CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-372/8008/5010
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW; S 2
`
`

`

`Interdisciplinary Review Team for QT Studies
`Response to a Re uest for Consultation: TQT Study Review
`
`NDA
`21372
`
`
`Brand Name
`.
`Aloxi®
`
`Generic Name
`Palonosetron
`
`
`
`Sponsor
`Helsinn Healthcare SA
`
`Drug Class
`Selective serotonin subtype 3 (5-HT3) receptor
`
`antagonist
`
`Approved Indication
`Prevention of chemotherapy induced nausea and
`
`vomiting (CINV)
`
`Sought Indication
`Prevention of postoperative nausea and vomiting
`
`(PONV)
`
`Dosage Form
`
`
`IV Solution
`
`Therapeutic Doses
`
`Chemotherapy Induced Nausea and Vomiting:
`o
`0.25 mg injected intravenously over 30 seconds
`30 minutes before starting chemotherapy
`
`Postoperative Nausea and Vomiting:
`
`i immediately before induction ofanesthesia
`
`o
`
`0.075 mg injected intravenously over 10 seconds
`
`
`
`
`
`Duration of Therapeutic Use
`Acute
`
`Application Submission Date
`
`27 Jun 2007
`
`Review Classification
`
`TQT Study Report
`
`Date Consult Received
`
`28 Jun 2007
`
`Clinical Division
`
`DGP / HFD-180
`
`PDUFA Date
`
`01-September 2007
`
`1
`
`SUMMARY
`
`1.1
`
`OVERALL SUMMARY OF FINDINGS
`
`No significant effect of palonosetron administration on the QT interval was detected in
`this thorough QT study. The maximum increase (and corresponding upper two-sided
`90% bound) in the placebo-corrected mean change in QTcl from baseline for the
`0.25 mg, 0.75 mg and 2.25 mg dose groups were -0.6 ms (3.3 ms), 0.6 ms (5.] ms) and 1
`ms (4.8 ms). Similar results were observed for QTcF.
`
`The study was a randomized, double—blind, positive- and placebo-controlled parallel
`study in which 221 healthy subjects were administered single doses of palonosetron 0.25
`mg, palonosetron 0.75 mg, palonosetron 2.25 mg, moxifloxacin 400 mg, or placebo. At
`the supratherapeutic dose (2.25 mg), palonosetron plasma concentrations were 9—fold
`
`

`

`higher than concentrations following the therapeutic dose (0.25 mg). The plasma
`concentrations attained are sufficient to cover the increase in plasma concentrations
`expected due to known intrinsic factors.
`
`A single dose of 400 mg moxifloxacin increased the QT interval by 11 ms (lower 95%
`confidence bound 8 ms) 2 hours after dosing indicating that the study was adequately
`designed and conducted to detect a mean increase in the QTc of about 5 ms.
`
`1.2 ADDITIONAL QT INTERDISCIPLINARY REVIEW TEAM’S COMMENTS
`
`1.2.1 Postmarketing experience
`ICH E14 recommends post-marketing adverse event reports if available can be an
`additional source of information on a drug’s proarrhythmic potential. The QT-IRT
`suggests that the division consider evaluating the postmarketing experience ofALOXI®.
`
`1.2.2 Labeling
`The QT-IRT suggests that the sponsor’s proposed label be changed so that the final
`sentence state “The study demonstrated no significant effect on any ECG interval
`including QTc duration (cardiac repolarization) at doses up to 2.25 mg.” Aloxi®
`has an effect on the QT interval but it is small. Additionally, we recommend that the
`statement in the current label “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” be retained.
`
`2
`
`PROPOSED LABEL
`
`The sponsor proposed the following label:
`
`12. CLINICAL PHARMACOLOGY
`
`12.2 Pharmacodynamics
`
`The effect of palonosetron on QTc interval was evaluated in a double blind,
`randomized, parallel, placebo and positive (moxifloxacin) controlled trial in adult
`men and women. The objective was to evaluate the ECG effects of IV
`administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in 221
`healthv subiects.
`(b) (4)
`(b) (4)
`
`The current label states:
`
`“The effect of palonosetron on blood pressure, heart rate, and ECG parameters
`including QTc were comparable to ondansetron and dolasetron in clinical trials.
`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. In clinical trials, the dose-response relationship to the QTc interval has
`not been fully evaluated.”
`
`“Although palonosetron has been safely administered to 192 patients with pre-
`existing cardiac impairment in the Phase 3 studies, ALOXI should be
`administered with caution in patients who have or may develop prolongation of
`
`(b) (4)
`
`(b) (4)
`
`

