HIG HLI(;‘H'I‘S OI-' I'RES(.'RIBIN(;‘ IN I"0R.\IA'I'ION
`These highlights do not Include all the Information needed to use ALOXI
`safely and etTectivel_\'. See full prescribing Information for ALOXI
`
`-------------------DOSAGE FOR.\‘IS AND SI‘REN(:"I'HS---—----—--------—----
`0.25 mgs‘5ml (free base) single-use vial (3)
`0.075 mg.‘1,5ml (free base) single-use vial (3)
`
`.........................."C05;'1'RA1y1)[(;A'f[()Ns-....-..-...--_-.-.-....._-.-.
`ALOXI is contraindicated in patients known to have liypersensitivity to the
`drug or any of its components (4)
`
`--------------------WARNINGS AND PRECAUTIONS-----u------------------
`0
`I-I_\t'pcrsensitivit_v reactions may occur in patients who have exhibited
`ll)‘]')Cr‘SCItS1Il\’ll)' to other selective 5-IIT3 receptor antagonists (5.1)
`
`-------------------------- --Al)\'F.RSl-I RE;-\(.'Tl()NS--------------------------------
`The most common adverse reactions in cltemotherap_V-induced nausea and
`vomiting (incidence -_=5°o) are headache and constipation (6.1)
`
`Hie most common adverse reactions in postoperative nausea and vomiting
`(incidence 1: 2° o) are QT prolongation. bradycardia. headache. am!
`constipation.
`
`To report SUSPECTED ADVERSE REA(."I‘IONS, contact MGI
`PI-l.=\RMA at 1-800-562-5580 or FDA at l-800-FDA-1088 or
`wnw.I‘da.gov/metlw atch.
`
`—----————j--DRUG INTERA(‘TIONS----Z--—-———---Zn
`The potential for clinically significant drug interactions with palonosetron
`appears to be low (7)
`
`-—--------------- USE IN SPECIFIC POPIQLATIONS ------------------------
`Sat’et_\' and effectiveness in patients below the age of 18 years have not been
`established (8.4)
`
`See 17 for PATIENT (TOUNSELING INFORMATION and FDA-
`approvcd Patient Labeling
`
`Revised: 02/2008
`
`14
`
`13.1 Carcinogenesis. Nlulagertesis. Impainnent of FeI1ilit_\-'
`(TLINICTAL STUDIES
`14.1 Chemotherap}-‘—1nduced Nausea and Vomiting
`14.2
`Po.stoperati\'e Nausea and \>"on1iting
`16 HO\\' SUPPLIED/STORAGE AND HANDLING
`17
`PATIENT COUNSELING INFORMATION
`17.1
`Instructions for Patients
`17.2
`FD.»\-.»'\ppro\'ed Patient Labeling
`
`* Sections or subsections omitted from the full prescribing inlbnnation are
`not listed.
`
`AIJ()XI"° (palonosetmn IICI) Injection for Intravenous Use
`Inltlul
`A[Ipr0\t|I: 2003
`——————————————————————«RECENT MAJOR
`Indications and llsage.
`Postoperative Nausea and Vomiting (1.2)
`Dosage and Administration.
`Rccommcndcd Dosing (2.1)
`Wamings and Precautions.
`QTc Intervals (5.2) - Deletion
`
`022008
`
`022008
`
`02"‘2008
`
`——------------in-lNI)l(7A'l‘l()NS AND IISAGE-——-----————-:
`ALOXI is 21 serotonin subtype 3 (5-HT3) receptor antagonist indicated for:
`0
`Moderately-' emetogenic cancer c1ien1othcrapy-- prevention of
`acute and delayed nausea and vomiting associated with initial and
`repeat courses (1.1)
`Hig,hl_\v' emetogenic cancer clieiitotlierapy -- prevention of acute
`nausea and vomiting associated with initial and repeat courses
`(1-1)
`Prevention ofpostoperativc nausea and vomiting (PON V) for up
`to 24 hours following surgery. F.t'ficac_v beyond 24 hours has not
`been demonstrated (1.2)
`
`0
`
`0
`
`--------------------I)()SAGF. AND ADNIINIS'l‘RA'l‘l0N-----------------------
`(.‘l1en1otherapy-Induced .\lausea and Voiniting (2.1)
`0
`Adult Dosage: a single 0.25 mg l.V’. dose administered over 30
`seconds. Dosing should occur approximately 30 minutes before the
`stan of chemotherapy.
