{~·""·~ DEPARTMENT OF HEALTH & HUMAN SERVICES
`.,~~--------------------------
`
`PllbllcHealth SeNlca
`
`Food and Drug Adminlstra!ion
`Rockville, MD 20857
`
`NDA21-372
`
`Helsinn Healthcare S.A.
`c/o August Consulting
`Attention: Craig Lehmann, Phann. D.
`515 Capital of Texas Highway, Suite 150
`Austin, TX 78746
`
`Dear Dr Lehmann;
`
`:Please refer to your new drug application (NDA) dated September 26, 2002, received
`September 27, 2002, submitted under section 50S{b) of the Federal Food, Drug, and Cosmetic Act for
`Aloxi'M (palonosetron hydrochloride injection).
`
`We acknowledge receipt of your submissions dated October 11 and November 21,2002 and
`January 24, April9, April24, May 15, June 6, June 9, June 13, June 16, June 18, Jtule 20; June 25,
`July 1, July 17, and July 22, 2003.
`·
`
`This new drug application provides for the use of Aloxi™ (palonosetron hydrochloride injection) for:
`1)
`the prevention of acute nausea and vomiting associated with initial and repeat courses of
`moderately and highly emetogenic cancer chemotherapy, and
`2) the prevention. of delayed nausea and vomiting associated with initial and repeat courses of
`moderately emetogenic cancer chemotherapy.
`
`We completed our review of this application, as amended, It is approved, effective on the date of this
`letter, for use as recommended in the agreed-upon labeling text.
`
`Please note that, based on the primary stability data submitted, we are granting a 24-month expiration
`period for this product. When additional stability data are available, an extension of the expiration
`period may be requested by submission of a prior approval supplemental new drug application.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package illllert)
`and submitted labeling (carton lii.bel submitted June 25, 2003 and immediate container label submitted
`July 1, 2003). Marketing the product with FPL that is not identical to the approved labeling text may
`render the product misbranded and an unapproved new drug.
`
`Please submit an electronic version of thll FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format- NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 3Q <lays after it is printed. Individually mount 15
`ofth~ copies on heavy-weight p!lper or similar material. For administrative purposes, designate this
`· submission"Fl'L for approved NDA 21-372." Approval of this submission by FDA 1s not required
`. before the labeling is used.
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
`
`HELSN0387519
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`Page 1 of 15
`
`Helsinn Healthcare Exhibit 2055
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
`
`

`
`-1
`'
`
`NDA21-372
`Page2
`
`FDA's Pediatric Rule [at 21 CFR 314.55/21 CFR 601.27} was challenged in court On October 17,
`2002, the court ruled that FDA did not have the authority to issue the Pediatric Rule and has barred
`FDA from enforcing it. Although the government decided not to pursue an appeal in the courts, it will
`work with Congress in an effort to enact legislation requiring phannaceutical manufacturers to conduct
`appropriate pediatric clinical trials. In addition, third party interveners have decided to appeal the
`court's decision striking down the rule. Therefore, we encourage you to submit a pediatric plan that
`describes development of your product in the pediatric population where it may be used. Please be
`aware· that whether or not this pediatric plan and subsequent submission of pediatric data will be
`required depends upon passage of legislation or the success of the third party appeal In any event, we
`hope you will decide to submit a pediatric plan and conduct the appropriate pediatric studies to provide
`important infonnation on the safe and effective use of this drug in the relevant pediatric populations.
`
`The pediatric exclusivity provisions ofFDAMA as reauthorized by the Best Pharmaceuticals for
`Children Act are not affected by the court's ruling. Pediatric studies conducted under the terms of
`section SOSA of the Federal Food, Drug, and Cosmetic Act may result in additional marketing
`exclusivity for certain products. You should refer to the Guidance for Industry on Qualifying for
`Pediatric Exclusivity (available on our web site &t www.fda.gov/cder/pediatric) for details. We
`acknowledge your June 26, 2003 "Proposed Pediatric Study Request" submitted under JND 39,797.
`We are reviewing your submission and will respond to your proposal in a separate letter. FDA
`generally does not consider studies submitted to an NDA before issuance of a Written Request as
`responsive to the Written Request. App!iGants should obtain a Written Request before submitting
`pediatric studies to an NDA.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one coPY to
`this division and two copies of both the promotional materials. and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HF:0-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`
`Please submit one market package of the drug product when it is available.