`

`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 baseline and 24 hours after subjects received
`palonosetron or a comparator drug. In a subset of patients ECGs were also
`obtained 15 minutes following dosing. The percentage of patients (<1%) with
`changes in QT and QTc intervals (either absolute values of > 500’ ms or changes
`of > 60 ms from baseline) was similar to that seen with the comparator drugs.”
`
`3 BACKGROUND
`Palonosetron is an antiemetic and antinauseant agent. It is a selective serotonin subtype 3
`(5—HT3) antagonist with a prolonged duration of action.
`
`3.1 MARKET APPROVAL STATUS
`ALOXI® (palonosetron) is approved in the USA for prevention of acute CINV associated
`with highly or moderately emetogenic chemotherapy and for prevention of delayed CINV
`associated with moderately emetogenic chemotherapy. The recommended dosage of
`ALOXI® is 0.25 mg administered as a single dose approximately 30 minutes before the
`start of chemotherapy. The sponsor has submitted a sNDA seeking approval to market
`ALOXI® for prevention of postoperative nausea and vomiting.
`Palonosetron has also been approved for use for the prevention of chemotherapy induced
`nausea and vomiting (CINV) in 52 countries outside the US. Palonosetron has not been
`denied market approval in any country due to safety reasons, and palonosetron has not
`been withdrawn from the market in any country where it has been approved.
`
`3.2
`
`PRECLINICAL INFORMATION
`
`The sponsor states the following in the Dec 2005 IB:
`“Palonosetron inhibited hERG and hHNa channels stably expressed in HEK293 cells in
`a concentration dependent manner. The ICso values were 1.9-2.04 uM and 6.5 uM for
`hERG and hHNa channels, respectively.”
`
`“In dog Purkinje fibers, Palonosetron induced a dose dependent increase in action
`potential duration (APDm and APDgo) at 0.3 pM and 3.0 uM, under normal (60 ppm) and
`— to a larger extent - under low (12 ppm) stimulation rates, suggesting a reverse use—
`dependency.”
`“In conscious dogs administered Palonosetron by the intravenous route and monitored
`via telemetry for 24 hours (10 and 100 pg/kg) or 72 hours (1000 pg/kg), there were no
`pharmacologically relevant effects on arterial blood pressures, heart rate, PR interval,
`QRS complex duration, QT interval, QTc and in the frequency and occurrence of
`atrioventricular blocks.”
`
`

`

`PREVIOUS CLINICAL EXPERIENCE
`3.3
`The sponsor states in the Dec 2005 1B that through September 21, 2005, approximately
`(b) (4)vials of palonosetron have been sold worldwide and only one case of
`ventricular tachycardia has been reported (which is termed “unassessable”)
`Reviewer ’s comment: The QT—IRT did not review datafrom other portions ofthe current
`sNDA. Nor did the QT-IRT query AERS to assess ifpalonosetron is associated with an
`unusualfrequency ofadverse events that might be associated with QT-prolongati0n, i.e.
`sudden death, torsade de pointes, ventricular tachycardia, syncope, seizures, and QT
`prolongation.
`
`3.4
`CLINICALPHARMACOLOGY
`Table 1 summarizes the key features of palonosetron’s clinical pharmacology.
`
`(b) (4)
`
`

`

`Pfincignal adverse Wants
`
`Ta_b_le 1_: Highlights of __Clinical Pharmacology
`
`
`
`Theta {14213-952
`{1.2:: m IV
`
`Maximum toierated desist
`Appmx 5 mg {9% gig teswi:3 1322mm. Stuck: 2339)
`
`
`
`NEDAEL (theme £05: ailidies}
`1 mg‘kg{1 111131
`
`6 mgjkgid in dog
`
`AL13§D1111~30 mgkg111 mics
`
`313-11141 mgi‘izg:11 mt
`1:120 maikg in dog
`
`headache cansfipanmi diarrhea. dizzinezs. fafigue.
`
`iiLticimimi a a'
`-
`
`Shah; dgse ’
`
`
`Multile dime
`
`91} tigigg {Sim}; 2330}
`
`
`
`Single Daze;
`
`wa—— 33:5,[1110 ng’L (2813)
`Mean {13%
`
`
`
`
`
`AUCgim"— 87900L1161131 1'43":
`
`
`{1.25 mg 21:1); 3 CPALG02—123
`
`Mifltiyle D053;
`
`
`mean {34811)
`Bay 3 Cm.“- 2430 11.321. (47}
`
`
`9{1:3 pgfkg mica;
`
`
`
`
`cancer a‘ienzs Said '» 26 >
`
`PALO-02'12; 3- daifiy timesoffi.221 mgWIV
`
`Accumiiatian at Steafiy state
`
`Acmiflatian Ratio Ba} 3: '2.10 C21)
`
`[1338311840143 :3: SD]
`
`
`
`sz—— 2.43 3: 114 ng’L 011931;:
`
`PK smmmm. {103131th stead" Sign: 13a}! 1 {P41013241}
`
`sz—— 3mm}: 3.3% gel at sieadv—siate
`1215131301115
`M4 ME}; Amin- i£~ 1""a of Mimi
`
`
`
`IVA {oral i’ormiihtwn NDA m be submitted m4QQ'.’r
`Absorption
`
`
`
`511mm; F= 91- 18014.
`(b) (4).3}:51116
`
`femuiatiom; 90‘?" C15 were 91.3— 1131.9 and 945— 1054,
`~.
`far the {we formulaiiiins res ecsivei. {PAL(140441431
`
`
`Approx 62"A. 13::qu £0 plasma protein;
`fiistrflmiion {mean {SD}}
`
`
`
`
`Vii = 3.3 Lilia 5.1.5: {SD} (3111113: 233%)
`
`
`4-
`214144 skated mtfibnlicaiiy {primarily CY?450 2136 and
`
`Eiimimtion imam; {WSW}
`
`
`to 3 1253.21 extent 3A4 anti 1A2)
`48% {geared 1211311}!
`
`.060
`Clearmca: 1.65 mb‘min‘kg (36} (Stutfy‘ 233B}
`Tamil eiimimiiou‘mlf-iife: apgaiox 40 hours
`
`Tammi eiimination half-fife Mg: 1111 1:611:5{184} fer
`
`90 ugikg {Ease (Study 2330)
`
`. Terminal eiimitiatimi half15136: a’\.4: unable. to i-‘elia'blv
`detenniiie
`
`(b) (4)
`
`