`
`Postoperative Nausea and Vomiting (2.1)
`0
`Adult Dosage: a single 0.075 mg I.\-’. dose administered over 10
`seconds iiinnediately before the induction of anesthesia.
`
`FULL PRESCRIBINC INFORMATION: CONTENTS’
`
`I
`
`2
`
`INDICATIONS AND USAGE
`1.1
`Cliemotlierapy-Induced Nausea and Vomiting
`1.2
`Postoperative Nausea and Vomiting
`DOSAGE AND ADMINISTRATION
`21
`Recommended Dosing
`2.2
`Instructions for 1.\". Adntinistration
`l)()SA(:F, FORMS AND S'I‘Rl<‘,l\'(;'l‘lIS
`(‘0.‘lTRAINDI(‘ATI()1\'S
`WARNINGS AND PRECAUTIONS
`5. 1
`Hypersensitivit_v
`ADVERSE Rl7.A(.'l‘IONS
`6.1
`C11emotlierapy-Induced Nausea and Vomiting
`6.2
`Postoperative Nausea and V"omiting
`6.3
`Postmarkcting Experience
`DRUG I.VTF.RA('I'IONS
`USE IN SPECIFIC‘ POPULATIONS
`8.1
`Pregnancy Teratogenic Effects
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.-'1
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impainnent
`8.7
`Hepatic lmpainnenl
`8.8
`Race
`10 O\"I:ZRDOSl:'.
`ll DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanisrn of .-\ction
`I 2 .2 Phamiacodynamics
`12.3 Pharmacokinetics
`_\'ONCLINICAL TOXICOLOCY
`
`UIJ-bi
`
`6
`
`W4
`
`13
`
`Page 1 of 8
`
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PG R2016—00007
`
`Helsinn Healthcare Exhibit 2054
`
`

`
`FULL PRESCRIBING INFORMATION
`
`I
`
`2
`
`3
`
`4
`
`INDICATIONS AND USAGE
`1.1 Chemotherapy-lnducerl Nausea and Vomiting
`ALOXI is indicated for:
`o
`Moderatelv emetogenic cancer chemotherapy -- prevention of
`actite and delayed nausea and vomiting associated with initial and
`reveal
`nausea and vomiting associated with initial and repeal courses
`»os»o»mn~e«~a-ma
`ALOXI is indicated for:
`the prevention ofpostoperative nausea and vomiting (P()N\") for
`0
`"P '° 24 ‘W "°"°“'*"g
`E“‘°“°>' '*=>'°'"* 24
`has
`"°"’°‘"'de"'°"s
`d‘
`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. .'-\I .()Nl
`-.
`_
`d
`,
`,
`-3* .
`.
`-.
`‘
`:T::;inegdi:‘l::£~here the mu‘ em: ofposiopemme nausea
`"
`DOSAGE AND ADMINISTRATION
`2.};ml§;]€e0|m'm“'l3:::‘:el:°I::Eea and vommng
`Dosage for Adults — a single 0.25 mg LV. dose administered over 30
`seconds. Dosing should occur approximately 30 minutes before the
`Stan of chemotherapy
`Posto crative Nausea and Voinitin
`Dosage For Adults - a single 0.075 mg l.V. dose administered over I0
`seconds ininiediately before the induction of anesthesia.
`
`lmtrudions for L“ Adminisuaflon
`2.2
`ALOXI is supplied ready for intravenous injection. ALOXI should not
`be mixed with other drugs. Flush the infusion line with nonnal saline
`before and an” administmion of ALOXL
`Parenteral dnig products should be inspected V'iSlIall_V for particulate matter
`and discoloration before administration. whenever solution and
`‘
`»
`‘
`, I
`wmanm pmm
`DOSAGE FORM AND STRENGTHS
`ALOXI is supplied as a single-use sterile. clear. colorless solution in
`glass was that provide:
`.
`25 mg (hie aw) Per 5 ml
`o
`0.075 mg (tree base) per 1.5 ml.
`
`.
`.
`.
`_
`.
`CON1:R.‘uNDI(._‘w."0N$
`ALOM is contraindicated in patients known to have hypersensitn-'it_v to
`the drug or any of its components.