`
`We have not completed validation of the regulatory methods. However, we expect your continued
`. cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and314.81). In addition, we request that you initiate a 15-day report [21 CPR 314.80(c)] for
`each of the following:
`• All spontaneous reports of constipation requiring hospitalization or emergency room visit
`• All spontaneous reports of possible complications of constipation such as obstruction,
`perforation, intestinal ulceration, toxic megacolon, ileus, or impaction resulting in
`hospitalization or emergency room visit
`• All spontaneous reports of any cardiovascular adverse event
`
`The MedWatch-to-Manufacturer Program provides ~anufacturers with copies of serious adverse event
`reports that are received directly by the FDA. New molecular entities and important new biologics
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
`
`HELSN0387520
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`Page 2 of 15
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`

`
`NDA21-372
`Page3
`
`qualify for inclusion for three yea.rs after approval. Your finn is eligible to receive copies of reports for
`this product. To participate in the program, please see the enrollment instructions and program
`descrip~on details at www. fda.gov/medwatchlreport!mmp.htm.
`
`If you have any questions, call Brian Strongin, R.Ph., M.B.A., Regulatory Project Manager at (301)
`827-7473.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Julie Beitz, M.D.
`Deputy Director
`Office of Drug Evaluation III
`Center for Dmg Evaluation and Research
`
`Enclosure
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
`
`HELSN0387521
`
`Page 3 of 15
`
`

`
`NDA21-372
`Page4
`
`Aloxi™ (Palonosetrou Hydrochloride) Injection
`
`Helsinu Healthcare S.A. NDA 21-372 Palonosetron: Proposed Labeling
`
`DESCRlPTION
`Aloxi1 (palonosetron hydrochloride) is an antiemetic and antinauseant agent. It is a selective serotonin
`subtype 3 (5-HT~) receptor antagonist with a strong bmding affinity for this receptor Chemically,
`palonosetron hydrochloride is: (3aiD.-2-[(ID-1-Azabicyc!o [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-
`oxo-1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C19Hz4N20 HCl, with a
`molecular weight of 332 87 Palonosetron hydrochloride exists as a single isomer and has the
`following structural fonnula:
`
`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 inject10n is a sterile, clear, colorless, non-pyrogenic, isotonic, buffered solution for intravenous
`administration. Each 5-rnl vial of Aloxi injection contains 0.25 mg palonosetron base as
`hydrochloride, 207.5 mg mannitol, dis odium edetate and Citrate buffer in water for intravenous
`administration. The pH of the solution is 4.5 to 5.5.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacodynamics
`Palonosetron is a selective 5-HT3 receptor antagonist with a strong binding affinity for this receptor
`and little or no affmtty for other receptors.
`
`Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly
`when certain agents, such as cispiatin, are used. 5-HT3 receptors are located on the nerve tenninals of
`the vagus in the periphery and centrally m the chemoreceptor trigger zone of lhe 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 serotomn then activates 5-HT,
`receptors located on vagal affercots to initiate the vomitmg reflex.
`
`1 Pendln(llrddemarl< of Helslno Heallncaro SA
`lugane>, Switzerland
`COPYRIGHT © Hefsinn Healthcare SA, 2003
`All dghts reoerved
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
`
`HELSN0387522
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`Page 4 of 15
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`

`
`NDA21-372
`PageS
`
`The effect ofpalonosetron on blood pressure, heart rate, and ECG parameters including QTc were
`comparable to ondansetron and dollllletron in clinical trials. In non-clinical studies palonosetron
`possesses the ability to block ion channels involved in ventricular de- andre-polarization and to
`prolong action potential duration. In clinical trials, the dose-response relationship to the QTc interval
`has not been fully evaluated.
`Pharmacokinetics
`
`-I
`
`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 (C., •• ) and area under the concentration-time curve (AUCo-) are generally dose(cid:173)
`proportional over the dose range of 0.3-90 )J.g/kg in healthy subjects and in cancer patients. Following
`single N dose ofpalonosetron at 3 J.lg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD)
`maximum plasma concentration was estimated to be 5.6 ± 5.5 ng/mL and mean AUC was 35.8 ± 20.9
`ng•hr/mL.
`
`Distribution
`
`Palonosetron hllll 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 ofpalonosetron. In vitro metabolism
`studies have suggested that CYP2D6 and to a lesser extent, CYP3A 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.
