CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`' APPLICATION NUMBER
`
`'
`
`21-372
`
`Administrative Documents
`
`

`

`Helsinn Healthcare SA: Palonosetron
`NDA 21-372
`
`.
`
`L
`
`0 O O 2
`page 2
`
`13.0
`
`'Patent Information Pursuant to 21 C.F.R. § 314.53
`
`The following is provided in accordance with the Drug Price Competition and Patent
`
`Term Restoration Act of 1984, 21 U.S.C. §355(b)(1):
`
`
`
`
`
`
`
`
`
`
`
`In accordance with 21 CPR. § 314.53, the following information is provided for each
`
`United States patent that claims the drug product that is the subject of this NDA, a drug
`
`substance that is a component of such drug product, or a method of using such drug
`
`product, and with respect to which a claim of patent infiingement could reasonably be
`
`asserted if a person not licensed by the owner of the patent engaged in the manufacture,
`
`use, or sale ofthe drug product:
`
`PATENT NUMBER:
`
`
`
`5,202,333
`
`DATE OF EXPIRATION:
`
`13 April 2010
`
`
`
`
`
`
`
`Drug substance, drug product (composition and
`TYPE OF PATENT:
`
`formulation), and method ofuse inter alia for the
`
`prevention of chemotherapy-induced nausea and
`
`vomiting
`
`
`
`NAME OF PATENT OWNER:
`
`Symex (U.SA.) LLC
`
`The undersigned declares that US. Patent Number 5,202,333 covers the drug substance
`
`palonosetron, formulations and/or compositions of palonosetron, and/or methods of using
`palonosetron. The drug product palonosetron is the subject of this NDA for which
`
`approval is being sought.
`
`CONFIDENTIAL
`
`l3_FlNAL_l Aug02.doc
`Original Application
`
`

`

`0 0 0 3
`Helsinn Healthcare SA: Palonosetron
`Page 3
`NDA 21-372
`
`
`U "
`
`The undersigned certifies that the exclusive right and license to make, have made,
`
`develop, register, market, distribute, and sell palonosetron under US. Patent Number
`
`5,202,333 is granted by the owner of the patent, Syntex (U.S.A.) LLC, to the applicant of
`this NDA, Helsinn Healthcare SA, under a licensing agreement between Syntex (U.S.A.)
`
`LLC and Helsinn Healthcare SA dated 23 June 1998.
`
`’_
`.
`A ' J .
`it/d/Lw-
`Z ‘5’45/
`
`.
`_
`I Dan'o Cen'ani
`Senior Manager, Regulatory Affairs
`Helsinn Healthcare SA
`
`
`
`Date
`
`
`
`Matteo Missaglia
`/ Director, Legal Affairs
`Helsinn Healthcare SA
`
`Date
`
`CONFIDENTIAL
`
`13_FINAL_l Aug02.doc
`Original Application
`
`

`

`EXCLUSIVITY SUMMARY for NBA #
`Trade Name Aloxi"
`
`21-372
`
`SUPPL #
`
`
`N/A
`
`Generic Name palonosetron HCl injection
`
`Applicant Name Helsinn Healthcare S.A.
`
`HFD- 180
`
`Approval Date
`
`; July 25, 2003
`
`PART I:
`
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1.An exclusivity determination will be made for all original
`applications, but only for certain supplements. Complete
`Parts II and III of this Exclusivity Summary only if you
`answer "YES" to one or more of the following questions about
`the submission.
`
`a)Is it an original NBA?
`
`YES/_§/ NO /___/
`
`b)Is it an effectiveness supplement? YES [___/
`
`NO /g/
`
`If yes, what
`
`type(SEl, SE2, etc.)?
`
`c)Did it require the review of clinical data other than to
`support a safety claim or change in labeling related to
`safety?
`(If it required review only of bioavailability
`or bioequivalence data, answer "NO ")
`
`ms/i/
`
`NO/
`
`/
`
`d)Did the applicant request exclusivity?
`
`e)Has pediatric exclusivity been granted for this Active
`Moiety?
`'
`
`YES /_/ NO /§/
`
`YES /_/
`
`NO /_x/
`
`IF YOU HAVE ANSWERED "NO“ TO ALL OF THE ABOVE QUESTIONS, GO
`
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`2.Has a product with the same active ingredient(s), dosage form,
`strength, route of administration, and dosing schedule
`previously been approved by FDA for the same use? (Rx to OTC)
`Switches should be answered No - Please indicate as such).
`
`YES /_/
`
`NO /_x/
`
`Page 1
`
`

