`
`
`
` -------------------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)
`
`
`
`----------------------------ADVERSE REACTIONS-------------------------------­
`
`The most common adverse reactions in chemotherapy-induced nausea and
`
`
`vomiting in adults (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 (6.2).
`
`
`
`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 ------------------------­
`
`
`
`
`Chemotherapy-Induced Nausea and Vomiting
`
`
`Pediatric use: Safety and effectiveness in neonates (less than 1 month of age)
`
`
`
`
`
`
`
`have not been established (8.4)
`
`
`
`
`Postoperative Nausea and Vomiting
`
`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
`
`
`
`
`
`
`
`
`Revised: 05/2014
`
`
`
`
`
`
`
`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
`
`
`14.1 Chemotherapy-Induced Nausea and Vomiting in Adults
`
`
`
`14.2 Chemotherapy-Induced Nausea and Vomiting in Pediatrics
`
`
`
`14.3 Postoperative Nausea and Vomiting
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
`* 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—----------------------­
`
`07/2013
`Warnings and Precautions, Hypersensitivity (5.1)
`
`
`
`Indication (1.2)
`05/2014
`
`
`Dosage and Administration, Pediatric Cancer Patients (2.1)
`05/2014
`
`
`
`
`
`------------------------INDICATIONS AND USAGE--------------------------­
`
`
`ALOXI is a serotonin-3 (5-HT3) receptor antagonist indicated in adults 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 (1.3)
`
`ALOXI is indicated in pediatric patients aged 1 month to less than 17 years
`
`
`
`
`
`
`for:
`
`
`
`•
`
`
`•
`
`
`•
`
`Prevention of acute nausea and vomiting associated with initial
`
`
`and repeat courses of emetogenic cancer chemotherapy, including
`
`highly emetogenic cancer chemotherapy (1.2)
`
`
`
`
`
`
`
`
`
`--------------------DOSAGE AND ADMINISTRATION----------------------­
`Chemotherapy-Induced Nausea and Vomiting (2.1)
`
`
`
`
`
`Age
`Dose*
` Infusion Time
`
`
` Infuse over 30
`
` 0.25 mg x 1
`
`
`
`Adults
`
` seconds beginning
` approx. 30 min before
`
`
`
`
`
` the start of chemo
`
`
` Infuse over 15
`
`
`
` minutes beginning
` approx. 30 min before
`
`
`
`
`
` the start of chemo
`
`
`
`
` 20 micrograms per
`
` Pediatrics
` kilogram (max 1.5
`
`
`
`
` (1 month to less
`
`
`
`
` than 17 years)
`
`
`mg) x 1
`
` *Note different dosing units in pediatrics
`
` Postoperative Nausea and Vomiting (2.1)
`
`
`
` Adult Dosage: a single 0.075 mg intravenous 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 in Adults
`
`
`
`1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric
`
`
`Patients Aged 1 month to Less than 17 Years
`
`
`
`Postoperative Nausea and Vomiting in Adults
`1.3
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`
`
`2.2
`Instructions for Intravenous Administration
`
`
`
`DOSAGE FORM 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
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`8.8 Race
`
`
`
`
`
`Reference ID: 3513457
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`
`
`•
`
`INDICATIONS AND USAGE
`
`
`
`1.1 Chemotherapy-Induced Nausea and Vomiting in Adults
`
`
`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 Chemotherapy-Induced Nausea and Vomiting in Pediatric
`
`
`
`
`
`Patients Aged 1 month to Less than 17 Years
`
`ALOXI is indicated for prevention of acute nausea and vomiting
`
`
`associated with initial and repeat courses of emetogenic cancer
`
`chemotherapy, including highly emetogenic cancer chemotherapy.
`
`
`
`1.3 Postoperative Nausea and Vomiting in Adults
`
`
`
`
`
`
`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.