`
`Eliminatbm
`
`After a single intravenous dose of 10 )lg/kg [14C)-palonosetron, approximately 80% of the dose was
`recovered within 144 hours in the udne with palonosetran representing approximately 40% of the
`administered dose. In healthy subjects the total body clearance ofpalonosetron was 160 ± 35 roUh/kg
`· and rena! c!earance was 66.5± 18.2 miJh/kg. Mean tenninal elimination half-life is approximately 40
`hours.
`
`Special Populations
`Geriatrics
`
`Population PK analysis and clinical safety and efficacy data did not reveal any differences between
`cancer patients<:: 65 years of age and younger patients. (18 to 64 years). No dose adjustment is
`required for these patients.
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
`
`HELSN0387523
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`Page 5 of 15
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`

`
`NDA21-372
`Page6
`
`Race
`
`Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects
`over the dose range of 3 - 90 ftg/kg. Total body clearance was 25% higher in Japanese subjects
`compared to Whites, however, no dose adjustment is required, The pharmacokinetics of palonosetron
`in Bla<::ks has not beeh adequately characterized.
`
`Renallmpairment
`Mild to moderate renal impairment does not· significantly affect palonosetron phannacokinetic
`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
`
`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:
`Jmpairmimt.
`
`Drug-Drug Interactions.
`
`;'-,-;, ...
`.. :
`
`:
`
`Palonosetron is elimib.ated 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 ofCYPlA2, CYP2A6, CYP2B6, CYP2C9, CPY2D6, CYP2El and CYP3A4/5 .
`(CYP2Cl9 was not investigated) nor does it induce the activity ofCYPlA2, CYP2D6, or CYP3A4/5.
`Therefore the potential for clinically significant drug interactions with palonosetron appears to be Iow.
`
`A study in healthy volunteers involving single"dose IV 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.
`
`CLINICAL STUDIES
`
`Efficacy of single-dose palonosetron injection in pr<~venting acute and delayed nausea and vomiting
`induced by both moderately and highly emetogenic chemotherapy was studied in three Phase 3 trials
`and one Phase 2 trial. In these double-blind studies, complete response rates (no emetic episodes and
`no rescue medication) and other efficacy parameters were assessed through at least 120 hours after
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
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`HELSN0387524
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`Page 6 of 15
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`

`
`_l
`
`NDA21-372
`Page7
`
`administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of
`chemotherapy was also studied.
`
`Moderately Emetogenic ChemotheraPY
`Two Phase 3, double-blind trlals involving 1132 patients compared single-dose IV Aloxi with either
`single-dose IV ondansetron (study 1) or dolasetron (study2) given 30 minutes prior to moderately
`emetogenic chemotherapy including carboplatin, cisplatin S 50 mg/m2
`, cyclophosphamide< 1500
`mg/m2, dox:orubicin > 25 mg!m•, epirubicin, irinotecan, and methotrexate> 250 mgtm•. Concomitant
`corticosteroids were not administered prophylactically in study I and were only used by 4-6% of
`patients in study 2. The majority of patients in these studies were women (77%), White (65%) and
`nai've to previous chemotherapy (54%). The mean age was 55 years.
`
`Highly Emetogenic Chemotherapy
`A Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose IV palonosetron
`from 0.3 to 90 f!glkg (equivalent to< 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naive adult
`cancer patients receiving highly-emetogenic chemotherapy (either cisplatin;::: 70 mg/m2 or
`cyclophosphamide> 1100 mg/m'). 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 fV Aloxi with single-dose
`IV ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including
`cisplatin 2: 60 mg/m2, cyclophosphamide > 1500 mg/m2 , and dacarbazine. Corticosteroids were co(cid:173)
`administered prophylactically before chemotherapy in 67% of patients. Of the 667 patien,ts, 51% were
`women, 60% White, and 59% nai've to previous chemotherapy. The mean age was 52 years.
`
`Efficacy Results
`
`·
`
`The antiemetic activity of Aloxi was evaluated during the acute phase (0-24 hours) [Table 1], delayed
`phase (24-120 hours) (Table 2J, and overall phase (0·120 hours) [Table 3} post-chemotherapy in Phase
`• 3 trials.
