`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ALOXI
`INJECTION safely and effectively. See full prescribing information for
`ALOXI INJECTION.
`
`
`-------------------DOSAGE FORMS AND STRENGTHS----------------------
`Injection:
`• 0.25 mg palonosetron in 5 mL (0.05 mg/mL) in a single-dose vial (3)
`• 0.075 mg palonosetron in 1.5 mL (0.05 mg/mL) single-dose vial (3)
`
`ALOXI® (palonosetron HCl) injection, for intravenous use
`Initial U.S. Approval: 2003
`
`-----------------------------CONTRAINDICATIONS------------------------------
`Hypersensitivity to palonosetron or any of its components (4)
`
`------------------------INDICATIONS AND USAGE---------------------------
`ALOXI is a serotonin-3 (5-HT3) receptor antagonist indicated in:
`Adults for prevention of:
`• acute and delayed nausea and vomiting associated with initial and repeat
`courses of moderately emetogenic cancer chemotherapy (MEC). (1)
`• acute nausea and vomiting associated with initial and repeat courses of
`highly emetogenic cancer chemotherapy (HEC). (1)
`• postoperative nausea and vomiting (PONV) for up to 24 hours following
`surgery. Efficacy beyond 24 hours has not been demonstrated (1)
`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 (HEC). (1)
`
`--------------------DOSAGE AND ADMINISTRATION-----------------------
`Chemotherapy-Induced Nausea and Vomiting (2.1)
`Age
`Dose*
`Infusion Time
`0.25 mg as a single dose Infuse over 30
`Adults
`seconds beginning
`approximately 30
`minutes before the start
`of chemotherapy
`Infuse over 15
`minutes beginning
`approximately 30
`minutes before the start
`of chemotherapy
`
`20 micrograms per
`kilogram (maximum 1.5
`mg) as a single dose
`
`Pediatrics
`(1 month to less
`than 17 years)
`
`*Note different dosing units in pediatrics
`
`Postoperative Nausea and Vomiting (2.1)
`• The recommended adult dosage is 0.075 mg as a single intravenous dose
`administered over 10 seconds immediately before the induction of
`anesthesia.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2
`Instructions for Intravenous Administration
`DOSAGE FORM AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity Reactions
`5.2
`Serotonin Syndrome
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Serotonergic Drugs
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Lactation
`8.4
`Pediatric Use
`8.5 Geriatric Use
`
`7
`
`8
`
`6
`
`---------------------WARNINGS AND PRECAUTIONS-------------------------
`• Hypersensitivity reactions, including anaphylaxis and anaphylactic shock:
`reported in patients with or without known hypersensitivity to other
`selective 5-HT3 receptor antagonists. If symptoms occur, discontinue
`ALOXI and initiate appropriate medical treatment. (5.1)
`• Serotonin syndrome: reported with 5-HT3 receptor antagonists alone, but
`particularly with concomitant use of serotonergic drugs. (5.2, 7.1)
`
`----------------------------ADVERSE REACTIONS--------------------------------
`Most common adverse reactions in
`• chemotherapy-induced nausea and vomiting in adults (≥5%) are: headache
`and constipation (6.1)
`• postoperative nausea and vomiting (≥ 2%) are: QT prolongation,
`bradycardia, headache, and constipation. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact HELSINN at
`1-844-357-4668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`---------------------------DRUG INTERACTIONS---------------------------------
`Serotonergic Drugs: Monitor for serotonin syndrome; if symptoms occur,
`discontinue ALOXI and initiate supportive treatment. (7.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`Revised: 04/2020
`
`
`
`
`
`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
`14.1Prevention of Nausea and Vomiting Associated with MEC and
`HEC in Adults
`14.2 Prevention of Nausea and Vomiting Associated with
`Emetogenic Chemotherapy, Including HEC in Pediatric Patients
`14.3 Prevention of Postoperative Nausea and Vomiting in Adults
`16. HOW SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information are
`not listed.
`
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`
`FULL PRESCRIBING INFORMATION
`
`
`
`1.