`

`
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9.
`
`3. Is this drug product or indication a DESI upgrade?
`
`YES /_/
`
`no /_x/
`
`IF THE ANSWER TO QUESTION 3 IS “YES,“ GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9
`upgrade).
`
`(even if aflfitudy was required for the
`
`
`PART II: FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`(Answer either #1 or #2, as appropriate)
`
`1.Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any
`drug product containing the same active moiety as the drug
`under consideration? Answer "yes" if the active moiety
`(including other esterified forms, salts, complexes, chelates
`or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g.,
`this particular
`ester or salt
`(including salts with hydrogen or coordination
`bonding) or other non-covalent derivative (such as a complex,
`chelate, or clathrate) has not been approved. Answer "no" if
`the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug)
`to produce
`an already approved active moiety.
`
`YES/
`
`/No/x/
`
`IF THE ANSWER TO QUESTION 1 UNDER PART II IS ”NO,“ GO DIRECTLY TO
`THE SIGNATURE BLOCKS.
`
`Page 2
`
`

`

`{See aEEended.electronic signature page}
`Signature of Preparer
`Title: Brian Strongin, R.Ph., M.B.A.
`Regulatory Health Project Manager
`Division of GI and Coagulation Drug Products
`
`Date
`
`age
`ended electronic si nature
`See a
`Signature of Office or Division Director
`Title:
`Julie Beitz, M.D.
`
`Degutx Director, ODE III
`
`Date
`
`cc;
`Archival NDA
`
`HFD-lBO/RPM
`
`HFD—093/Mary Ann Holovac
`HFD-lO4/PEDS/T.Crescenzi
`
`FCI'TI'I OGD-Oll347
`Revised 8/7/95; edited 8/8/95; revised 8/25/98, edited 3/6/00
`
`Page 3
`
`

`

`‘\
`
`(Complete for all APPROVED original applications and efficacy supplements)
`
`NDA/BLA # : NDA 21-372
`
`Supplement Type (e.g. SE5): N/A
`
`Supplement Number: N/A
`
`PEDIATRIC PAGE
`
`Stamp Date: 9/26/02
`
`Action Date:
`
`7/25/03
`
`HFD-180
`
`Trade-and generic names/dosage form: AloxiTM (palonosetron HCl injection)
`
`Applicant: Helsinn Healthcare S.A.
`
`Therapeutic Class:
`
`5-HT;Receptor Antagonist
`
`lndication(s) previously approved:
`
`N/A
`
`Each approved indication must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number ofindications for this application(s):
`
`2
`
`Indication #1: the prevention of acute nausea and vomiting associated with initial and repeat courses
`of moderately and highly emetogenic cancer chemotherapy
`
`Is there a full waiver for this indication (check one)?
`
`Cl Yes: Please proceed to Section A.
`
`PartialWaiver
`X No: Pleasecheckall that apply: X
`NOTE: More than one may apply
`Please proceed to Section B, Section C, and/or Section D and complete as necessary.
`
`X Deferred
`
`Completed
`
`Section A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`UDUDCI
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`
`Too few children with disease to study
`There are safety concerns
`Other:
`
`Ifstudies are fully waived, then pediatric information is complete for this indication. If there is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`Section B: Partially Waived Studies
`
`Age/weight range being partially waived:
`
`Min
`Max
`
`kg
`kg
`
`yr.
`mo. Birth
`mo. < 1 month yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for partial waiver:
`
`[3 Products in this class for this indication have been studied/labeled for pediatric population
`Cl Disease/condition does not exist in children
`
`\-
`
`Cl Too few children with disease to study
`Cl There are safety concerns
`Adult studies ready for approval
`
`