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
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`HELSN0387525
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`Page 7 of 15
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`

`
`NDA 21-372
`PageS
`
`I
`-1
`
`Table 1:
`
`Chemo-
`therapy
`
`Moderate
`ly
`Ernetoge
`nic
`
`Highly
`Emetoge
`nic
`
`l
`
`2
`
`3
`
`lS
`9
`
`18
`5
`
`18
`9
`
`19
`l
`
`22
`3
`
`81
`
`69
`
`63
`
`53
`
`59
`
`57
`
`NS
`
`NS
`
`0.009
`
`(l%lzj%J
`
`I: (-~o/\11%1
`
`I
`
`!~'ml
`
`5
`
`Prevention of Acute Nausea and Vomiting (0-24 hours):
`l
`Complete Response Rates
`%with
`Study Treatm Nn Complete p-value 97.5% Confidence Interval
`Response
`h
`Aloxi minus Comparator c
`ent
`Group
`Aloxi
`0.25
`mg
`On dans
`etron
`32mg
`IV
`Aloxi
`0.25
`mg
`Dolaset
`ron 100
`mgiV
`Aloxi
`o.zs-
`mg
`Ond~ns 22
`etron
`1
`32mg
`IV
`
`I
`.s 0
`.Jo
`!0 IS 20 25
`DI(Tereue In Co.mplde Re!!ponu Rote;
`
`lO
`
`lS
`
`• lolent-to-lt .. t oohort
`b l·&idud Fjsbcr'.s cx"ct wst. SigqU'i~rtc13le.vel at n ... 0,02.5,
`c These stUdies were designed to show non-inferiority. A lower b{)und gTeator than -15% demanstretes non-tnfcriority between Aloxi and cOmparator.
`
`These studies. show that Aloxi was effective in the prevention of acute nausea and vomiting associated
`with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. In study 3,
`efficacy was greater when prophylactic corticosteroids were administered concomitantly. Clinical
`superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute
`phase.
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
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`

`
`NDA21-372
`Page9
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`Table2:
`
`Chemo·
`therapy
`
`Moderate
`ly
`Emetoge
`nic
`
`Prevention of Delayed Nausea and Vomiting (24-120 hours):
`omt ete espouse ates
`C
`I R
`R
`%with
`Study Treatm N" Com pie p-value 97.5% Confidence Interval
`b
`te
`ent
`Aloxi minus Comparator'
`Res pons
`Group
`e
`74
`
`l
`
`2
`
`Aloxi
`0.25mg
`Ondanse
`tron 32
`mglV
`Aloxi
`0.25 mg
`Dolasetr
`on 100
`mgiV
`
`18
`9
`18
`5
`
`18
`9
`19
`1
`
`<0.001
`
`(8%,JO%J
`
`55
`
`54
`
`39
`
`[3%, >1% I
`
`0.004
`
`·lO-S " • 10 15 Zlt Z6 3-0
`
`-35
`Dl!fcrcn.c=q In Comphtc R.,HipGI\5'11! Rall:1
`
`n lntent-to-ltent (:Qbort
`b 2 .. ided Fisher's exact tcSl. Significance level at «:0.1)2;,
`t- These .studies were. d-esigned to show non·infurlority. A low-er bound grenler than -15% demcmstrates: non-inferiority between AJQxt and oeomparator.
`
`These studies show that Aloxi was effective in the prevention of delayed nausea and vomiting
`associated with initial and repeat courses of moderately emetogenic chemotherapy,
`
`Table3:
`
`Chemo-
`therapy
`
`Moderate
`ly
`Bmetoge
`nic
`
`Prevention of Overall Nausea and Vomiting (0-120 hours):
`om ete esponse
`
`Ra tes
`C
`l R
`%with
`Study Treatm N" Comple p-value 97.5% Confidence Interval
`b
`ent
`te
`Aloxi minus Comparator<
`Group
`Respons
`e
`69
`
`<0.001
`
`[7Yo-.ll%J
`
`50
`
`46
`
`34
`
`I D"l"a, 14'"1o)
`
`0.021
`
`.•• . s 0
`2.() 25- ~0 ss
`s 10
`l-5
`DUfcrcncc Jn. Comp1el-c Rcsp.otuc lt:u.l~:,
`
`1
`
`2
`
`Aloxi
`0.25mg
`Ondanse
`tron32
`mg_IV
`Aloxi
`0,25mg
`Dolasetr
`on 100
`mgiV
`
`18
`9
`18
`5
`
`18
`9
`19
`1
`
`a lnt-ent~tD·trent cohort
`b 2.-.sidc<l Plsher'sexPcttest. Significance lcvei Att'i=0.025.
`c These studies were. designed tet .show no-n~inf-eriority. A 1ow...-:r bound. great-er thali ~IS% dl.?lmDiiStrates non·lnferior.ity bcDNc~ Aloxi and -oornparntor.