`
`INDICATIONS AND USAGE
`ALOXI injection is indicated in adults for prevention of:
`• acute and delayed nausea and vomiting associated with initial and repeat courses of moderately
`emetogenic cancer chemotherapy (MEC).
`• acute nausea and vomiting associated with initial and repeat courses highly emetogenic cancer
`chemotherapy (HEC).
`• 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.
`
`ALOXI injection is indicated in pediatric patients 1 month to less than 17 years of age for prevention of:
`• acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer
`chemotherapy, including highly emetogenic cancer chemotherapy.
`
`2. DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`Prevention of Chemotherapy-Induced Nausea and Vomiting
`The recommended dosage of ALOXI injection for prevention of nausea and vomiting associated with
`HEC and MEC in adults and associated with emetogenic chemotherapy, including HEC in pediatric
`patients 1 month to less than 17 years of age is shown in Table 1.
`Table 1: Recommended Dosage of ALOXI Injection for the Prevention of Nausea and Vomiting
`Associated with Chemotherapy in Adults and Pediatric Patients 1 Month to Less than 17 Years
`
`Age
`
`Dose*
`
`Infusion Time
`
`Adults
`
`0.25 mg as a single dose Infuse over 30 seconds beginning approximately 30 minutes
`before the start of chemotherapy
`
`20 micrograms per
`Pediatrics (1
`kilogram (max 1.5 mg)
`month to less
`than 17 years)
`as a single dose
`*Note different dosing units in pediatrics
`
`Infuse over 15 minutes beginning approximately 30 minutes
`before the start of chemotherapy
`
`Postoperative Nausea and Vomiting
`The recommended dosage of ALOXI injection in adults for PONV is 0.075 mg administered as a single
`intravenous dose over 10 seconds immediately before the induction of anesthesia.
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`2.2
`
`Instructions for Intravenous Administration
`• ALOXI injection is supplied ready for intravenous administration at a concentration of 0.05 mg/mL
`(50 mcg/mL).
`• Do not mix ALOXI injection with other drugs.
`• Flush the infusion line with normal saline before and after administration of ALOXI injection.
`• Inspect ALOXI injection visually for particulate matter and discoloration before administration.
`• Discard unused portion.
`
`
`
`3. DOSAGE FORM AND STRENGTHS
`ALOXI injection is sterile, clear, and colorless solution:
`• 0.25 mg palonosetron in 5 mL (0.05 mg/mL) in a single-dose vial
`• 0.075 mg palonosetron in 1.5 mL (0.05 mg/mL) in a single-dose vial
`
`4. CONTRAINDICATIONS
`ALOXI is contraindicated in patients known to have hypersensitivity to palonosetron [see Warnings and
`Precautions (5.1)].
`
`5. WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity Reactions
`Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with
`administration of ALOXI injection [see Adverse Reactions (6.2)]. These reactions occurred in patients
`with or without known hypersensitivity to other 5-HT3 receptor antagonists. If hypersensitivity reactions
`occur, discontinue ALOXI injection and initiate appropriate medical treatment. Do not reinitiate ALOXI
`injection in patients who have previously experienced symptoms of hypersensitivity [see
`Contraindications (4)].
`5.2 Serotonin Syndrome
`The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports
`have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake
`inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase
`inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the
`reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor
`antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3
`receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.
`Symptoms associated with serotonin syndrome may include the following combination of signs and
`symptoms: mental status changes (e.g. agitation, hallucinations, delirium, and coma), autonomic
`instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia),
`neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with
`or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for
`the emergence of serotonin syndrome, especially with concomitant use of ALOXI and other serotonergic
`drugs. If symptoms of serotonin syndrome occur, discontinue ALOXI and initiate supportive treatment.
`Patients should be informed of the increased risk of serotonin syndrome, especially if ALOXI is used
`concomitantly with other serotonergic drugs [see Drug Interactions (7.1)].
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`6. ADVERSE REACTIONS
`Serious or otherwise clinically significant adverse reactions reported in other sections of labeling:
`• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
`• Serotonin Syndrome [see Warnings and Precautions (5.2)]
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`Chemotherapy-Induced Nausea and Vomiting
`Adults
`
`In double-blind randomized clinical trials for the prevention of nausea and vomiting induced by MEC or
`HEC, 1374 adult patients received a single dose of ALOXI injection, ondansetron (Studies 1 and 3) or
`dolasetron (Study 2) administered 30 minutes prior to chemotherapy [see Clinical Studies (14.1).