`

`NDA 21-372
`
`Page 2
`
`D Formulation needed
`
`\ ’e will consider a waiver of pediatric studies for this age group if the Pediatric Rule is
`X Other:
`reactivated.
`
`lfstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`
`Section C: Deferred Studies
`
`Age/weight range being deferred:
`
`Min
`Max
`
`kg
`kg
`
`mo. >1 month yr.
`mo. < 18 years yr.
`
`Tanner Stage
`Tanner Stage
`
`
`
`
`Reason(s) for deferral:
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`
`CI Too few children with disease to study
`C] There are safety concerns
`X Adult studies ready for approval
`CI Formulation needed
`Other:
`
`Date studies are due (mm/dd/yy): July IS, 2008
`
`Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`Section D: Completed Studies
`
`Age/weight range of completed studies:
`
`Min
`Max
`
`Comments:
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`
`Tanner Stage
`
`Tanner Stage
`
`If there are additional indications, please proceed to Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`
`This page was completed by:
`
`{See appended electronic signature page}
`
`Regulatory Project Manager
`
`cc: NDA
`HFD-950/ Terrie Crescenzi
`HFD-960/ Grace Carmouze
`
`(revised 9-24-02)
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT, PEDIATRIC TEAM, HFD-960
`301-594-7337
`
`

`

`NDA 21-372
`
`Page 3
`
`(This attachment is to be completed for those applications with multiple indications only.)
`
`Attachment A
`
`the prevention of delayed nausea and vomiting associated with initial and repeat
`Indication #2:
`courses of moderately emetogenic chemotherapy
`
`Is there a full waiver for this indication (check one)?
`
`D Yes: Please proceed to Section A.
`
`x Partial Waiver
`X No: Please check all that apply:
`NOTE: More than one may apply
`Please proceed to Section B, Section C, and/or Section D and complete as necessary.
`
`X Deferred
`
`Completed
`
`Section A: Fully Waived Studies
`
`-
`
`Reason(s) for full waiver:
`
`UUUDD
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`
`Too few children with disease to study
`There are safety concerns
`Other:
`
`lfstudies are fully waived, then pediatric information is complete for this indication. Ifthere is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`Section B: Partially Waived Studies
`
`Age/weight range being partially waived:
`
`Min
`Max
`
`kg
`kg
`
`yr.
`mo. Birth
`mo. < 1 month yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for partial waiver:
`
`UD'UUUU
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`Too few children with disease to study
`There are safety concerns
`Adult studies ready for approval
`Formulation needed
`
`Other:
`
`We will consider a waiver of the reguirement for pediatric studies if the Pediatric Rule is reactivated.
`
`lfstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`
`

`

`NDA 21-372
`
`Page 4
`
`f‘
`
`Section C: Deferred Studies
`
`.
`
`Age/weight range being deferred:
`
`Min
`Max
`
`kg
`kg
`
`> 1 month yr.
`mo.
`mo. < 18 years
`yr.
`
`Tanner Stage
`Tanner Stage
`
`
`
`Reason(s) for deferral:
`
`.
`
`CI Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`
`[J Too few children with disease to study
`CI There are safety concerns
`X Adult studies ready for approval
`D Formulation needed
`D Other:
`
`Date studies are due (mm/dd/yy):
`
`Julv IS, 2008
`
`Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`[Section D: Completed Studies
`
`Age/weight range of completed studies:
`
`Min
`Max
`
`kg
`kg
`
`Comments:
`
`mo.
`mo.
`
`yr.
`yr.
`
`
`
`Tanner Stage
`Tanner Stage
`
`I
`
`Ifthere are additional indications, please copy the fields above and complete pediatric information as directed. Ifthere are no
`other indications, this Pediatric Page is complete and should be entered into DFS.
`
`This page was completed by:
`
`{See appended electronic signature page}
`
`Regulatory Project Manager
`
`cc: NDA
`HFD-960/ Terrie Crescenzi
`
`(revised 1-18-02)
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT, PEDIATRIC TEAM, HEB-960
`301-594-7337
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Brian Strongin
`7/21/03 04:25:45 PM
`
`

`

`b- 0006
`
`16
`
`DEBARMENT CERTIFICATION
`
`HELSINN HEALTHCARE SA _
`
`PALONOSETRON
`
`CONFIDENTIAL
`
`l 6_FINAL_6Aug02.doc
`Original Application
`
`

`

`0 O O 7
`Helsinn Healthcare SA: Palonosetron
`Page 2
`NDA 21-372
`
`
`L’ '
`
`16.0 Debarment Certification
`
`Helsinn Healthcare SA hereby certifies that it did not and will not use in any capacity the
`services of any person debarred under section 306 ofthe Federal Food, Drug, and
`
`Cosmetic Act in connection with this application.
`
` [jug/144,4 331124907,
`
`—__—7.—_—_L_
`Date ‘
`
`Dan'o Ceriani
`
`Senior Manager, Regulatory Affairs
`Helsinn Healthcare SA
`
`CONFIDENTIAL
`
`] 6_FINAL_6Aug02.doc
`Original Application
`
`