`[see Adverse Reactions (6..?)]
`
`5 WARNINGS AND PRECAUTIONS
`
`.
`.
`.
`.
`5'1 H3.P‘i'i“ins'h“t‘l'
`lI_vpersensitivit_v reactions l1I2l_V' occur in patients who have exhibited
`h_\perseiLsi1ivit_v to other 5-HT; receptor antagonists.
`
`6
`
`ADVERSE REACHONS
`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 rellect the rates obsen-‘ed in practice.
`
`6.1 Chemotherapy—Induced Nausea and Vomiting
`
`In clinical trials for the prevention of nausea and vomiting induced by
`inodcratcly or highly cmctogeiiic chcniothcrapy. I374 adult patients received
`palonosetron. Adverse reactions were similar in freqiieiicy and severity with
`ADOXI and ondansetron or dolasetron. Following is a listing of all adverse
`reactions reported by 2 2% of patients in these trials (Table 1).
`
`Page 2 of 8
`
`Table 1: Adverse Reactions from (.‘li(-motlierapy-Inrluct-d Nausea and
`Vomiting Studies 2 2% in any Treatment Group
`Event
`ondanmron
`
`Dolaseuon
`
`M“. 015 mg
`(N=633)
`
`33 mg 1-“
`(N=“0)
`
`100 mg 1-"-
`03:19‘)
`
`'1-«~d«~ch-
`
`.
`
`.
`
`c
`
`
`
`3 (1%)
`
`.
`
`.
`
`.
`
`.
`.
`.
`tc}:nst;P'é:l:nuf°l]°w'ng a
`qhgl
`ecie..
`‘e
`._i
`e
`..c
`e
`.
`.
`.e_'.
`.
`recommended dose. One patient received a 10 mcgfkg 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.
`zlt'1:I\\::?]t'SC‘l'CaC‘il0nS.d
`' I:dc1l‘iilii'ca'|‘ trials. the following iiil'reqtti:ntl)'
`mm’ °".“u"e
`3s’.
`-l'dln‘.ei"gm.°r$ 3:. ‘relmlgelmqle:1: °r.°ausa I
`0 omng n mmlsmmon O '
`‘
`‘D a u pauems recewmg concommmt
`cancer chemotherapy:
`,
`I
`.
`‘ W
`,
`_
`,
`.
`I
`‘
`.
`K _
`fT‘1lr‘fi'f)l‘la$”‘ul‘j" ,10°‘ n°"1"s‘:“:!tf"'l"fa"d‘l1“"‘”l1:\'wfdm‘ biadf carldla‘
`E.
`“°’ W"m'n.s'°n‘ myow .'a '5” mug‘ "mms3' “O
`“nus ml‘ .'l ‘a la‘
`sinus arrhythmia. supraventricular extrasystoles and QT prolongation.
`In
`many‘ cases, the relationship to ALO.\.I was unclear.
`_
`'
`,
`_
`,
`D"""am|°g"'al‘
`1%‘ antrgk d"mmm'S’ mfih‘
`.
`:'—
`‘'0:
`‘c’
`K.’
`._'
`Hearing and Vision ‘ 1° motion si kness tinnitus ese irritation and
`ambl~V°p'a'
`Gqsunimesfinal Svstem lo ‘ dhnhea‘ V
`4
`.
`_
`.
`.-o.
`t
`mouth. hiccups and flatulence.
`.
`_
`.
`_,
`_
`_,
`1%‘ fimgw’ fever‘ hm flash’ H“'1'!” syndrome’
`General’ 1%‘ ‘waknflkl-‘
`Liver‘ -1 1%‘ transient asmtptomatic increases in AST aiid’or ALT and
`hiliruhiii. These changes occurred predominaiitlv in patients receiving highly
`emelogenjc chemmhempv
`'
`
`,.
`
`10 _ dvsptpsia 1bdominal pain dw
`‘o.
`_
`.«
`.
`_
`
`Metabolic: 1%: hyperkalemia. ‘'11 1%: electrolyte lluctuations. hyperglycemia.
`metabolic acidmifi
`lwmuria 3 mm demmw a"m_“ia
`'
`i ’ g '
`i
`’ W
`I
`i
`i
`i
`..
`s vs. 9‘;
`'.
`I‘ 1““"'°““ "ml"
`'
`‘’ ‘"""‘‘'g’“
`
`Nervous System: 1%: diuiiiess.