`
`
`
`
`
`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
`
`
`Age
`Dose*
`
`
`
` 0.25 mg x 1
`Adults
`
`
`
`
`
` Infusion Time
` Infuse over 30
`
`
`
` seconds beginning
` approx. 30 min before
`
`
`
`
`
` the start of chemo
`
`
` Infuse over 15
`
`
`
` minutes beginning
` approx. 30 min before
`
`
`
`
`
` the start of chemo
`
`
`
`
`
`
`2
`
`
`3
`
`
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
` 20 micrograms per
`
`
` Pediatrics
`
`
`
` kilogram (max 1.5
`
` (1 month to less
`
`
`
`
` than 17 years)
`
`
`mg) x 1
`
` *Note different dosing units in pediatrics
`
` Postoperative Nausea and Vomiting
`
`
`
`
`
`
`Dosage for Adults - a single 0.075 mg intravenous dose administered
`
`over 10 seconds immediately before the induction of anesthesia.
`
`
`
`
`2.2 Instructions for Intravenous Administration
`
`
`
`
`
`ALOXI is supplied ready for intravenous administration at a
`
`
`
`
`
`concentration of 0.05 mg/mL (50 mcg/ mL). ALOXI should not be
`
`
`
`
`
`
`mixed with other drugs. The infusion line should be flushed 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 (concentration: 0.05 mg/mL, 50
`
`•
`
`mcg/mL)
`
`
`
`
`0.075 mg (free base) per 1.5 mL (concentration: 0.05 mg/mL, 50
`
`mcg/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
`
`
`5.1 Hypersensitivity
`
`
`
`Hypersensitivity reactions, including anaphylaxis, have been reported
`
`
`with or without known hypersensitivity to other 5-HT3 receptor
`
`
`antagonists.
`
`
`
`
`
`Reference ID: 3513457
`
`
`
`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
`
`
`
`
`
`6.1 Chemotherapy-Induced Nausea and Vomiting
`
`
`
`Adults
`
`
`
`
`
`
`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).
`
`
`
`Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and
`
`
`
`
`Vomiting Studies ≥ 2% in any Treatment Group
`Ondansetron
`
`
`
`Event
`
`
`Headache
`
`Constipation
`
`
`Diarrhea
`
`
`Dizziness
`
`
`Fatigue
`
`
`Abdominal Pain
`
`
`Insomnia
`
`
`
`
`Dolasetron
`
`
`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.
`
`Pediatrics
`
`
`
`
`
`
`
`In a pediatric clinical trial for the prevention of chemotherapy-induced
`
`
`
`nausea and vomiting 163 cancer patients received a single 20 mcg/kg
`
`
`
`
`(maximum 1.5 mg) intravenous infusion of palonosetron 30 minutes before
`
`
`
`
`
`beginning the first cycle of emetogenic chemotherapy. Patients had a mean
`
`
`
`
`
`
`
`
`
`
`
`
`age of 8.4 years (range 2 months to 16.9 years) and were 46% male; and 93%
`
`white.
`
`
`
`The following adverse reactions were reported for palonosetron:
`
`
`
`Nervous System: <1%: headache, dizziness, dyskinesia.
`
`
`General: <1%: infusion site pain.
`
`
`
`Dermatological: <1%: allergic dermatitis, skin disorder.
`
`
`
`
`
`In the trial, adverse reactions were evaluated in pediatric patients receiving
`
`
`palonosetron for up to 4 chemotherapy cycles.
`
`
`
`
`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 similar. 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
`
`
`
`
`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.
`
`
`Reference ID: 3513457
`
`
`
`
`
`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.
`
`
`DRUG INTERACTIONS
`7
`
`
`
`
`
`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).
`
`
`
`
`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
`
`
`
`Pregnancy Category B
`Risk Summary
`
`
`
`
`
`
`Adequate and well controlled studies with ALOXI have not been
`
`conducted in pregnant women. In animal reproduction studies, no effects on
`
`
`
`
`
`embryo-fetal development were observed with the administration of oral
`
`
`
`
`
`
`palonosetron during the period of organogenesis at doses up to 1894 and
`
`
`
`
`
`3789 times the recommended human intravenous dose in rats and rabbits,
`
`
`
`
`
`respectively. Because animal reproduction studies are not always predictive
`
`
`of human response, ALOXI should be used during pregnancy only if clearly
`
`needed.
`
`
`
`Animal Data
`
`
`In animal studies, no effects on embryo-fetal development were
`
`
`
`
`
`observed in pregnant rats given oral palonosetron at doses up to 60
`
`
`
`mg/kg/day (1894 times the recommended human intravenous dose based on
`
`
`
`
`
`
`body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day
`
`
`
`(3789 times the recommended human intravenous dose based on body
`
`
`
`surface area) during the period of organogenesis.
