CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-372/5008/8010
`
`MEDICAL REVIEWg-SQ
`
`

`

`Division of Gastroenterology Products
`Clinical Review
`
`Application Type
`Submission Date
`
`NBA 21—372/8008,
`3 June 2007
`
`(b) (4)
`
`$010
`
`PDUFA Goal Date
`
`3 March 2008
`
`Drug
`Therapeutic Class
`
`Aloxi® Palonosetron
`5HT3 Receptor Antagonist
`
`Applicant
`Regulatory Contact
`
`Helsinn Healthcare SA
`
`Dr; Craig Lehmann
`August Consulting, Inc
`515 Capital of Texas Highway
`Austin, Texas 78746
`
`S I
`
`ntravenous
`
`0.075 mg
`
`Priority Designation
`Formulation
`Dosing Regimen
`
`Indication(s)
`
`Post operative nausea and
`vomiting (PONVI:
`
`Intended Population
`
`Adults
`
`Reviewer
`
`Dr. Nancy F. Snow
`Medical Officer
`
`HFD-l 8O
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`
`Nancy F. Snow
`NDA 21-372/S~008
`Palonosetron, Aloxi®
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY................................................................................................................................5
`
`1.1
`1.2
`
`1.3
`
`RECOMMENDATION ON REGULATORY ACTION ........................................................................................... 5
`RECOMMENDATION ON POST MARKETING ACTIONS .................................................................................... 6
`Risk Management Activity .................................................................................................................... 6
`Required Phase 4 Commitments...
`....6
`
`Other Phase 4 Requests.......................................................................................................................... 6
`SUMMARY OF CLINICAL FINDINGS .............................................................................................................. 7
`
`Brief Overview of Clinical Program.
`....7
`Efficacy .................................................................................................................................................. 7
`Safety ..................................................................................................................................................... 8
`Dosing Regimen and Administration...
`
`Special Populations .............................................................................................................................. 10
`
`1.2.]
`1.2.2
`1.2.3
`
`1.3.1
`1.3.2
`1.3.1
`1.3.2
`1.3.3
`
`1.3 .4
`
`2
`
`INTRODUCTION AND BACKGROUNDll
`
`3
`
`4
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`PRODUCT INFORMATION ........................................................................................................................... 11 ‘
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS ...............................
`
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ..............................................
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ................................................... 12
`PRESUBMISSION REGULATORY ACTIVITY ...............................................
`
`OTHER RELEVANT BACKGROUND INFORMATION ......................................................................................
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .................................................... 13
`
`3.1
`3.2
`
`4.1
`4.2
`4.3
`4.4
`4.5
`4.6
`
`CMC (AND PRODUCT MICROBIOLOGY,.IF APPLICABLE) ........................................................................... 13
`ANIMAL PHARMACOLOGY/TOXICOLOGY .......................................................................... l4
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY...
`................................. 14
`
`SOURCES OF CLINICAL DATA
`................................. 14
`
`TABLES OF CLINICAL STUDIES .
`...... 14
`
`REVIEW STRATEGY ......................
`..14
`
`
`DATA QUALITY AND INTEGRITY ........................
`1 5
`
`COMPLIANCE WITH GOOD CLINICAL PRACTICES.
`...... 15
`FINANCIAL DISCLOSURES .......................................................................................................................... 15
`
`5
`
`CLINICAL PHARMACOLOGY ................................................................................................................... 15
`
`5 . 1
`5.2
`5.3
`
`6.1
`
`6
`
`PHARMACOKINETICS ................................................................................................................................. l 5
`PHARMACODYNAMICS....
`
`EXPOSURE-RESPON SE RELATIONSHIPS .....................................................................................................
`
`
`INTEGRATED REVIEW OF EFFICACY ................................................................................................... 16
`INDICATION; PONV
`(b) (4)........................................................................................................... 16
`6.1.1 Methods ......................................................... l 8
`
`General Discussion of Endpoints...
`................ 18
`6.1.2
`
`Study Design ..................................
`..20
`6.1.3
`
`Efficacy Findings...............24
`6.1.4
`
`......28
`6.1.5
`Clinical Microbiology..
`Efficacy Conclusions ........................................................................................................................... 28
`6.1.6
`
`7.
