25 mg
`
`
`223
`
`59
`
`NS
`
`
`Ondansetron
`
` 32 mg I.V.
`
`221
`
`57
`
`[ -9%, 13% ]
`]
`
`[
`
`-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
`
`
`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):
`Complete Response Rates
`
`
`
`
`97.5% Confidence Interval
`ALOXI minus Comparator c
`
`
`
`
`
`
`
`
`
`
`
`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 I.V.
`
`
`185
`
`55
`
`[ 8%, 30% ]
`]
`
`[
`
`
`2 ALOXI
`
`0.25 mg
`
`189
`
`54
`
`0.004
`
`Dolasetron
`
` 100 mg I.V.
`
`191
`
`39
`
`[ 3%, 27% ]
`]
`
`[
`
`-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
`
`
`delayed nausea and vomiting associated with initial and repeat courses of
`
`moderately emetogenic chemotherapy.
`
`
`
`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
`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 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 I.V. ALOXI with either single-dose I.V. 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 only 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 I.V. 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 I.V. ALOXI with single-dose I.V. 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 3], delayed phase (24-120 hours) [Table 4], and overall
`phase (0-120 hours) [Table 5] post-chemotherapy in Phase 3 trials.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3448951
`
`

`

`
`59/138 (42.8%)
`
`35/135 (25.9%)
`
`16.8%
`
` 0.004
`
`
`
`7.8%
`
` 0.188
`
`
`
`Table 6: Prevention of Postoperative Nausea and Vomiting: Complete
`Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo
`
`Palonosetron Vs Placebo
`Treatment
`n/N (%)
`
`Δ
`p-value*
`Co-primary Endpoints
`
` CR 0-24 hours
`
`
`
`Palonosetron
`
`
`Placebo
` CR 24-72 hours
`
`
`67/138 (48.6%)
`
`
`Palonosetron
`
`
`55/135 (40.7%)
`
`
`Placebo
`* To reach statist