`
`These studies show that Aloxi was effective in the prevention of nausea and vomiting throughout the
`120 hours (S days) following initial and repeat courses of moderately emetogenic cancer
`chemotherapy.
`
`HIGHLY CONFIDENTIAL- OUTSIDE COUNSEL EYES ONLY
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`HELSN0387527
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`Page 9 of 15
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`

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`NDA21-372
`Page 10
`
`INDICATIONS AND USAGE
`
`Aloxi is indicated for;
`1) the prevention of acute nausea and vomiting associated with inittal and repeat courses of
`moderately and highly emetogenic cancer chemotherapy, and
`2) the prevention of delayed nausea and vomiting associated with initial and repeat courses of
`moderately emetogenic cancer chemotherapy.
`
`CONTRAINDICATIONS
`Aloxi is contraindicated in patients l<nown to have hypersensitivity to the drug or any of its
`components.
`
`PRECAUTIONS
`
`Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other selective
`5-HT3 receptor antagonists.
`
`Although palonosetron has been safely administered to 192 patients with pre-existing cardiac
`impainnent in the Phase 3 studies, Aloxi should be administered with caution m patients who have or
`may develop prolongation of cardiac conduction intervals, particularly QTc. These include patients
`with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte
`abnormalities, patients with congenital QT syndrome, patients taking anti-arrhythmic drugs or other
`drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy. In 3 pivotal
`trials, ECGs were obtained at basel me and 24 hours after aubjects received palonosetron or a
`comparator drug. In a subset of patients BCGs were also obtained 15 minutes following dosing. The
`percentage of patients(< 1%) with changes in QT and QTc intervals (either absolute values of> 500
`msec or changes of> 60 msec from baseline) was similar to that seen with the comparator drugs.
`
`Drug Interactions
`
`Palonosetron is elimmated from the body through both renal excretion and metabolic pathways.
`Thecefore, the potential for clinically significant drug interactions with palonosetron appears to be low
`(See CLINICAL PHARMACOLOGY, Drug-Drug Interactions section).
`
`Carcinogenesis, Mutagenesis, Jropairrnent of Fertility
`
`In a !04-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of
`palonosetron at 10, 30 and 60 mg/kgfday. Treatment with palonosetron was not tumorigenic. The
`highest tested dose produced a systemic exposure to palonosetron (Plasma AU C) of about 150 to 289
`times the human exposure (AUC= 29.8 ng•hlml) at the recommended intravenous dose of0.25 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 mglkgfday and 15, 45 and 90 mgikglday, respectively. The highest doses
`produced n systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human
`
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`
`NDA21-372
`Page 11
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`exposure at the recommended dose. Treatment with palonosetron produced increased incidences of
`adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased
`incidences of pancreatic Islet cell adenoma and combined adenoma and carcinoma and pituitary
`adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased
`the incidences of thyroid C-cel! adenoma and combined adenoma and carcinoma.
`
`Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell {CHO/HGPRT)
`forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis (UDS) test or the mouse
`micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian
`(CHO) cell chromosomal aberration test.
`Palonosetron at oral doses up to 60 mglkg/day (about 1894 times the recom.n'iended human intravenous
`dose based on body surface area) was found to have no effect on fertility and reproductive performance
`of male and female rats,
`
`-i
`
`Pregnancy. Teratogenic Effects: Category B
`Teratology studies have been performed in rats at oral doses up to 60 mg/kglday (1894 times the
`recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60
`mglkglday (3789 times the recommended hum~ intravenous dose based on body surface area) and
`have revealed no evidence of impaired f-ertility or·harm to the .fetus due tri 'palonosetron. There are,
`however, no adequate and well-controlled studies in pregnant women. Because animal reproduction
`studies are not always predictive of human response, palonosetron should be used during pregnancy
`only if clearly needed.
`
`,••'
`
`Labor and Delivery
`Palonoseiron has not been administered to patients undergoing labor and delivery, so its effects on the
`mother or child are unknown.
`Nursing Mothers
`It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in
`human milk and because of the potential f()r 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<
`
`Pediatric Use
`Safety and effectiveness in patients below the age of 18 years have not been established<
`Geriatric Use
`Ofthe 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 effectivenl,lSS were observed
`between these subjects and the younger subjects but greater sensitivity in some older individuals
`cannot be ruled out. No dose adjustments or sp~cial monitoring are required for geriatric patients.