`aresthesia
`
`l°-o: somnolence. iiisonuiia. l1\’p€t'St)llll1l21,
`'
`
`'
`p
`'
`l
`'.~'Ii 1°":
`l’. 'l't' :l°v':.
`o eup ioric moo
`syc iia ric
`o '|l1\Iel_V
`Urinary System:
`1%: urinary retention.
`
`d.
`
`Vascular: =1 1%: vein discoloration. vein distention.
`
`6.2 Postoperative Nausea and Vomiting
`
`lhe adverse reactions cited in Table 2 were reported in 3' 2% of adults
`receiving I.V. Aloxi 0.075 mg iininediatel)-' 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 ofpalonosetron effect
`on QT.-'QTc.
`
`

`
`Table 2: Adverse Reactions from Postoperative Nausea and Vomiting
`Studies 2 2% in any Treatment Group
`Alo xi 0.075 mg
`Placebo
`
`Event
`
`(N-336)
`
`(N-369)
`
`Electrocardiogram
`QT prolongation
`
`Headache
`
`I6 (.">°.v'o)
`
`I l (3%)
`
`Constipation
`
`In these clinical trials. the following infrequently reported adverse
`reactions. assessed by investigators as treatment-related or causality
`unknown. occurred following administration of .—’\l.OXI to adult patients
`receiving concomitant perioperative and intraoperative medications including
`those associated with anesthesia:
`
`Cardiovascular: 1"-o Electrocardiogam QTc prolongation. sinus bradycardia.
`tachycardia‘.
`1%: blood pressure decreased. hypotension. hypertension.
`arrhythmia. ventricular cinrasvstoles. 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%: pmritus.
`
`1%: Dry mouth. upper abdominal
`Gastrointestinal S_vstem: 1%: flatulence,
`pain. salivary hypersecretion. dyspepsia. diarrhea. intestinal hypomotility.
`anorexia.
`
`General:
`
`1%: chills.
`
`Liver: 1%: increases in AST and.v'or z-\I,'l'-=3 l"«o: hepatic enzyme increased
`
`Metabolic: ~'—' 1%: hypokalemia. anorexia.
`
`Nervous System; <1 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.
`
`\-‘cry rare cases ("I 1 .' 10.000) of hypersensitivity reactions and injection
`site reactions (buming. induration, discomfort and pain) were reported from
`poslmarketing 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 vrtro studies indicated that palonosetron is not an inhibitor of
`CYP1A2. CYP2A6, CYP2B6, CYl’2C9. CYPZDG. CYP2E1 and CYP3;-\4.v"5
`(CYPZCI9 was not investigated) nor does it induce the activity of CYP1A2.
`CYPZD6. or CYP3A4»5. Therefore. the potential for clinically significant
`dnrg interactions with palonosetron appears to be lo\v.
`
`Coadministration of 0.25 mg I.\'. palonosetron and 20 mg I.V'.
`dexamcthasone in healthy subjects revealed no pharmacokinetic drug-
`interactions between palonosetron and dexamethasone.
`
`In an interaction study in healthy subjects where palonosetron 0.25 mg
`(LV. bolus) was administered on day I and oral aprepitant for 3 days (125
`nrgi“80 mg."80mg). the pharmacokinetics of palonosetron were not
`significantly altered (AIIC : no change. Cmax: 15% increzse).
`
`Page 3 of 8
`
`A study in healthy volunteers involving single-dose I.\~'. 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. antiemeticsiantinauseants.
`antispzsmodics and anticholinergic agents.
`
`Palonosetron did not inhibit the antitumor activity of the live
`chemotherapeutic agents tested (cisplatin. cyclophosphamide. cytarabine.
`doxorubicin and mitomycin C) in murinc tumor models.
`
`8
`
`USE IN SPE(.‘lFI(.‘ POPULATIONS
`8.1 Pregnancy
`Tcratogcnic l{fTccts: Category B
`Teratology studies have been perfomied 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;kgv"da_v (3789 times
`the recommended human intravenous dose based on body surface area) and
`have revealed no evidence ofimpaired 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 ofhuman response. palonosetron should be used during pregnancy
`only ifclearly 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 hlotlrers
`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 phamiacokinetics between cancer patients 2 65 years of age and
`younger patients (18 to 64 years). Of the 1374 adult cancer patients in
`clinical studies of palonosetron, 316 (23%) were 2 65 years old, while 71
`(5%) \\ ere 2 75 years old. No overall differences in safety or effectivetless
`were observed between these subjects and the younger subjects. but greater
`sensitivity in some older individuals cannot be nrled out. No dose
`adjustment or special monitoring are required for geriatric patients.