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`
`
`
`It is not known whether ALOXI is present 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 [see
`
`
`
`Nonclinical Toxicology (13.1)], 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
`
`
`
`Chemotherapy-Induced Nausea and Vomiting
`
`
`
`
`Safety and effectiveness of ALOXI have been established in pediatric
`
`
`
`
`
`
`patients aged 1 month to less than 17 years for the prevention of acute nausea
`
`
`
`
`
`
`
`and vomiting associated with initial and repeat courses of emetogenic cancer
`
`
`
`
`chemotherapy, including highly emetogenic cancer chemotherapy. Use is
`supported by a clinical trial where 165 pediatric patients aged 2 months to
`
`
`
`
`
`<17 years were randomized to receive a single dose of palonosetron 20
`
`
`
`
`mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30
`
`
`
`
`
`
`minutes prior to the start of emetogenic chemotherapy [see Clinical Studies
`
`
`
`
`
`(14.2)]. While this study demonstrated that pediatric patients require a higher
`
`
`
`
`palonosetron dose than adults to prevent chemotherapy-induced nausea and
`
`
`
`vomiting, the safety profile is consistent with the established profile in adults
`
`
`
`
`
`[see Adverse Reactions (6.1)].
`
`
`Safety and effectiveness of ALOXI in neonates (less than 1 month of
`
`
`
`age) have not been established.
`
`
`
`Postoperative Nausea and Vomiting Studies
`
`
`
`
`Safety and efficacy have not been established in pediatric patients for
`
`
`
`
`
`prevention of postoperative nausea and vomiting. Two pediatric trials were
`
`
`
`
`performed.
`
`
`
`Pediatric Study 1, a dose finding study was conducted to compare two
`
`
`
`
`
`
`
`
`
`
`
`
`
`doses of palonosetron, 1 mcg/kg (max 0.075 mg) versus 3 mcg/kg (max 0.25
`
`
`
`
`
`mg). A total of 150 pediatric surgical patients participated, age range 1 month
`
`
`to <17 years. No dose response was observed.
`
`
`
`Pediatric Study 2, a multicenter, double-blind, double-dummy,
`
`randomized, parallel group, active control, single-dose non-inferiority study,
`
`
`
`compared I.V. palonosetron (1 mcg/kg, max 0.075 mg) versus I.V.
`
`
`
`
`ondansetron. A total of 670 pediatric surgical patients participated, age 30
`
`
`
`days to <17 years. The primary efficacy endpoint, Complete Response (CR:
`
`
`
`
`
`no vomiting, no retching, and no antiemetic rescue medication) during the
`
`
`
`
`first 24 hours postoperatively was achieved in 78.2% of patients in the
`
`
`
`palonosetron group and 82.7% in the ondansetron group. Given the pre-
`
`specified non-inferiority margin of -10%, the stratum adjusted Mantel-
`
`Haenszel statistical non-inferiority confidence interval for the difference in
`
`
`the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore
`
`
`
`non-inferiority was not demonstrated. Adverse reactions to palonosetron
`
`
`were similar to those reported in adults (see Table 2).
`
`
`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-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.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3513457
`
`

`

`
`
`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 5630 ± 5480 ng/L and mean AUC was
`
`
`35.8 ± 20.9 h•mcg/L.
`
`
`
`
`
`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 0.160 ±
`
`
`
`
`
`
`
` 0.035 L/h/kg and renal clearance was 0.067± 0.018 L/h/kg. Mean terminal
`
` elimination half-life is approximately 40 hours.
`
`
`
` Specific populations
`Pediatric Patients
`
`Single-dose I.V. ALOXI pharmacokinetic data was obtained from a subset of
`
`
`
`
`pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg. When the
`
`
`
`
`
`
`dose was increased from 10 mcg/kg to 20 mcg/kg a dose-proportional
`
`
`
`increase in mean AUC was observed. Following single dose intravenous
`
`
`
`infusion of Aloxi 20 mcg/kg, peak plasma concentrations (CT) reported at the
`
`
`
`
`
`
`
`
`
`end of the 15 minute infusion were highly variable in all age groups and
`
`
`
`
`tended to be lower in patients < 6 years than in older patients. Median half-
`
`
`
`
`
`life was 29.