`

`
`
`
`Na efiec: 9% age «m PK {3410-99-3 3}
`intrinsic Factors; mam {CV}
`
`No efiacz a?“ race am Hi {PALS-9933); hewever tom:
`
`hwy ciearagce “r35 2.5% highex in Iapanes‘a mbfiems
`
`{Baldy mm. Na damage adgustmm messm.
`
`No effect cf gamer elucidated in pepufiatim PK
`
`{PKLQ—Qg-BS}; in recent s‘méies inhealihy‘ m’ujectz
`
`Cmx and AUG appeared afiightfiy higher in femalag
`mmpared to males (PALO—OE- 12'} Bay fi:
`
`Female Cm= 2618 ngil (333
`Male. Cm = 225% ngz‘L {59)
`
`Femalg AUCMME 54.5% ng*hI:‘L (‘20)
`Male AUCMnfi 44,000 ngfiztel (29}
`
`0 Renal Empamwwgz the {image adjustmenf necessary
`Heaiflly Sabjxecits
`
`Cm: = 2349 ngfL (35}
`
`AUG MR: ’333 ugfln‘l (38)
`
`Ivfilrcix’Mmi Impairment
`
`Cw; = 233’4 ugél, [dB-I)
`AUG (Him: ‘78.? ug'shz‘l {23)
`
`Severe Impairment
`
`{gm = 2600 ngéL (-47}
`AUG Mm = 385 ugilfi. {44:1
`
`. Hepatic 1319mm; no fiasage aégus/tment neceszary
`Hamill}: S‘ifiajecéa
`
`Cm“ = 2549 agFL {3 5}
`
`AUG Mm: 53.9 ug‘hrfi. (35}
`
`Milt? Impailmeni
`
`Cm; = 1T79 gal. {45)
`
`AUG 9.4355 6&3 ugshx‘l. (4?)
`
`Moderate Empailmem
`
`Cm; = HQ? ngr'L (31}
`
`AUG M155 64.3 ugfilfi. {#7)
`
`Severe Impaimm
`
`Cm; = 99:1 ngsl {36}
`
`AUG Mm = EBA} ughfl. {49)
`
`- No éifi'ereace én PK yrofiig ranemaeen rapid and slow
`
`membefizexs 0f CYPZDIS.
`
`Exm’nsiz: Fatima
`Dmg Iaieraciinn Sméies; effeet 011 9313 Hi
`' Nu efiecé an PK witéz administration at“
`
`
`mafocbpxamiée {PALS-9934)
`0 No effecz on PK. mfi: admimsmtion of dexamefiaasume
`951033-16)
`
`. Nu effeté an PK mm adnmisu‘afion nf aprepitam
`EALO-OS-Di}
`
`' No efieng an co—meds peI 130131113503 PK mode}
`
`WALD-9913 3}
`
`
`MA fix IV femmlatinn. Oral fanmflafion RDA to be.
` Feed Bf§ects
`
`mbmitgeé fa M207 gllmvs no effect of a high fa; meal on
`
`absemfioa ofgalomzetma QALO-{Eé—O'g}
`
`
`
`Ewes axe admimgteged by; a healthcare pmvider,
`Expected High C'Iinim§ Exposure.
`
`
`miserdczgage is cauaidered xmjke‘éy. Degas adminiztered qd
`
`1-; 3 day; in Study PALQ-OZ-lz provided Eess exposure.
`
`than a sin ale 03$ mg dose. whith was smdied in Phase 3.
`
`
`
`