`
`Ofthe 1520 adult patients in Alosi PONV-' clinical studies. 73 (5%)
`were 265 years old. No overall differences in safety were obsenred between
`older and younger subjects in these studies, though the possibility of
`heightened sensitivity in some older individuals cannot be excluded. No
`ditferenccs in efficacy were obscwed in geriatric patients for the CINV’
`indication and none are expected for geriatric PONV’ patients. However.
`Aloxi efticacy in geriatric patients has not been adequately evaluated.
`
`8.6 Renal lmpainnent
`Mild to moderate renal impairment does not significantly alfect
`palonosetron pharmacokinetic parameters. Total systemic exposure
`increased by approximately 28% in severe renal impainnent relative to
`healthy subjects. Dosage adjustment is not rteoessary in patients with airy
`degee of renal impainnent.
`
`Ilepntic lmpainnent
`8.7
`Hepatic impaimient 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 megikg.
`
`

`
`Total body clearance was 25% higher in Japanese subjects compared to
`Whites. however, no dose adjustment is required. The phannacokinetics of
`palonoselron in Blacks has not been adequately cliaracteiized.
`
`the Q'l‘c 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.
`
`10 OVERDOS.-\GE
`There is no known antidote to Al,OXI_ Overdose sltould be managed
`with supportive care.
`
`Fifly 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 he 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.
`
`1] DESCRIPTION
`Al.( )X| (palonosetron hydrochloride) is an antiemetic and antinauseant
`agent. It is a serotonin subtype 3 (5-H'l‘;) receptor antagonist with a strong
`binding affinity for this receptor. Chemically. palonosetron hydrochloride is:
`(3a§)-2-[(S_‘)-1-Azabicyclo [2.2.2]oct-3-yl]-2.3.3a.4.5.6- hcxahydro- l -oxo-
`1Hbcnz[de]isoquinolinc hydrochloride. The empirical fomiula is
`C|9HuN30.HCl, with a molecular weight of 332.87. Palonosetnon
`hydrochloride exists as a single isomer and has the following structural
`fomiulaz
`
`-
`1
`t
`/"\.
`3,
`§_ &x..-%»./
`(1 .2
`*
`‘:” Y.”
`K‘/l
`"
`
`t-:2
`
`Palonoselron hydrocliloride is a white to off-wltite 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 pyrogeuic. 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 h_vdrocl1loride_. 207.5 mg mzuuiitol,
`disodium edetate and citrate buffer in water for intravenous administration.
`Each 1.5 mL vial contains 0.075 mg palonosetron base as
`hydrochloride. 83 mg mannitol, disodium edetate and citrate butter in water
`for intravenous administration.
`The pH ofthe solution in the 5 rnL and 1.5 mL vials is 4.5 to 5.5.
`
`12
`
`(.‘LI.\'l(.‘AL PHARMACOLOGY
`12.] Mechanism of Action
`Palonosctron is a 5-HT‘ 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-HT; receptors are located on the nerve tenninals 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 cntcrochromaflin cells of the small
`intestine and that the released serotonin then activates 5-HT; 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 gzmrointcstinal tract. The 5-ll'l's receptor has been dcmonstrated to
`selectively panicipate in the emetic response.
`
`12.2 Phannacodynamics
`'lhe effect of palonosetron on blood pressure. heart rate. and l-ECG
`parameters including QT»: were comparable to ondansetron and dolaselron in
`CINV’ clinical trials.
`In PONV clinical trials the effect of palonosetron on
`
`The effect of palonosetron on Q'l‘c interval was evaluated in a double
`blind. randomized. parallel. placebo and positive (moxilloxacin) controlled
`trial in adult men and women. The objective was to evaluate the ECG effects
`of I.\'. 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 Pharlnacoklnetlcs
`Alter intravenous dosing ofpalonosetron in healthy subjects and cancer
`patients. an initial decline in plasma concentrations is followed by a slow
`climination from the body.