`Adverse reactions were similar in frequency and severity in all 3 treatment groups. Common adverse
`reactions reported in at least 2% of patients in these trials are shown in Table 2.
`Table 2: Common Adverse Reactions* in Adults with Receiving MEC (Studies 1 and 2) or HEC
`(Study 3)
`
`Dolasetron
`100 mg
`intravenously
`(N=194)
`16%
`6%
`2%
`2%
`2%
`2%
`2%
`
`Ondansetron
`32 mg
`intravenously
`(N=410)
`8%
`2%
`2%
`2%
`1%
`< 1%
`1%
`
`ALOXI injection
`0.25 mg
`intravenously
`(N=633)
`9%
`Headache
`5%
`Constipation
`1%
`Diarrhea
`1%
`Dizziness
`< 1%
`Fatigue
`< 1%
`Abdominal Pain
`< 1%
`Insomnia
`* Reported in at least 2% of patients in any treatment group
`Less common adverse reactions, reported in 1% or less of patients, in Studies 1, 2 and 3 were:
`• Cardiovascular: non-sustained tachycardia, bradycardia, hypotension, hypertension, myocardial
`ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT
`prolongation.
`• Dermatological: allergic dermatitis, rash
`• Hearing and Vision: motion sickness, tinnitus, eye irritation and amblyopia
`• Gastrointestinal System: diarrhea, dyspepsia, abdominal pain, dry mouth, hiccups and flatulence
`• General: weakness, fatigue, fever, hot flash, flu-like syndrome
`• Liver: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred
`predominantly in patients receiving highly emetogenic chemotherapy
`• Metabolic: hyperkalemia, electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria,
`appetite decrease, anorexia
`• Musculoskeletal: arthralgia
`• Nervous System: dizziness, somnolence, insomnia, hypersomnia, paresthesia
`• Psychiatric: anxiety, euphoric mood
`• Urinary System: urinary retention
`• Vascular: vein discoloration, vein distention
`
`
`Adverse Reaction
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`In other studies, 2 subjects experienced severe constipation following a single ALOXI injection dose of
`approximately 0.75 mg (three times the recommended dose).
`Pediatrics Aged 2 Months to 17 Years
`In a pediatric clinical trial, 163 pediatric cancer patients with a mean age of 8 years received a single 20
`mcg/kg (maximum 1.5 mg) intravenous infusion of ALOXI injection 30 minutes before beginning the
`first cycle of emetogenic chemotherapy [see Clinical Studies (14.2)]. Adverse reactions were evaluated in
`pediatric patients receiving ALOXI injection for up to 4 chemotherapy cycles. The following adverse
`reactions were reported in less than 1% of patients:
`• Nervous System: headache, dizziness, dyskinesia.
`• General: infusion site pain.
`• Dermatological: allergic dermatitis, skin disorder.
`Postoperative Nausea and Vomiting
`The most common adverse reactions reported in at least 2% of adults receiving ALOXI injection 0.075
`mg intravenously immediately before induction of anesthesia in 3 randomized placebo-controlled trials
`[see Clinical Studies (14.3)] are shown in Table 3. Rates of adverse reactions between ALOXI injection
`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. A
`thorough QT/QTc study demonstrated ALOXI injection does not prolong the QT interval to any clinically
`relevant extent [see Clinical Pharmacology (12.2)].