`

`3.5
`
`‘THOROUGH QT’ (TQT) STUDY
`
`3.5.1 Title
`
`Dose-response evaluation of single doses of IV palonosetron 0.25, 0.75, 2.25 mg and oral
`moxifloxacin 400 mg versus placebo on ECG parameters: a double blind, randomized,
`parallel study in male and female healthy volunteers
`
`3.5.2 Protocol Number
`
`PALO-03-11 / SPC 343-3
`
`3.5.3 Objectives
`
`0 To evaluate the dese response for the effects of palonosetron on ECG parameters in
`male and female healthy volunteers.
`0 To evaluate the safety and tolerability of palonosetron and the relative safety in
`comparison with moxifloxacin with focus in ECG parameters in male and female
`healthy volunteers.
`
`3.5.4 Design
`
`3.5.4.1 Description
`
`Randomized, single—dose, double blind, double dummy, parallel group, placebo and
`active comparator controlled study.
`
`3.5.4.2
`
`Sponsor’s Justification for Design
`
`A parallel design was used due to the long half life of palonosetron (about 40 hours). A
`crossover design would have required too long a washout time between treatment periods
`to be practical.
`
`3.5.4.3 Controls
`
`The Sponsor used both negative (placebo) and positive (moxifloxacin) controls.
`
`3.5.4.4 Blinding
`
`The study was double blind using a double dummy approach. Each subject received
`three separate 5 m1 injections of palonosetron and/or its placebo and an oral tablet of
`moxifloxacin or its placebo.
`
`

`

`3.5.5 Dosing Regimens
`
`3.5.5.1 Treatment Arms
`
`
`Treatment group
`
`'
`
`Treatment Administration
`
`,
`
`
`
`
`
`I.
`.
`,
`.
`.
`Treatment!»
`.
`placebo are:
`_ placebo N (3X5 mt)
`ilachoe-
`_
`paionosetron {3.25 mg EV ("E x 0.25 mg palonosatron
`ETreatment B»-
`EPaio‘raosetmn 213.25 m' N . in 5m! + 2 x 5 ml ptaoebo N + ‘iaceho oral
`paicaeeelron {315 mg N {i x 0.75 mg patcncsatron
`’iFamnstm W5 mi N in 5
`2 X
`Eacebo W + iacebo mat
`..
`.. _.
`jTreatment E}-
`paioeosetron 2.25 mg EV (3 x 0.15 mg paionosetron
`Paioncsetrpn 2.25 mg. iv . in 5 ml) + ptacebn ore:
`placebo W {'3 .x 5 mi) + moxifloxacin 400 mg oral
`(b)
`
`.
`
`..
`.
`. .
`
`.
`
`,. -
`
`.
`
`5
`
`3.5.5.2 Sponsor’s Justification for Doses
`
`”The upper dose foreseen in the study is 2.25 mg which seems sufficiently high to cover
`the dose range requested by the guidelines. This dose is indeed 9 times higher than the
`recommended dose (0.25 mg) and approximately 3 times lower than the highest dose
`ever employed in humans. This dose, corresponding to 90 ug/kg, is equivalent to a fixed
`dose of approximately 6 mg and it has been administered to healthy subjects and cancer
`patients in early phase 1 and 2 dose—ranging studies (N=104).”
`
`3.5.5.3 Instructions with regard to meals
`
`The dosing of palonosetron relative to the timing of meals was not described.
`
`3.5.5.4 Study Assessments
`Table 2: Hi - hli - hts of Schedule of Interventions
`
`
`
`1
`
`
`
`
`12-Lead ECGs
`
`Record ECGs
`Baseline
`
`Single dose
`
`Record ECGs
`
`
`
`
`'
`
`
`
`
`
`
`
`# 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h
`##Pre-dose and 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 24h, 26h, 30h, 36h, 40h and 48
`hours post start of dosing.
`###Pre-dose and 15 min, 30 min, 1h, 2h, 4h, 8h, 10h, 12h, 24h, 36h, and 48h post start of dosing.
`
`3.5.5.5 Baseline
`
`Time-matched baselines were used in the study.
`
`3.5.6 ECG Collection
`
`Twelve-lead ECGs were acquired in digital format and transmitted to a central ECG
`laboratory. Triplicate interval duration measurements were first obtained by trained
`analysts using the proprietary
`(b) (4) system applied on a computer
`
`(b) (4)
`
`(b) (4)
`
`

`

`screen. A cardiologist then Verified the interval durations and performed the morphology
`analysis being careful to note any T-U wave complex that suggested an abnormal form
`compatible with an effect on cardiac repolarization. Manual on-screen measurements of
`the RR, PR, QRS and QT interval durations were performed.
`
`Readers were blinded to time, treatment and subject identifier. A single reader
`interpreted all the ECG recordings from a given subject. The degree of inter- and intra-
`reader variability should be established by having a subset of them reread.
`
`3.5.7 Sponsor’s Results
`
`3.5.7.1 Study Subjects
`
`239 healthy male and female subjects with normal baseline ECGs and BMIs were
`randomized (48 to placebo, 48 to palonosetron 0.25 mg, 48 to palonosetron 0.75 mg, 48
`to palonosetron 2.25 mg, and 47 to moxifloxacin). Eighteen of the total 239 subjects
`enrolled did not receive any study treatment and were excluded from analysis. A total of
`220 subjects (92.1 %) of the 239 randomized completed the study (41 were administered
`placebo, 44 palonosetron 0.25 mg, 46 palonosetron 0.75 mg, 46 palonosetron 2.25 mg,
`and 43 moxifloxacin). Nineteen subjects (7.9%) discontinued the study; including the 18
`subjects who were not administered any study medication and one other who was treated
`with placebo and discontinued for personal reasons.
`
`3.5.7.2 Statistical Analyses
`
`3.5. 7.2.] Primary Analysis
`
`Table 3 displays the results of the time-matched analysis, presented as upper one-sided
`95% ANOVA model based confidence limit in milliseconds at each time point for values
`of the QTcI adjusted for both placebo and baseline (delta delta analysis) for the three
`palonosetron dose groups and moxifloxacin.
`
`