`.\'lean maximum plasma concentration (Cam) and
`area under the concentration-time curve (.'-\UC¢,..,) are generally dose-
`proportional over the dose range of 0.3 90 meg.-‘kg in healthy subjects and in
`cancer patients. Following single l.V". dose ofpalonosetron at 3 mcg.-“Kg (or
`0.21 mg«'70 kg) to six cancer patients. mean (iSD) maximum plasma
`concentration was estimated to be 5.6 1' 5.5 ngfml. and mean .'~\llC was 35.8
`2 20.9 ngohr.-'mL.
`
`Following l.V". administration of palonosetron 0.25 mg once every
`other day for 3 doses in 11 cancer patients, the mean increase in plasma
`palonosetron concentmtion from Day 1 to Day 5 was 42:34%. Following
`I.\’. administration of palonosctron 0.25 mg once daily for 3 days in 12
`healthy subjects. the mean (+81)) increase in plasma palonosetron
`concentration from Day 1 to Day 3 was 1 l0i459"o.
`
`Afier intravenots dosing ofpalonosetron in patients undergoing
`surgery (abdominal surgery or vaginal hysterectomy). the phannacokinetic
`characteristics of palonosetron were similar to those observed in cancer
`patients.
`
`Distribution
`Palonosctron has a volume of distribution of approximately 8.3 i
`2.5 Iikg. Approximately 62"-‘o of palonosetron is bound to plasma proteins.
`
`Metabolism
`Palonosetron is eliminated by multiple routes with approximately 50%
`metabolized to fomi two primary metabolites: N-oxide-palonosetron and 6-S-
`hydroxy-palonosetron. These metabolites each have less than 1% of the 5-
`HT_; receptor antagonist activity of palonosetron. In vitro metabolism studies
`have suggested that CYP2D6 and to a lesser extent. CYP3A4 and CYP l A2
`are involved in the metabolism of palonosetron. However. clinical
`pharmacokinetic parameters are not significantly different between poor and
`cxtcmive metabolizers of CYl’2D6 substrates.
`
`After a single intravenous dose of 10 mcglkg ["C]-palonosetron.
`approximately 80% ol'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 palonosctron was 160 1 35
`mL-'11-"kg and renal clearance was 66. Si 18.2 ml.2‘l1r‘kg.
`l\-‘lean terminal
`elimination half-life is approximately 40 hours.
`
`Special Populations
`[See USE IN SPECIFIC POPUL.-ITIONS (8.5 — 8.8}
`
`13
`
`l\'0N(.‘l.lNl(.‘.-\l.TOXl(f0l.0(lY
`13.1 Carcinogenesis, Nlutagenesls, Impairment ol'FeI1lllty
`In a 104-week carcinogenicity study in C Di mice. animals were
`treated with oral doses of palonosctron at I0. 30 and 60 mgxkg-“da_v.
`Treatment with pal onosetron was not tumorigenic. The highest tested dose
`produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to
`289 times the human exposure (.=\L'C-V 29.8 ngoh«’mL) at the recommended
`intravenous dose of 0.25 mg. In a 104-week carcinogenicity study in
`Sprague-Dawley rats. male and female rats were treated with oral doses of
`15. 30 and 60 mg“kgxda_v and 15. 45 and 90 mgakg.-‘da_v. respectively. The
`highest doses produced a systemic exposure to palonosctron (Plasma AUC)
`of 137 and 308 times the human exposure at the recommended dose.
`Treatment with palonosetron produced increased incidences of adrenal
`benign pheochromocy1oma and combined benign and malignant
`
`Page 4 of 8
`
`

`
`Table 3: Prevention of Acute Nausea and Vomiting (0-24 hours):
`Com I lete Res I onse Rates
`
`97.5% Confldenoe Interval
`Al/OXI rllnur C omparltor ‘
`
`'/owtthCompleteResponse
`
`[.z'.t. 12-.‘»|
`l—~—l
`
`'
`
`mg
`.__.:._.:__.
`IOISZDLSJDJS
`-10-!