`

`Division Director Summary Review ofa New Drug Application
`
`NDA: 21-372
`
`.
`
`Drug: AloxiTM (palonosetron hydrochloride 0.25 mg for injection)
`Applicant: Helsinn Healthcare SA
`Date: July 21, 2003
`
`Palonosetron is a selective 5-HT3 receptor antagonist which has been studied for use as
`an antiemetic with moderately and highly emetogenic cancer chemotherapy. The
`application was submitted on September 27, 2002. The applicant seeks approval of the
`following indications: (l) the prevention of acute and delayed nausea and vomiting
`associated with initial and repeat courses of moderately emetogenic cancer chemotherapy
`and (2) the prevention of acute nausea and vomiting associated with initial and repeat
`courses of highly emetogenic chemotherapy.
`
`Clinical Review
`
`' The clinical review was performed by Narayan Nair, M.D.. Two studies were submitted
`in support of each indication. Study PALO-99-03 is a multicenter, double-blind, active-
`controlled trial in 563 patients receiving moderately emetogenic chemotherapy. Patients
`were allocated to palonosetron 0.25 mg, palonosetron 0.75 mg, or ondansetron 32 mg
`administered intravenously 30 minutes prior to chemotherapy. Moderately emetogenic
`chemotherapy included carboplatin, cisplatin _<_ 50 mgmz, cyclophosphamide < 1500
`mymz, doxorubicin > 25 mg/m2, epirubicin, irinotecan, and methotrexate > 250 mg/mz.
`The primary endpoint was the complete response rate in the first 24 hours. A complete
`response was defined as no emetic episode and no rescue medication. Non-inferiority to
`control therapy was prospectively defined as a lower limit of the 97.5% confidence
`interval for the difference in complete response rates (palonosetron - ondansetron) during
`the first 24 hours of greater than -15%. The results for the acute (0-24 hours) and delayed
`phases (24-120 hours) are shown below and were obtained from Table 14 of the Medical
`Officer Review by Dr. Nair.
`
`
`
`
`
`Time Period
`hours
`
`24-120-
`‘p<0.05
`
`Number and percentage (%) Subjects with
`a Com-lete Res-onse
`
`
`
`Palonosetron Palonosetron Ondansetron
`0.25 mg
`0.75 mg
`32 mg
`=l89)
`=l89)
`(N=l85
`153(8l.0)
`13903.5)
`127(68.6
`140(741
`122(64.6
`102 (55.1
`
`Pal. 0.25 mg
`minus
`0nd. 32 mg
`l.8%,22.8%*
`7.5%,30;3%*
`
`
`
`Stud PALO-99-03
`
`
`
`
`
`Difference in CR rates,
`97.5% Confidence Intervals
`
`
`
`
`
`
`Pal. 0.75 mg
`minus
`0nd. 32 m_
`-6.l%,15.9%
`-2.4%,21.3%
`
`These results show that palonosetron at a dose of 0.25 mg is superior to ondansetron in
`the acute and delayed phases. The palonosetron dose of 0.75 is non-inferior to
`
`