`
`INTEGRATED REVIEW OF SAFETY ........................................................................................................29
`METHODS AND FINDINGS ..........................................................................................................................29
`Deaths ..................................................................................................................................................30
`
`7.1 .1
`
`7:1
`
`2
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21-372/S—008
`
`Palonosetron, Aloxi® '%
`
`7.1.2
`Other Serious Adverse Events .............................................................................................................30
`7.1.3
`Dropouts and Other Significant Adverse Events
`......... 33
`
`7.1.4
`Other Search Strategies....................................................... 34
`
`7.1.5
`Common Adverse Events ...............................................34
`
`7.1.6
`............36
`Less Common Adverse Events
`
`7.1.7
`Laboratory Findings..................................................... 36
`7.1.8
`Vital Signs ............................................................... 37
`
`7.1.9
`..... 38
`Electrocardiograms (ECGs).
`
`7.1.10
`..................................................42
`Immunogenicity
`7.1.11
`Human Carcinogenicity ..............................................................42
`
`7.1.12
`..42
`Special Safety Studies ...........................................
`
`7.1.13
`Withdrawal Phenomena and/or Abuse Potential ........................
`..42
`
`7.1.14
`..42
`Human Reproduction and Pregnancy Data ................................
`
`7.1.15
`Assessment of Effect on Growth......................42
`
`7.1.16
`Overdose Experience ....................................................................................42
`
`7.1.17
`Post marketing Experience ............................................................................43
`ADEQUACY 0F PATIENT EXPOSURE AND SAFETY ASSESSMENTS ..............................................................43
`7.2.]
`Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to
`Evaluate Safety ...‘...............................................................................................................................................43
`
`7.2.2
`Description of Secondary Clinical Data Sources Used to Evaluate Safety..
`.....45
`7.2.3
`Adequacy of Overall Clinical Experience ...........................................................................................47
`
`Adequacy of Special Animal and/or In Vitro Testing .........................................................................47
`7.2.4
`Adequacy of Routine Clinical Testing ..........................................47
`7.2.5
`7.2.6
`Adequacy of Metabolic, Clearance, and Interaction Workup ..............................................................47
`7.2.7
`Adequacy of Evaluation for Potential Adverse Events for Any New Drug and Particularly for Drugs
`in the Class Represented by the New Drug; Recommendations for Further Study ............................................47
`
`7.2.8
`Assessment of Quality and Completeness of Data ...................................
`7.2.9
`Additional Submissions, Including Safety Update ..............................................................................48
`SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND
`7.3
`CONCLUSIONS ..........................'. ..............................................................................................................................48
`.............................................. 48
`7.4
`GENERAL METHODOLOGY
`
`Pooling Data across Studies to Estimate and Compare Incidence ..
`.....48
`
`Explorations for Predictive Factors .....................................................48
`
`Causality Determination ...................................................................49
`
`
`ADDITIONAL CLINICAL ISSUES ..........................................................49
`
`DOSING REGIMEN AND ADMINISTRATION .............................49
`..............49
`DRUG—DRUG INTERACTIONS
`
`SPECIAL POPULATIONS.................50
`
`........................................................................ 50
`PEDIATRICS
`ADVISORY COMMITTEE MEETING .......................................................... 50
`
`LITERATURE REVIEW ........................................... 5 I
`POST MARKETING RISK MANAGEMENT PLAN ..................................................5i
`OTHER RELEVANT MATERIALS ............................................'..................................................................... 51
`
`7.2
`
`7.4.]
`7.4.2
`7.4.3
`
`8
`
`8.1
`8.2
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8
`
`9
`
`OVERALL ASSESSMENT............................................................................................................................. 51
`
`9. I
`9.2
`9.3
`
`9.4
`
`9.3.1
`9.3.2
`9.3.3
`
`CONCLUSIONS ........................................................................................................................................... 5 I
`RECOMMENDATION ON REGULATORY ACTION ..................... 51
`RECOMMENDATION ON POST MARKETING ACTIONS ..................... 52
`
`Risk Management Activity .............................................. 52
`
`..... 52
`Required Phase 4 Commitments"
`
`Other Phase 4 Requests ............................................. 52
`LABELING REVIEW .................................................................................................................................... 52
`
`

`

`Clinical Review
`
`Nancy F. Snow
`NDA 21-372/8-008
`Palonosetron, Aloxi®
`
`10 APPENDICES... . ...............................................53
`
` ..................................................................................53
`REVIEW OF INDIVIDUAL STUDY REPORTS .