`

`Upper boundary of the one—sided 95% ANOVA model based confidence
`Table 3:
`interval for the placebo and baseline corrected values (delta delta analysis) of QTcI
`Time Point
`Palonosetron
`Palonosetron
`Palonosetron
`MoxifloxacEn
`hr
`0.25 m
`0.75 m-
`2.25 m-
`400 m-
`
`
`
`
`
`1
`4.9
`6.7
`8.1
`12.4
`
`
`5.1
`7.6
`5.6
`14.5 ‘
`5 24 5 12.8
`
`
`4.0
`4.4
`.
`
`"‘1.”
`
`
`
`
`
`
`
`
`6 7
`
`.
`12
`2.2
`3.3
`14
`2.3
`14
`6.6
`8.4
`
`16
`2.6
`2.1
`5.7
`9.0
`24
`5.4
`5.1
`4.3
`9.8
`
`26
`4.0
`5.0
`5.8
`5.7
`
`
`30
`5.7
`5.6
`6.9
`7.8
`36
`1.8
`3.4
`3.1
`3.5
`
`
`40
`4.0
`4.3
`6.2
`7.2
`
`
`48
`3.3
`3.5
`3.6
`5.2
`
`(Source: Final report study Palo-03-ll / SPC 343-3 Table 11.4-1)
`
`
`
`
`
`
`3. 5. 7.2.2 Categorical Analysis
`A categorical analysis was done to identify the percentage of subjects that exhibit a
`change in QTcI from baseline of 30-60 or > 60 ms and a new absolute QTcI > 500 ms or
`> 480 ms or > 450 ms in the palonosetron dose groups compared to placebo.
`The following Table 4 summarizes the mean change from baseline (average analysis) and
`the new outliers from baseline for Day 1 for the different Palonosetron dose groups, the
`Moxifloxacin group and the Placebo group. Only one outlier for QTcI was found in the
`palonosetron dose groups. This subject, from the 2.25 mg palonosetron dose group, had a
`30-60 ms change from baseline.
`
`10
`
`

`

`Table 4: Mean change from baseline and new outliers from baseline to Day 1
`
`
`
`Evaluable subjects
`
`
`
`Change in mean value
`Da -1 to Day 1*
`Heart Rate tachycardic
`outliers N
`
`Hear: Rate bradycardic
`outliers N
`
`PR in msec
`
`
`Change in mean value
`Day —1 to Day 1*
`PR ouiliers N
`
`'
`
`‘1 5
`‘
`O
`QRS in msec
`
`Change in mean value
`Da -1 to Da 1*
`QRS outliers N
`
`0 1
`
`'
`'
`0
`
`
`
`QT in msec '
`
`Change in mean value
`Da -1 to Da 1*
`
`_5 8
`‘
`
`
`
`QT new >500 msec N
`
`Q? new>480 msec N
`
`QT new>450 msec N
`
`
`
`(Source: Final report study Palo-03-11 / SPC 343-3 Table 11.4—2)
`
`

`

`Table 5:
`Mean change from baseline and new outliers from baseline to Day 1
`
`.
`1—n
`.
`.
`
`
`Palonosetron Palonosetron Paionosetro Moxrfloxacm
`
`
`Evaluabte subjects
`
`
`Change in mean value
`Da ~1 to Da 1"
`
`
`
`Change in maximum value
`2.
`.
`.
`.
`
`‘ Day_4 to Dav}:
`0
`
`chl new >500 msec N
`
`0.
`
`
`
`o0
`
`o
`
`(No! 30-60 msec inc N (%) n
`QTci >60 msec inc N
`
`
`
`
`”“3“—n
`
`
`
`
`
`
`Change in mean value
`
`Day «1 to 0311‘
`
`QTcF new >500 msec N
`
`
`QTCF new >480 msec N
`0
`
`
`QTcF new >450 msec N n
`
`QTcF 30-60 msec inc N nu
`
`
`
`
`
`
`Change in mean value
`Da —1 to Da 1*
`
`
`
`
`
`0
`0
`QTCB new >500 msec N
`
`
`O
`
`31
`
`O
`
`0
`
`QTcB new >480 msec N
`
`Q?c8 new >450 msec N
`
`
`
`
`
`
`New abnormal U waves N
`
`
`New ST segment elevation
`
`
`changes N
`
`New ST segment depression
`
`
`changes N
`
`New T wave inverted N
`
`
`
`
`New Second & Third Degree
`
`
`Heart Block. Complete RBBB
`
`& LBBB, M} N
`
`Source: Section 14.2, Tables 1 to 16‘
`N= number of subjects
`* negative values mean that predose value is higher than post close value
`bpm =beals per minute; msec=mill¥seconds; QTcl: individual Correction; QTcB: Bazett correction;
`QTcF= Fridertcia correction; RBBB=right bundle branch block; L888: left bundle branch block,
`Ml= myocardial infarction pattern; “new" means not present at baseline and only seen post baseline
`
`(Source: Final report study Palo—O3-11 / SPC 343-3 Table 1 1 .4-2)
`
`12
`
`