`

`ondansetron in the acute and delayed phases. The applicant’s recommended dose in the
`labeling is 0.25 mg.
`
`Study PALO—99-04 is a second multicenter, double-blind, active—controlled trial in 569
`patients receiving moderately emetogenic chemotherapy. Patients were allocated to
`palonosetron 0.25 mg, palonosetron 0.75 mg, or dolasetron 100 mg administered
`intravenously 30 minutes prior to chemotherapy. The primary endpoint, the definition of
`non-inferiority, and the definition of moderately emetogenic chemotherapy were the
`same as in study PALO-99-03. The results are shown in the table below and were
`obtained from Table 14 of Dr. Nair’s review.
`
`Stud PALO-99-04
`
`
`
`Number and percentage (%) Subjects with
`a Com lete Res uonse
`Palonosetron Palonosetron Dolasetron
`0.25 mg
`0.75 mg
`100 mg
`(N=l89
`(N=189)
`=191
`119 63.0
`108(57.1
`10152.9
`102(54.0)
`107(56.6)
`74(38.7)
`
`
`
`
`
`Difference in CR rates,
`97.5% Confidence Intervals
`Pal. 0.25 mg
`Pal. 0.75 mg
`minus
`minus
`Dol. 100 m-
`Dol. 100 m-
`-1.7%,21.9% —7.7%,16.2%
`3.404371%,t
`6.0%,29.7%*
`
`
`
`
`
`
`
`Time Period
`(hours)
`
`
`
`
`
`
`
`24-120
`*p<0.05
`
`In this study both doses of palonosetron were non-inferior to dolasetron in the acute
`phase and superior to dolasetron in the delayed phase. The results in the delayed phase
`confirm the finding with the 0.25 mg dose in study PALO-99-03.
`
`Two studies were submitted in support of the highly emetogenic chemotherapy
`indication. Study PALO-99-05 is a multicenter, double-blind, active-control trial in 667
`patients receiving highly emetogenic chemotherapy. Patients were allocated to
`palonosetron 0.25 mg, palonosetron 0.75 mg, or ondansetron 32 mg administered
`intravenously 30 minutes prior to chemotherapy. Highly-emetogenic chemotherapy
`included cisplatin 2 60 mg/m2, cyclophosphamide > 1500 mg/mz, and dacarbazine. The
`primary endpoint and definition of non-inferiority were the same as in the above studies.
`The results are shown in the table below and were obtained from Table 25 of Dr. Nair’s
`review.
`
`
`
`
`Difference in CR rates,
`97.5% Confidence Intervals
`
`Pal. 0.25 mg
`Pal. 0.75 mg
`
`minus
`minus
`0nd. 32 m_
`0nd. 32 m_
`
`~8.8%, 13.1% -2.3%, 19.2%
`-4.6%, 17.3% -l.9%, 20.0%
`
`
`
`
`
`Stud PALO-99-05
`
`Number and percentage (%) Subjects with
`a Comlete Res nonse
`Palonosetron Palonosetron Ondansetron
`0.25 mg
`0.75 mg
`32 mg
`(N=223)
`=223
`(N=221
`132 59.2
`146 (65.5
`126 (57.0)
`101 (45.3)
`107 (48.0)
`86 (38.9
`
`
`
`—
`
`
`
`
`0-24
`24-120
`
`(hours)
`
`These results show that both doses of palonosetron are non-inferior to ondansetron.
`
`

`

`Study PALO-OO-Ol is a randomized, Phase 2, double-blind, dose-ranging study in 161
`patients receiving highly emetogenic chemotherapy consisting of either cisplatin 2 60
`mg/m2 or cyclophosphamide > 1100 mg/mz. Patients were randomized to 0.3, 1, 3, 10, or
`30 ug/kg day. However, in the analysis patients were placed in a fixed dose group of <
`0.1 mg, 0.25 mg, 0.75 mg, 2 mg, or 6 mg. The primary endpoint was the complete
`response rate'during the first 24 hours. The results were compared to a historical placebo
`group and are shown below (from Table 27 of Dr. Nair’s review).
`
`
`Stud PALO-OO-Ol, Com lete Res . onse in the First 24 Hours
`Historical
`Palonosetron Dose
`Placebo
`
`
`
`
`- m
`
`
`
`
`l-__-—_-
`
`
`
`
`This study demonstrates that all doses are superior to the historical placebo and that doses
`higher than 0.25 mg do not provide substantially greater effectiveness.
`
`In subgroup analyses by gender, the complete response rates for women were lower than
`for men in studies PALO-99-03, PALO-99-04, and PALO-99-05. This appears to be a
`class effect since it is also observed in the comparator arms. These analyses are
`summarized in the reviews by Drs. Nair and Korvick.
`
`Adverse events occurring in 2 2% of patients in the chemotherapy-induced nausea and
`vomiting trials are listed in the applicant’s table below. Since the 0.75 mg dose will not
`be used, this dose is not included in the table.
`
`
`
`
`
`
`
`Event
`
`
`
`Adverse Events Occurrin in 2 2%
`Palonosetron 0.25 mg Ondansetron 32 mg
`~
`=633
`(N=410
`
`
`
`
`
`__
`Dolasetron 100 mg
`(N=194)
`
`
`
`
`
`
`
`Adverse events occurring at a rate of 1% included non-sustained tachycardia,
`bradycardia, hypotension and diarrhea. Adverse events occurring at a rate of < 1%
`included hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus
`arrhythmia, superventricular exu'asystoles, QT prolongation, allergic dermatitis, rash,
`motion sickness, tinnitus, eye irritation, amblyopia, dyspepsia, abdominal pain, dry
`mouth, hiccups, and flatulance. The sponsor notes that in many cases the relationship to
`palonosetron was unclear.
`
`
`
`