`ll
`5
`lfllmauin (‘lupin Vnqoiiic llllll
`
`Omlaitsetrut
`32 mg] \’
`
`Z
`
`ALOXI
`0.25 mg
`
`
`
`lment-to-treat cohort
`t1
`ll 2-sided F'rslter's exact test. Sigitilicaiice level at u=0 025
`c These stitches were designed to show nm-mfenoxity. A lower bound greater than -15% demonstrates
`non-inferiority between ALOXI and cunparntor
`
`These studies shovt that ALOXI was effective in the prevention of
`acute nausea and vomiting associated with initial and repeat courses of
`moderately and highly emetogcnic cancer chemotherapy.
`In study 3. efficacy
`was greater when prophylactic corticosteroids were administered
`concomitamly. 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):
`
`(‘nemottiernp_v
`
`Eirietogctuc
`
`I‘.IllhComplete
`
`97.5’-o Confidence Interval
`ALOXI mlmn Cotnparator‘
`
`|ll'b,!l‘l‘b|
`
`[J‘k2'l*t]
`
`tl]t52J):.‘J)JS
`S
`40-5 0
`Diltrureifqnliucllupuuellxtu
`
`ti httent-ttureil cohort
`b 2-sided Fi§tci's exact test Signili-:am;e level at o-0.025
`c The»: siinlies were ilerigtieil to show mt:-itttet'iority A lower lllllllll greater than -1 SP?» rlentommes um-
`i.rtt’eru\n'ly between AL(_)_‘(l and comparator.
`
`These studies show that ALOXI was effective in the prevention of
`delayed nausea and vomiting associated with initial and repeat courses of
`nioderately emetogenic chemotherapy.
`
`pheochromocytoma. increased incidences of pancreatic Islet cell adenoma
`and combined adenoma and carcinoma and pituitary adenomzi in male rats.
`In female rats, it produced liepatocellular adenoma and carcinoma and
`increased the incidences ofthyroid C-cell adenoma and combined adenomzi
`and carcinoma.
`
`Palonosetron was not genotoxic in the Ames test. the Chinese hamster
`ovarian cell (CHO-"HGPRT) forward mutation test. the ex vzvo hepatocyte
`unscheduled DNA synthesis (1 D8) test or the mouse inicronucleus test.
`It
`was, however, positive for clastogenic effects in the Chinese hamster ovarian
`(CHO) cell chromosomal aberration test.
`
`Palonosetron at oral doses tip to 60 mgikg/day (about 1894 times the
`recommended human intravenous dose based oti body surface area) was
`found to have no effect on fertility and reproductive performance of male and
`female rats.
`
`14 CLINICAL STUDIES
`
`14.1 (Tu-motherapy Induced Nansen 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 I20 hours after administration of chemotherapy.
`The safety and effcacy 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.\-'. ALOXI with either siiigle-dose I.\'. ondansetron (stud_v l) or
`dolasetron (study 2) given 30 minutes prior to moderately emetogenic
`cltemotlierapy including carboplzitin, cisplatin <1 50 mg-"I112.
`cyclophosphamide
`1500 mg.-‘m’, doxorubicin
`25 mgfmi, epirubicin.
`irinotccrtn. and metliotrcxatc
`250 mgr"m=. Concomitant corticosteroids were
`not administered prophylactically in study I and were only used by 4-6% of
`patients in stud_v 2. The majority of patients in these studies were vtomen
`(77%), White (65%) and naive to previous chemotherapy (54%). The mean
`age was 55 years.
`
`Highlv Emetogenic Cliernotliergpv
`A Phase 2. double-blind. dose-ranging study evaluated the efficacy of
`single-dose l.\-'. palonosetron from 0.3 to 90 nicgrkg (equivalent to <1 0.] mg
`to 6 mg fixed dose) in l6l chemotherapy-nalve adult cancer patients
`receiving highly-emetogenic chemotherapy (either cisplatin
`70 mg-"m3 or
`cyclophosphztmidc 11‘ 1100 mg/m3). Concomitant corticosteroids were not
`administered prophylactically. Analysis of data from this trial indicates that
`0.25 mg is the lowest effective dose in preventing acute nausea and vomiting
`induced by highly emetogenic chemotherapy.
`
`A Phase 3, double-blind trial involving 667 patients compared single-
`dose l.\'. ALOXI with single-dose l.\’. ondansetron (study 3) given 30
`minutes prior to highly emetogenic chemotherapy including cisplatiit 3 60
`nig"ni’, cyclophospliamide i1=- I500 nigv'ni°. and dacarbazine. Corticosteroids
`were co-administered prophylactically before chemotherapy in 67% of
`patients. Of the 667 patients. 51% were women. 60°» White, and 59% naive
`to previous chemotherapy. The mean age was 52 years.