`Table 3: Common Adverse Reactions* in Trials of Adults with Postoperative Nausea and Vomiting
`ALOXI injection
`0.075 mg
`intravenously
`(N=336)
`5%
`4%
`3%
`2%
`
`Adverse Reaction
`
`Placebo
`(N=369)
`
`
`
`3%
`4%
`4%
`3%
`
`Electrocardiogram QT prolongation
`Bradycardia
`Headache
`Constipation
`* Reported in at least 2% of patients in any treatment group
`Less common adverse reactions, reported in 1% of less of patients, in these PONV clinical trials were:
`• Cardiovascular: QTc prolongation, sinus bradycardia, tachycardia, 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: pruritus
`• Gastrointestinal System: flatulence, dry mouth, upper abdominal pain, salivary hypersecretion,
`dyspepsia, diarrhea, intestinal hypomotility, anorexia
`• General: chills
`• Liver: increases in AST and/or ALT, hepatic enzyme increased
`• Metabolic: hypokalemia, anorexia
`• Nervous System: dizziness
`• Respiratory: hypoventilation, laryngospasm
`• Urinary System: urinary retention
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`6.2 Postmarketing Experience
`The following adverse reactions have been identified during postapproval use of palonosetron HCl.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not always
`possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
`• Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus,
`rash, urticaria, anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1)]
`• Injection site reactions: including burning, induration, discomfort and pain
`
`
`
`7. DRUG INTERACTIONS
`7.1 Serotonergic Drugs
`Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular
`symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other
`serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and
`noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If
`symptoms occur, discontinue ALOXI and initiate supportive treatment [see Warnings and Precautions
`(5.2)].
`
`8. USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`There are no available data on palonosetron HCl use in pregnant women to inform a drug-associated risk.
`In animal reproduction studies, no effects on embryo-fetal development were observed with the
`administration of oral palonosetron HCl during the period of organogenesis at doses up to 1,894 and 3,789
`times the recommended human intravenous dose in rats and rabbits, respectively (see Data).
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
`Data
`Animal Data
`In animal reproduction studies, no effects on embryo-fetal development were observed in pregnant rats
`given oral palonosetron HCl at doses up to 60 mg/kg/day (1,894 times the recommended human
`intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day
`(3,789 times the recommended human intravenous dose based on body surface area) during the period of
`organogenesis.
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`8.2 Lactation
`Risk Summary
`There are no data on the presence of palonosetron in human milk, the effects of palonosetron on the
`breastfed infant, or the effects of palonosetron on milk production. The developmental and health benefits
`of breastfeeding should be considered along with the mother’s clinical need for ALOXI and any potential
`adverse effect on the breastfed infant from palonosetron or from the underlying maternal condition.
`8.4 Pediatric Use
`Chemotherapy-Induced Nausea and Vomiting
`Safety and effectiveness of ALOXI injection 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 HEC. Use is supported by a clinical trial where
`165 pediatric patients aged 2 months to less than 17 years were randomized to receive a single dose of
`ALOXI injection 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 effectiveness 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
`(maximum 0.075 mg) versus 3 mcg/kg (maximum 0.25 mg). A total of 150 pediatric surgical patients
`participated, age range 1 month to less than 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 intravenous palonosetron HCl (1 mcg/kg, maximum 0.075
`mg) versus intravenous ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to
`less than 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.
`8.5 Geriatric Use
`Of the 1374 adult cancer patients in clinical studies of intravenously administered palonosetron HCl, 316
`(23%) were 65 years and over, while 71 (5%) were at least 75 years and over. Of the 1520 adult patients
`in clinical studies of intravenously administered palonosetron HCl, 73 (5%) were at least 65 years old [see
`Clinical Studies (14.1, 14.3)]. No overall differences in safety or effectiveness were observed between
`these subjects and younger subjects, but greater sensitivity in some older individuals cannot be ruled out.
`Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics
`between cancer patients 65 years of age and older compared to younger patients [see Clinical
`Pharmacology (12.3)]. No dose adjustment is required for geriatric patients.
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`10. OVERDOSAGE
`There is no known antidote to palonosetron. Overdose should be managed with supportive care.
`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 HCl 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) injection contains palonosetron as palonosetron HCl, 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 a 5 mL or 1.5 mL single-dose vial.
`Each 5 mL vial contains: 0.25 mg palonosetron (equivalent to 0.28 mg palonosetron HCl), 207.5 mg
`mannitol, disodium edetate and citrate buffer in water for intravenous administration.
`Each 1.5 mL vial contains: 0.075 mg palonosetron (equivalent to 0.084 mg palonosetron HCl), 62.25 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
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`nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively
`participate in the emetic response.