`

`The potential for QT prolongation was reviewed by Drs. Nair and Korvick. The best
`ECG data was obtained from the phase 3 studies in which ECGs were collected at
`baseline and at 24 hours and 6-8 days after dosing.
`In addition, a subset of 193 patients
`(143 on palonosetron and 50 on an active comparator) had Holter monitoring two hours
`before to 22 hours after dosing and an ECG 15 minutes afier dosing. The QTc data from
`the Phase 3 trials are shown below (modification of applicant’s table 3.4.428 in volume
`1.1, page 185). Although the ECG’s were performed at different time intervals, each
`patient’s worst QTc value is included in the table. The 15-minute ECG is closest to the
`expected Cm“, and with a terminal half-life of 40 hours the 24-hour ECG’s were
`performed at a time when there should have‘been substantial blood levels, particularly at
`the 0.75 mg dose. The data suggest that if palonosetron has clinically significant effects
`on QTc, the effects are similar to those of the approved drugs ondasetron and dolasetron.
`There is no evidence for a dose response effect on QTc for palonosetron in the Phase 3
`studies or in the dose-ranging studies (data not shown).
`In an integrated analysis of all
`trials, the effect on QTcB or QTcB was 2 msec at both palonosetron doses and 4-5 msec
`for ondansetron and dolasetron.
`
`
`
`
`
`0.25 mg
`N=594
`
`0.75 mg
`N=610
`
`32 mg
`N=404
`
`30-.60 msec
`
`41 (6.9%)
`
`54 (8.9%)
`
`> 60 msec
`
`5 0.8%)
`
`3 (0.5%)
`
`100 mg
`N=l92
`
`13 6.8%)
`
`2 (1.0%)
`
`Post-Dose Chan es in QTc
`
`
`Dolasetron
`Palonosetron
`Palonosetron
`Ondansetron
`
`
`
`
`_-_ —
`
`
`
`
`___ -
`
`7 1.7%)
`——-——
`
`
`--——-
`_-—--
`
`
`-__
`
`
`
`>500 msec
`
`l 0.2%
`
`0 (0%)
`
`1 (0.2%)
`
`1 0.5%)
`
`30-60 msec
`
`27 (4.5%)
`
`31 (5.1%)
`
`32 (7.9%)
`
`11 (5.7%)
`
`> 60 msec
`
`5 (0.8%)
`
`2 (0.3%)
`
`4 (1.0%)
`
`1 (0.5%)
`
`>500 msec
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`l (0.5%)
`
`The Holter monitoring results are shown in Table 40, page 78, of Dr. Nair’s review. The
`review states that “individual infrequent cases of Mobitz Type 1] block, sinus pauses, and
`occasional runs of nonsustained ventricular tachycardia were identified, however no
`difference in treatment groups was s'e'en. Many of the subjects had underlying
`cardiopulmonary disease in addition to suffering from cancer and the physiologic stress
`of undergoing chemotherapy. Thus, there was a significant background rate-of events but
`no clinically relevant difference seen between palonosetron at two different doses
`compared to ondansetron and dolasetron.”
`
`