`LINE-BY-LINE LABELING REVIEW.............................................................................................................53
`
`10.1
`10.2
`
`REFERENCES .......................................................................................................................................................... 54
`
`

`

`Clinical Review
`
`Nancy F. Snow
`NDA 21-372/8-008
`PaIOnosetron, Aloxi®
`
`1 EXECUTIVE SUMMARY
`
`1.] Recommendation on Regulatory Action
`
`From a clinical standpoint, approval of this application, with modifications, is recommended.
`The sponsor has a
`lied for two indicationsgfiprevention of postoperative nausea and vomiting
`
`(PONV) for up trim)
`
`labeling.
`
`In two randomized, phase 3 clinical studies (PALO-04-06 and PALO-04-O7), at single doses of
`0.025. 0.050 or 0.075 mg, palonosetron was compared with placebo for the prevention of PONV
`(b) (4)1090 patients undergoing laparoscopic abdominal or gynecological surgery (04-
`06) or gynecological or breast surgery (04-06).
`
`The sponsor defines PONV as nausea and vomiting that occur from 0 to 6 hours postoperatively,
`while patients are in a post-operative, monitored setting.
`(b) (4)
`(b) (4)
`
`
`Smaller doses of palonosetron than the dose currently approved for CINV (0.25 mg) were
`studied in Phase 3 clinical trials, and administration of the study drug was on a one time basis,
`prior to the induction of anesthesia. Adverse events were minimal, and comparable to those
`attributed to Aloxi® in previous CINV trials. In addition to pivotal and supporting studies for the
`two above-mentioned indications, the sponsor submitted a thorough QT study (tQT) which
`demonstrated that at doses as high as 2.25 mg; a dose ~30 times higher than the intended
`PONV
`(b) (4)lose of 0.075 mg, palonosetron did not have a significant effect on the QT
`interval.
`'
`
`'
`
`Two co-primary endpoints (discussed in detail in section 6.1.2 of this review) were used for the
`PONV
`(b) (4)1dications; complete response (CR) from 0 to 24 hours, and CR from 24 to 72
`hours. Relevant secondary endpoints, which looked at CR at additional time intervals, were also
`considered.
`
`Results from pivotal study PALO-04-06 demonstrated a therapeutic benefit over placebo for the
`proposed 0.075 mg palonosetron dose for the time interval 0 to 24 hours. This dose level,
`however, failed to demonstrate significant advantage over placebo in achieving CR from 24 to
`72 hours (i.e., the co-primary endpoint was not met).
`
`A second study, PALO-04-07, originally designed as a pivotal study, was submitted as a
`supportive study due to potential unblinding of the first 130 patients. The FAS (full analysis set)
`used for a sensitivity analysis of the two co—primary efficacy variables showed that there was an
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`
`Nancy F. Snow
`NDA 21-372/S-008
`Palonosetron, Aloxi®
`
`advantage over placebo for all palonosetron doses from 0 to 24 hours, and for the 0.075 mg dose
`for the 24 to 72 hour time period. Results of PALO-04-07 provided some support for the findings
`of PALO-04—O6, although the potential unblinding limits the utility of the trial.
`
`The sponsor’s request to remove QT warning information from the label is based upon favorable
`results from an ICH compliant thorough QT study in which doses of palonosetron as high as 2.25
`mg failed to demonstrate significant effects on the QT interval
`
`Therefore, the following are conclusions regarding the two proposed indications, and removal of
`QT warning information from the product label:
`
`-
`
`PONV; Efficacy and safety are shown for the 0 to 24 hour time period, but
`efficacv was not shown for the period bevond 24 hours He. 24 to 72 hours]
`
`(b) (4)
`
`
`previous CINV trials
`
`0 Periodic post-marketing safety reviews have not identified new adverse reactions
`of concern or new safety signals related to palonosetron administration
`0 Removal of QT warning; some changes to the label are acceptable based on the
`tQT study. These will be addressed in labeling negotiations with the sponsor.