`12.2 Pharmacodynamics
`Cardiac Electrophysiology
`The effect of intravenous palonosetron on blood pressure, heart rate, and ECG parameters including QTc
`were comparable to intravenous 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.
`At a dose of 9 times the maximum recommended adult dose, ALOXI injection does not prolong the QT
`interval to any clinically relevant extent.
`12.3 Pharmacokinetics
` After intravenous dosing of palonosetron HCl in healthy subjects and cancer patients, an initial decline in
`palonosetron 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 to 90 mcg/kg in healthy subjects and in cancer patients. Following
`a single intravenous dose of palonosetron HCl 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 intravenous administration of ALOXI injection 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 intravenous administration of ALOXI injection 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 ALOXI injection 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.
`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.
`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.
`
`Reference ID: 4584815
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`9
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`Specific Populations
`Pediatric Patients
`Pharmacokinetic data was obtained from a subset of pediatric cancer patients that received 10 mcg/kg or
`20 mcg/kg as a single intravenous dose of ALOXI injection. When the dose was increased from 10
`mcg/kg to 20 mcg/kg a dose-proportional increase in mean AUC was observed. Peak plasma
`concentrations (CT) reported at the end of the 15-minute infusion of 20 mcg/kg were highly variable in all
`age groups and tended to be lower in patients less than 6 years than in older patients as shown in Table 4.
`The median half-life was 30 hours in overall age groups and ranged from about 20 to 30 hours across age
`groups after administration of 20 mcg/kg.
`The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There
`are no apparent differences in volume of distribution when expressed as L/kg.
`Table 4: Pharmacokinetics Parameters in Pediatric Cancer Patients following Intravenous Infusion
`of 20 mcg/kg ALOXI Injection Over 15 minutes
`
`PK Parameter a
`
`12 years
`to less than
`17 years
`N=44
`11831 (176)
`N=10
`124.5 (19.1)
`N=19
`0.16 (27.8)
`6.20 (29.0)
`
`Pediatric Age Group
`2 years
`6 years
`Less than
`to less than
`to less than
`2 years
`6 years
`12 years
`N=42
`N=38
`N=12
`
`CT b, ng/L
`9414 (252)
`16275 (203)
`9025 (197)
`N=5
`N=7
`
`
`AUC0-∞,
`103.5 (40.4)
`98.7 (47.7)
`
`h·mcg/L
`N=14
`N=13
`N=6
`
`Clearance c,
`0.23 (51.3)
`0.19 (46.8)
`0.31 (34.7)
`L/h/kg
`Vss c, L/kg
`5.29 (57.8)
`6.26 (40.0)
`6.08 (36.5)
`a Geometric Mean (CV) except for t1/2 which is median values
`b CT is the plasma palonosetron concentration at the end of the 15-minute infusion
`c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted
`Racial or Ethnic Groups
`The pharmacokinetics of palonosetron were characterized in 24 healthy Japanese subjects over an intravenous
`dose range of 3 to 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites,
`however, this increase is not considered to be clinically meaningful.
`Patients with Renal Impairment
`Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters.
`Total systemic exposure increased by approximately 28% in patients with severe renal impairment relative to
`healthy subjects. This increase is not considered clinically meaningful.
`Patients with Hepatic Impairment
`Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy
`subjects.
`Drug Interaction Studies
`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.
`
`Reference ID: 4584815
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`Dexamethasone
`Coadministration of 0.25 mg ALOXI injection and 20 mg dexamethasone administered intravenously in
`healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.
`Oral Aprepitant
`In an interaction study in healthy subjects where a single 0.25 mg intravenous dose of ALOXI injection 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).
`Metoclopramide
`A study in healthy subjects involving a single 0.75 mg intravenous dose of ALOXI injection and steady state
`oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.
`Corticosteroids, Analgesics, Antiemetics/Antinauseants, Antispasmodics and Anticholinergic Agents
`In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics,
`antiemetics/antinauseants, antispasmodics and anticholinergic agents.
`
`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
`HCl 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 h•mcg/L) 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/k