`

`Statistical Review
`
`The statistical review was performed by Stella Grosser, PhD. The review concluded that
`“there is sufficient evidence and reasonable certainty that palonosetron 0.25 mg is
`efficacious in the prevention of acute nausea and vomiting following moderately and
`highly emetogenic cancer chemotherapy. This conclusion is based on standard statistical
`analyses, a permutation analysis that takes the actual allocation method in account, and a
`meta-analysis of historical results. While the analyses are based on comparisons to
`approved anti-emetics (ondansetron and dolasetron), the efficacy conclusions and claims
`are relative to placebo; the label should reflect this distinction.”
`
`“There is also sufficient evidence that it is efficacious in the prevention of delayed emesis
`following moderately emetogenic chemotherapy. Again, the analyses are based on
`comparisons to ondansen'on and dolasetron, but the efficacy conclusions and claim are
`relative to placebo.”
`'
`
`Clinical Inspection Surnmag
`
`The assessment by the Division of Scientific Investigations was that “the clinical
`investigators that were inspected in support of NDA 21-3 72 did not adhere to the
`applicable regulations and good clinical practices governing the conduct of clinical
`investigations as noted herein. There were issues related to protocol deviation,
`inadequate and inaccurate recordkeeping, and inadequate informed consent. However,
`“in general, the inspection of documents support that audited subjects exist, met
`eligibility criteria, received assigned study medication, and completed subject diaries.”
`The overall conclusion was that “the data submitted in support of this NDA appear to be
`acceptable.”
`
`Clinical Pharmacology and Biopharrnaceutics Review
`
`The Clinical Pharmacology and Biophamiaceutics review was performed by Sue-Chih
`Lee, PhD. and Sulirnan Al—Fayoumi, PhD. The review noted that “to evaluate the
`potential QT effect of palonosetron following IV administration, the sponsor analyzed
`l2-lead ECG data collected from Phase 3 trials in which palonosetron was studied at two
`dos levels (0.25 mg and 0.75 mg). A subset of the patients also received Holter
`monitoring. Based on the overall QT data and cardiac safety profiles, the QT effect of
`palonosetron appears to be similar to the approved comparator drugs (dolasetron and
`ondansetron) used in the trials. Palonosetron is eliminated through both renal excretion
`and metabolic pathways with the latter mediated via multiple CYP isozymes, In vitro
`studies indicated that it does not inhibit or induce the activity of many CYP isozymes at
`. therapeutic concentrations. Therefore, the potential for drug interactions with
`palonosetron is low. No dosage adjustment is necessary based on age (I 8 years and up)
`or gender, nor is it necessary for any degree of renal or hepatic impairment. Safety and
`efficacy in pediatric patients have not been established.” The review concluded that “the
`Human Pharmacokinetics and Biopharrnaceutics section of the application is acceptable
`
`

`

`provided that a satisfactory agreement is reached between the Agency and the sponsor
`regarding the language in the package insert.”
`
`Chemistg Review
`
`The chemistry review was performed by Marie Kowblansky, Ph.D. The recommendation
`of the 6/24/03 review was that the application may be approved pending completion of a
`satisfactory GMP inspection and “a written decision by the toxicology reviewer that
`
`_
`impurities
`are qualified to be present at the relatively high levels of ——‘/o as proposed by
`--
`the applicant.” The Division of Manufacturing and Product Quality gave an overall
`recommendation on July 14, 2003.
`
`Microbiology Review
`
`The microbiology review was performed by James L. McVey. The conclusion of his
`review was that “this application is recommended for approval from a product quality
`microbiology perspective.”
`
`Pharmacology/Toxicology Review
`
`The pharmacology/toxicology review was performed by Yash Chopra, M._D., PhD. The
`overall recommendation was for approval of the application with changes in the labeling.
`
`The review noted that “ the cardiac physiology study with palonosetron showed that it
`prolonged action potential duration at concentrations of 0.3 and 3 p M (100 and 1000
`ng/ml).
`It inhibited maximal rate of depolarization at 3 and 30 t1 M in rabbit Purkinje
`fibers. The cardiovascular studies with palonosetron indicated that it inhibited fast
`sodium and potassium channels (hERG (Ikr) and hHNa (Ina) currents) in HEK293 cells
`with ICso of 19-204 t1 M and 6.5 p M, respectively. Palonosetron inhibited hERG
`current by ~17% at the lowest dose tested (10 ng/ml). This concentration was about 10.9
`times the maximum plasma level (0.92 ng/ml) of palonosetron attained by the
`administration ofan intravenous dose of0.25 mg (5 p. g/kg if 50 kg body weight
`assumed) to subjects in clinical trials.” The review also noted that “ondansetron also
`significantly inhibited the HERG'currents in a dose dependent manner with an ICso (1.8 [.1
`M), similar to that of palonosetron.” The cardiovascular effects of palonosenon on blood
`pressure, heart rate, and EKG were determined in conscious dogs. “The dogs were given
`palonosetron intravenously at 0.01, 0.1, and 1 mg/kg. Mean systolic and diastolic blood
`' pressure, heart rate, and EKG were measured for 15 seconds at intervals of 15 minutes
`beginning 24 hours before and until 72 hours afier dosing. No observed effects on these
`parameters were noted at doses up to the high dose of 1 mg/kg (20 mg/mz). This dose is
`approximately 36 fold ofclinical dose of 0.75 mg or 0.015 mg/kg if 50 kg body weight is
`assumed (0.56 mg/mz)!’ In an anesthetized rabbit study, palonosetron at a dose of 10
`mg/kg (120 mymz) produced QT prolongation and ventricular tachycardia. Torsades de
`Pointes was not observed. However, the dose of 120 mg/m2 is about 632 times the
`proposed dose of 0.25 mg (0.19 mg/mz).
`
`