`
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`NDA21-372
`Page 12
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`ADVERSE REACTIONS
`
`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 4).
`
`Table 4: Adverse Reactions from Chemotherapy-Induced Nausea and
`Vomiting Studies<:: 2% in any Treatment Group
`
`Event
`
`Headache
`Constipation
`
`Diarrhea
`Dizziness
`
`Fatigu~
`Abdorrrinal Pain
`
`Insomnia
`
`Aloxi 0.25 mg
`(N~633)
`
`60 (9%)
`
`29 (5%)
`8 (1%)
`
`8 (1%)
`3 (<I.%)
`
`1 (< 1%).
`I(< l%)
`
`Ondnnsetron
`32 mgiV
`
`(N=410)
`34(8%)
`
`8 (2%)
`
`7 (2%)
`
`9 (2%)
`
`4 (1%)
`2 (< 1%)
`
`3 (1%)
`
`Dolasetrun 100 mg
`IV (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 )!g/kg oral dose
`in a post-operative nausea and vomiting study and one healthy subject received a 0.75 rug IV dose in a
`pharrnacokinetic study.
`
`In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as
`treatment-related or causality unknown, occurred following adrrrinistration 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: < l %: allergic dermatitis, rash.
`
`Hearing 11nd Vision:< 1% motion sickness, tinnitus, eye irritation and amblyopia.
`
`Gastrointel!tinal system: 1%: diarrhea,< 1%: dyspepsia, abdominal pain, dry mouth, hiccups and
`flatulence.
`
`General: 1%: weakness, < l o/o; fatigue, fever, hot flash, flu-like syndrome.
`
`Liver: < I%: transient, asymptomatic increases in AST and/or AL T and bilirubin. These changes
`~ccu:n:ed predominantly in patients receiving highly emetogenic chemotherapy.
`
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`Metabolic: 1%: hyperkalemia,< I%: electrolyte fluctuations, hyperglycemia, metabolic acidosis,
`glycosuria, appetite decrease, anore:da.
`
`Musculoskeletal:< 1%: arthralgia.
`
`Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paraesthesia.
`
`Psychiatric: 1%: anxiety, < 1%: euphoric mood.
`
`Urinary System: < 1%: urinary retention.
`
`Vascular:< 1%: vein discoloration, vein distention.
`
`Overdosage
`There is no known antidote to Aloxi. Overdose should be managed with supportive c&re. Fifty adult
`cancer patients were administertJd palonosetron at a dose of 90 Jlg/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 trea1ment for palonosetron overdose.
`A single intravenous dose ofpalonosetron at jQ mglkg (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.
`
`DOSAGE AND ADMINISTRATION
`
`Dosagtl for Adults
`The recommended dosage of Aloxi is 0.25 mg administered as a single dose approximately 30 minutes
`before the start of chemotherapy. Repeated dosing of AloxiTM within a seven day interval is not
`recommended because the safety and efficacy of frequent (consecutive or alternate day) dosing in
`patients has not been evaluated.
`
`Use in Geriatric Patients and in Patients with Impaired Renal or Hepatic Function
`No dosage adjustment is recommended.
`
`Dosage for Pediatric Patients
`A recommended intravenous dosage has not been !)stablished for pediatric patients.
`
`Administration
`A!oxi is to be infused mtravenously over 30 seaonds. Aloxi should not be mixed with other drugs,
`Flush the infusion line with normal saline before and after administration of Aloxi.
`
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`NDA21-372
`Page 14
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`Stability
`Parenteral drug products should be inspected visually for particulate matter and discoloration before
`administration, whenever solution and container permit.
`
`HOW SUPPLIED
`
`Aloxi (palonosetron hydrochloride), 0.25 mg (free ba~e) in 5 ml, is supplied as a single-use sterile,
`clear, colorless solution in glass vials ready for intravenous injection.
`Store at controlled temperature of20-25°C (68°F-77°F). Excursions perinitted to 15-30 •c (59-
`86"F). Protect from freezing. Protect from light.
`NDC Number 58063-797-25
`Prescribing information as ofXXXX, 2003
`Mfd by Cardinal Health, Albuquerque, NM, USA and
`Helsinn Birex Pharmaceuticals, Dublin, Ireland
`Mfd for Helsinn Healthcare SA, Switzerland
`Distributed by MGI PHARMA, INC.; Bloomington, MN, U.S.A.
`
`-I I
`
`:_:
`
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`
`This Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Julie Beitz
`7/25/03 08:45:03 AM
`
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