`
`Efficacy Results
`The antiemetic activity of .=\LOXl was evaluated during the acute phase
`(0-24 hours) [Table 3]. delayed phase (24-l 20 hours) [Table 4]. and overall
`phase (0-120 hours) [Table 5] post-clieniotlierapy in Phase 3 trials.
`
`Page 5 of 8
`
`

`
`Table 6: Prevention of Postoperative Nausea and Vomiting: Complete
`Res I
`use CR , Sturlv I, Palonosetron 0.075 m Vs Placebo
`Treatment
`
`n/N (%)
`
`Palonosctron Vs Placebo
`
`
`
`V(:0—I‘ilflII'V’ElltI ts
`CR 0-ZJ hours
`Palonosetron
`Placebo
`. CR2-X-72 hours
`
`.
`
`59"138 42.8‘?-‘o
`35"l35 25.9%
`.
`
`16.8%
`
`.
`
`.
`
`7.8%
`
`0.188
`
`Placebo
`* To reach statistical significance for each co-primar_v endpoint. the required
`signilicance limit for the lowest p-value was p‘-110.017.
`ADifference (9-6): palonosetron 0.075 mg minus placebo
`
`Palonosetron 0.075 mg reduced the severity of nausea compared to
`placebo. Analyses of other secondary endpoints indicate that palonosetron
`0.075 mg was numerically better than placebo. however. statistical
`significance was not formally demonstrated.
`
`A phase 2 randomized. double-blind. multicenter, placebo-controlled.
`dose ranging study was perfonned to evaluate I.\'. palonosetron for the
`prevention of post-operative nausea and vomiting following abdominal or
`vaginal l1_vslerecton1_v. Five l.\". palonosetron doses (0.1. 0.3. 1.0. 3.0 and 30
`pg-"kg) were evaluated in a total of 381 intent-to-treat patients. The primary
`efficacy measure was the proportion of patients with CR in the first 24 hours
`alter recovery from surgery. The lowest effective dose was palonosetron 1
`pglkg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for
`placebo. p=0.004. Palortosetron I ugekg also significantly reduced the
`severity of nausea versus placebo. p*0.0(J9.
`
`16
`
`HOW" SUPPLIED/STORAGE AND HANDLING
`
`NDC #3 58063-797-25. 0.25 mg-“S mL (free base) single-use vial
`individually packaged in a carton.
`NDC :3 58063-797-37, 0.075 mg.-'1.5 mL (free base) single-use vial
`packaged in a carton containing 5 vials.
`
`Storage
`0
`
`0
`9
`
`Store at controlled temperature of 20—25’C (68"‘l‘—77"F).
`Excursions pemtitled to l5—30 "C (59-86"F).
`Protect from freezing.
`Protect from light.
`
`17
`
`PATIENT COUNSELING INFORMATION
`
`See F'D,-l-,-tpproved Patient Labeling ( I T. 3)
`
`17.] Instructions for Patients
`
`Patients should be advised to repon to their physician all of their
`medical conditions, any pain. redness. or swelling in and around the infusion
`site [see Adverse Reactions 6.2].
`Patients should be instructed to read the patient insen.
`
`17.2 FD.~\—Appmved Patient Labeling
`
`Table 5: I’rn'ention of Overall Nausea and Vomiting (0-I20 hours):
`
`Treallneut
`
`Cbunntbeutpy
`
`uoderstely
`Emetog.enic
`
`
`
`‘oMtlComplete
`
`?".5% (‘ottftrlmce Interval
`ALOXI Iilnm (‘oItpnratnr'
`
`IW-.14'l~|
`t—-—1
`
`-l-5 ll
`
`5
`
`lil5'.'ll!SIl3S
`
`Ditlqcme 'l (‘unit Regan: Pats
`
`
`
`a lnlealio-ueal utlnu
`I) 2-sided Fiateri exact test Sig.ra.ticanre level at a=0.tJ25
`c These studies were dedgncd to show non-iriferioiity A lower bound greater than I5°o demonstrates non-
`infcnonly between ALOXI mtlronpamur.
`
`These studies show that ;-\l,0XI was effective in the prevention of
`nausea and