`

`3.5.7.3 Safety Analysis
`There were no deaths or SAEs observed. No subject withdrew while experiencing an
`AB. The frequency and intensity of ABS were about the same in all treatment groups.
`Only one cardiac AE, palpitations, was observed and it occurred in a subject receiving
`placebo.
`
`3.5.7.4 Clinical Pharmacology
`
`3.5. 7.4.1 Pharmacokinetics
`The sponsor did not derive PK parameters from the concentration-time data.
`One subject (Subject 382) had extraordinarily high plasma concentrations, approximately
`IOOO—fold higher than other subjects. Subject 382 receiving palonosetron at the dose
`2.25 mg had a Cmax > 106 ng/mL at 15 minutes with plasma concentrations at 30
`minutes
`(b) (4)1 hour
`(b) (4) and 2 hours
`(b) (4) in this
`subject higher than the next highest Cmax in any subject (8 x 103 ng/mL). The analytical
`laboratory confirmed the accuracy ofthese results for these samples. A possible
`explanation based on feedback from the clinical study investigator is that blood samples
`for PK analysis were drawn from the same catheter used for palonosetron administration;
`it appears the catheter may not have been flushed after palonosetron injection. The QT
`data for subject 382 is presented in Table 6.
`Table 6: ECG Data for Subject 382
`Subtract: 357; Queue-n: ultimatum-w 2.23 31
`
`Reviewer ’s Comment: The reviewer computed mean concentration-time datafor this
`study in section 4.2.
`
`3. 5. 7.4.2 Exposure-Response Relationship
`A linear mixed effects model was calculated as the AQT or AQTc versus the plasma
`concentration (as a fixed effect) with subject included in the model as a random effect.
`The model is: AQTc= on + B*(plasma concentration) + y*(subject effect), where A is the
`change from baseline (calculated as time-match difference), on is the intercept, B is the
`slope of the plasma concentration, and y is the subject random effects parameter.
`
`l3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Ifthe p—value ofthe slope for plasma concentration ([5 in the above model) is less than
`0.05, then a linear effect'of delta QTc would be declared. In addition, two calculations
`were performed: (1) a predicted A QTc (maximum mean effect or a "model predicted
`QTc effect") at the mean Cmax and (2) the one-sided upper 95% confidence bound of
`this model predicted QTc effect. The primary analysis used the QTcI parameter, but was
`repeated for QTcF, QTcB, and QT intervals.
`The result of the linear mixed effects model is shown in Figure 1 for QTcI. Similar
`results were observed for QTcF.
`
`Figure 1: Sponsor’s Analysi
`
`s: QTcI Change from Baseline versus Palonosetron
`Plasma Concentration
`
`30.0]
`
`20.73
`
`(b) (4)
`
`
`
`10.0
`
`ginpw
`
`
`
`CharmfromBeeei‘nminum{um} i
`
`119
`
`
`m‘.‘
`m WWW 72am
`mama: am momma! {ngtmt}
`mm mm m as:
`
`Cross—reference: Figure 1a, page 10 ofAddendum 0] t0 CSR PALO-03—l J
`The sponsor concluded that no statistical or experimental evidence was found to
`demonstrate any potential relationship for corrected QT interval or QT intervals with
`plasma palonosetron concentrations after single dose administration of intravenous
`9-fold greater than the
`palonosetron including supratherapeutic doses up to 2.25 mg,
`current marketed 0.25 mg intravenous dose.
`Reviewer’s Comments: The sponsor’s exposure—response analysis is acceptable. We
`prefer, however, that the placebo response is also accountedfor in the model. The
`reviewer did not re-analyze the concentration and QTC data because the primary
`statistical endpoint was negative and there was no concentration- AQTc relationship.
`
`4 REVIEWERS’ ASSESSMENT
`
`4.1
`STATISTICALASSESSMENTS
`This was a parallel, double blind, placebo and positive (moxifloxacin) controlled study
`evaluating single doses in healthy male and female subjects to evaluate the
`electrocardiographic effects of three doses of Palonosetron (0.25, 0.75 and 2.25 mg IV).
`
`(b) (4)
`
`