`

`Dr. Chopra’s memorandum of July 10, 2003 addressed the amounts of impurities present.
`The conclusion was that “the amounts ofthe impurities present in the clinical iv dose of
`
`0.24 mg (5 ug/kg/day) palonesetron could be _ W"
`ng/kg/day of.
`‘ and
`M These are small fractions of safe doses of these compounds identified in these
`studies and support the proposed limit of the impurities."
`
`The memorandum of July 10, 2003 by Jasti Choudary, B.V. 80., PhD. provided specific
`recommendations for changes in the (1) Carcinogenesis, Mutagenesis, Impairment of
`Fertility, (2) Pregnancy and Pregnancy Category, (3) Nursing Mothers, and (4)
`OVERDOSAGES sections.
`
`Pre-Approval Safeg Conference
`
`In the pre-approval safety conference with OPDRA it was agreed that the approval letter
`should ask the sponsor to submit as 15-day reports all cardiac events and cases of
`constipation. Cardiac events are of concern because of the potential for QTc
`prolongation. Constipation is of concern because it occurred in 5% of patients and
`because a healthy volunteer who received 0.75 mg in a Phase 1 trial experienced
`abdominal pain and constipation that required treatment in the emergency room.
`
`Recommended Regulatog Action
`
`1. Once the labeling negotiations have been completed, palonesetron should be
`approved for
`0
`the prevention of acute nausea and vomiting associated with initial and repeat
`courses of moderately and highly emetogenic cancer chemotherapy and
`the prevention of delayed nausea and vomiting associated with initial and repeat
`courses of moderately emetogenic chemotherapy.
`2. The approval letter should state that the sponsor should submit all cardiac events and
`cases of constipation as 15-day reports.
`
`0
`
`{see appended electronic signature page}
`
`Robert L. Justice, M.D., M.S.
`Director
`
`Division of Gastrointestinal and Coagulation Drug Products
`Office of Drug Evaluation HI
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Robert Justice
`7/21/03 06:50:46 PM
`MEDICAL OFFICER
`
`

`

`MEMORANDUM -
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`FROM:
`
`'
`
`July is, 2003
`
`Julie Beitz, MD
`
`SUBJECT:
`
`Deputy Ot‘fice Director Memo
`
`TO:
`
`NDA 21-372 Aloxi (palonosetron hydrochloride injection); Helsinn Healthcare S.A.
`
`This memo documents my concurrence with the Division of Gastrointestinal and Coagulation Drug
`Product's recommendation for approval of Aloxi, indicated for (l) the prevention ofacute nausea and
`vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer
`chemotherapy, and (2) the prevention ofdel'ayea’ nausea and vomiting associated with initial and repeat
`courses of moderately emetogenic chemotherapy. Aloxi is a selective serotonin subtype 3 (5-HT3) receptor
`antagonist and is currently not marketed in any country. The studies submitted under NDA 21-372 support
`approval for use ofpalonosetron 0.25 mg administered as a single intravenous dose 30 minutes before the
`start of chemotherapy.
`
`Effectiveness: Comparative Claims
`The original NDA was submitted September 26, 2002. Evidence that palonosetron 0.25 mg was effective
`in preventing acute nausea and vomiting in patients receiving moderately or highly emetogenic
`chemotherapy was demonstrated in three active-controlled, double-blind studies designed as non-inferiority
`studies. Two studies (PALO-99—03 and PALO-99-O4) evaluated patients receiving moderately emetogenic
`chemotherapy and compared palonosetron to either ondansetron or dolasetron. The third study (PALO-99-
`05) compared palonosetron to ondansetron in patients receiving highly emetogenic chemotherapy. The
`primary endpoint for all studies was complete response rate defined as no emetic episodes and no rescue
`medications in the first 24 hours post-chemotherapy.
`
`In two studies, palonosetron was found to be not inferior to the comparator, however in PALO-99-03
`palonosetron was significantly better than the labeled dose ofondansetron. This finding is not replicated in
`other studies in the NDA and raised two concerns: (1) inclusion ofthis finding in labeling without an
`adequate disclaimer would imply that palonosetron is superior to ondansetron in preventing acute nausea
`and vomiting in patients receiving moderately emetogenic chemotherapy, and (2) exclusion of comparator
`drug names and