`

`The moxifloxacin group was used as a positive control to determine the assay sensitivity
`of this study.
`
`The sponsor presented the QTcI change from baseline for the primary analysis using a
`mixed model that included classification variables for treatment, subject (random effect),
`gender, time point, treatment by time point interaction. We did similar calculations for
`QTcl as well as for QTcF and reached the similar results. We also conducted a GLM
`statistical model which included the baseline QTc as a covariate and reached the similar
`results. We confirmed that the upper limits of the two sided 90% CI for the QTcI
`intervals for the difference in least square means between the respective palonosetron
`(0.25, 0.75 and 2.25 mg IV) and placebo were all less than 10 ms. The differences in
`treatment least square means were less than 5 ms for all time points and for all
`Palonosetron groups. Results conducted for QTcF were consistent with those for QTcI.
`
`Analysis of Time-Matched and Baseline Adjusted QTcI (ms) by Time Point
`Table 7:
`Least Square Means
`
`T‘
`P '
`t
` Palonosetron Palonosetron Palonosetron Palonosetron Palonosetron Palonosetron
`ime om Placebo
`(hr)
`0.25 mg
`0.75 mg
`2.25 mg
`0.25 mg
`0.75 mg
`2.25 mg
`(n = 44)
`(n = 46)
`(n = 46)
`- Placebo
`- Placebo
`- Placebo
`(n = 42)
`——_——-a_——
`M
`
`
`
`“M
`m—
`
`_——_—m
`
`—_——__—-E-
`
`
`
`
`
`
`
`
`
`
`
`
`—_-___—-m
`
`
`
`
`
`In addition, assay sensitivity was demonstrated by the time-matched analysis showing at
`least one lower bound of the mean difference of moxifloxacin and placebo after baseline
`correction for QTcI exceeded 5 ms. It should be noted that a multiple endpoint
`adjustment was not performed here.
`
`15
`
`

`

`
`
`
`—————‘I=-
`
`_—_——‘_
`_——_‘I=-_§=-
`“—_———
`“———“-E-
`
`———__-i_
`.
`
`—-E_
`
`For categorical analysis, we conducted the analysis on triplicate QT/QTc without
`averaging the replicates at each time points (see results in Table 9). We confirmed that
`no subject had an absolute QTcI interval above 450 ms post treatment. There were five
`subjects who had an increase from baseline between 30 and 60 ms in Palonosetron 2.25
`mg group and only one in placebo and Palonosetron 0.75 mg group, respectively, but no
`subject had an increase in QTcl from baseline of more than 60 ms.
`
`Assay Sensitivity Analysis of Time—Matched and Baseline Adjusted QTcI
`Table 8:
`(ms b Time Point in Da
`1
`
`Least Square Means
`Treatment Diff.
`T'
`P ' t
`_
`_
`Imfhrfm
`Placebo
`Moxifloxacin MOXIfloxacm -
`(n = 42)
`(n = 43)
`Placebo
`
`90% Confidence Intervals
`Moxifloxacin _ Placebo
`—
`Lower Bound
`Upper Bound
`
`
`
`
`
`
`
`
`
`
`
`
`'.
`
`
`
`
`Table 9: Freuerfl for Delta QTc: 30~60 ms.
`Total # 0
`Total # o
`.
`'.
`Obs.
`# of Obs. % ofObs.
`1--
`
`
`I.
`
`
`
`
`
`
`
`4.2
`CLINICAL PHARMACOLOGY ASSESSMENTS
`The mean palonosetron concentrations are shown in Figure 2 for the 0.25 mg, 0.75 mg
`and 2.5 mg dose groups. Mean concentrations obtained 15 minutes after IV dosing were
`527 ng/ml, 1780 ng/ml and 4570 ng/ml for the respective dose groups.
`
`16
`
`

`

`Figure 2: Mean Concentration—Time Profiles for 0.25 mg (black), 0.75 mg (blue) and
`2.25 mg (red) Dose Groups (Excludes Subject 382)
`
`5000 1
`
`
`
`Palonosetron,ng/ml
`
`4500 J
`4000 J
`3500 J
`
`3000 —
`
`
`
`2500 1
`
`2000 J
`1500 J
`1000 J
`5001K“J
`
`0
`I
`'r
`l
`'r
`|
`I
`_|
`i— —|
`
`0 612182430364248
`
`Time, h
`
`4.3 _ CLINICAL ASSESSMENTS
`None of the adverse events identified as significant in the ICH E14 guidelines (i.e.,
`sudden death, torsade de pointes, ventricular tachycardia, syncope, and seizures) were
`observed during the trial.
`
`17
`
`

`

`5 APPENDIX
`
`TABLE OF STUDY ASSESSMENTS
`5.1
`
`
`TREATMEENTPERIQU
`
`ism BASELENE
`
`EEVAWHIQN
`
`I mowed Cmsem
`_:I:I
`138.1 singise standard
`
`
`'
`
`.. mlfigy (Hepafifismew
`
`1mm; bmath test
`
`x
`;
`" _--
`
`
`
`
`
`
`BF: Isl-ind pressum
`PR: pufia rate
`{a}:
`“~23a45n1ia, «Zah‘sormn. x285, Jam Jim}, 4%. »16h, 44%, 4231* Hon. nah
`‘(nc ECG was performed at 34 h awarding 20 Amenémant m, defied DE-JM-EEQE)
`lmediawly inefere Study drug adn1lfiistrafion®rew§esal
`c‘iscmrge {mm the dinical mi:
`
`(33}:
`(cf):
`
`18
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Stephen Grant
`8/3/2007 06:38:57 PM
`MEDICAL OFFICER
`
`Joanne Zhang
`8/6/2007 10:37:05 AM
`BIOMETRICS
`
`Kate L Dwyer
`8/6/2007 10:39:12 AM
`BIOMETRICS
`
`Christine Garnett
`
`8/6/2007 10:48:56 AM
`PHARMACOLOGIST
`
`Norman Stockbridge
`8/6/2007 11:01:32 AM
`MEDICAL OFFICER
`
`

`

`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA:
`
`21—372
`
`Brand Name
`
`Generic Name
`
`Reviewer
`
`Team Leader
`
`OCP Division
`
`OND division
`
`Sponsor
`
`Submission Type; Code
`
`Submission Date(s): April 27, 2007, Jan 14, 2008
`
`Aloxi®
`
`Palonosetron hydrochloride
`
`PeiFan Bai, Ph.D.
`
`Sue-Chih Lee, Ph.D.
`
`Division of Clinical Pharmacology 3
`
`Division of Gastroenterology Products
`
`Helsinn Healthcare
`Supplement 008,
`
`(b) (4)010
`
`Formulation; Strength(s)
`
`0.075 mg/1.5 ml
`
`Indication
`
`Prevention of postoperative
`(D) (4)
`ID) I4) for up
`nausea and V0r&§§ir(1g)(PON\
`
`
`Table of Contents
`
`Table of Contents ............................................................................................................................ 1
`1
`Executive Summary ................................................................................................................. 1
`1 1
`Recommendation .............................................................................................................. 1
`1.2
`Phase IV Commitments .................................................................................................... 2
`1.3
`Regulatory Background ..................................................................................................... 2
`1 4
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings .............. 2
`2 Question Based Review ........................................................................................................... 3
`2.1
`General Attributes ............................................................................................................. 3
`2.2
`General Biopharmaceutics ................................................................................................ 9
`2.3
`Analytical Section ............................................................................................................ 10
`3
`Detailed Labeling Recommendations .................................................................................... 11
`4 Appendices ............................................................................................................................. 13
`4.1
`Proposed labeling ........................................................................................................... 13
`4.2
`Individual Study Reviews ................................................................................................ 21
`4.3
`Cover sheet and GOP Filing/Review Form ..................................................................... 21
`4.4
`Attendees at my briefing which took place ...................................................................... 21
`4.5
`Appendix 1 Individual study reviews .............................................................................. 22
`4.6
`Appendix 2. Jan-14—O8 amendment review ................................................................... 34
`
`1
`
`Executive Summary
`
`1.1
`
`Recommendation
`
`The application is acceptable from the clinical pharmacology perspective provided
`the labeling comments are adequately addressed by the sponsor.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`12
`
`Phase IV Commitments
`
`None
`
`Regulatory Background
`1.3
`Aloxi (palonosetron hydrochloride injectable) has been approved since July 25, 2003 for
`the prevention of chemotherapy-induced nausea and vomiting (CINV). The dose
`approvedIs 0. 25 mo (free base). On April 27, 2007, Helsinn Healthcare submitted
`supplements 008,
`(b) (4)to seek the approval of intravenous palonosetron for two
`new indications of preventinn postoperative
`(b) (4) nausea and vomiting
`(PONV
`(b) (4) up to
`(b) (4)3nd to add the safety data from a
`thorough QT/QTc study PALO—03-11 to label. For the newly submitted supplements and
`proposed indication, the dose is 0.075 mg (free base).
`
`1.4
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`Product: Aloxi® for the proposed indications contains palonosetron hydrochloride (0. 075
`mg free base per 1. 5 ml) for a single dose administration. Palonosetron is a selective 5—
`HT '2 rnnnnfnr nntnqonist The proposed new indications are prevention of postoperative
`(b) (4) nausea and vomiting (PONV
`(b) (4) up to
`(b) (4)
`
`(b) (4)
`
`In the target population of women with abdominal and
`Pharmacokinetic characteristics:
`vaginal hysterectomy, the pharmacokinetic parameters of palonosetron were highly
`variable. The AUC0_24 values showed a trend of dose proportionality over the dose range
`of 0.3 pg/kg to 30 pg/kg. Ove