`
`1.2 Recommendation on Post marketing Actions
`
`From a clinical standpoint, no post marketing actions are recommended.
`
`1.2.1 Risk Management Activity
`
`From a clinical standpoint, risk management activity is not recommended.
`
`1.2.2 Required Phase 4 Commitments
`
`From a clinical standpoint, no Phase 4 commitments are recommended.
`
`1.2.3 Other Phase 4 Requests
`
`No other Phase 4 requests are recommended.
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21-372/8-008
`Palonosetron, Aloxi®
`
`1.3 Summary of Clinical Findings
`
`1.3.1 Brief Overview of Clinical Program
`
`Two Phase 3 trials, PALO—04—06 and PALO-04-07, and Phase 2 study 2500, evaluated the
`clinical efficacy and safety of I.V. palonosetron, when administered before surgery to prevent
`PONV:
`(b) (4)
`
`One of the Phase 3 trials (PALO-04-06) is considered pivotal; the others (PALO-04-07), and
`study 2500, are confirmatory. The palonosetron PONV
`(b) (4)development program did not
`include any Phase 1 studies specifically designed as partofthedemonstration of efficacy and
`safety1n PONV
`(b) (4)
`Three Phase I trials conducted in association with the CINV indication are part ofthe sNDA
`submission because they were conducted afier the approval of CINV, and provide important data
`for an understanding of palonosetron Two studiesin healthy volunteers evaluated drug-drug
`interactions; the third was an E14 compliant thorough QT/QTc study Information from all 4
`PONV clinical trials, including 1.V. and oral administration, is considered1n the safety
`evaluation of palonosetron for PONV
`(b) (4)
`
`
`
`l 3.2 Efficacy
`
`As noted, this application15 filed1n support of a single I.V. dose of palonosetron for the
`fem“'M "““‘““‘ “(Station ofpost-0 erative nausea and vomiting (PONV),
`for up to
`(b) (4)
`
`
`
`PONV is defined by the sponsor as nausea and vomiting that occur from 0 to 6 hours
`postoperatively, while the patient is in a post-operative, monitored setting. I
`
`(8
`
`Three clinical studies provide data for the efficacy review to support the PONV l
`indications being sought. These include pivotal study PALO~04-06, and supportive Studies
`PALO-04-07 and 2500. The Phase 3 studies (PALO—04-06 and PALO-04-0—7) are double-blind,
`randomized investigations of palonosetron 0.025 mg, 0.050 mg or 0075 mg given as a single
`I.V. bolus within 5 minutes prior to anesthesia induction, compared to placebo. The objective of
`these studies is to demonstrate superiority of at least one of the three palonosetron doses
`evaluated, over placebo.
`
`(b) (4)
`
`(b) (4)0nly PONV was specified in the original
`Ofthe two proposed indications, PONVE
`.protocol. In PALO—O4—06, for the 0 to 24 hour time period
`(b) (4)1alonosetron demonstrated a distinct therapeutic advantage over
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`
`Nancy F. Snow
`NDA 21-372/S-008
`Palonosetron, Aloxi®
`
`levels. Significant p-values were obtained for palonosetron 0.050 mg (p=0.017), and 0.075 mg
`(p=0.0035). No significant p-values were observed for the 0.025 mg dose.
`
`For the time interval 24 to 72 hours, significant benefit over placebo was not shown for any dose
`level, and all p—values exceeded the pre—set adjusted significance levels. Thus for the PONV 777777
`(b) (4)
`(b) (4lindications, efficacy was seen in the 0 to 24 hour time fi'ame, but not the 24 to 72 hour
`time interval.
`
`Medical Oflicer’s Comments:
`As noted, efi’icacy conclusions are drawnfiom study PALO-04—06. PALO-04—07 is supportive
`only due to potential unblinding. In PALO—04—06, for the 0 to 24 hour time period, palonosetron
`demonstrated a distinct therapeutic advantage over placebo for the 0.050 mg @revention gain
`13.5%) and 0.075 mg (prevention gain 16.8%) dose levels. Significant p—values were obtained
`for palonosetron 0.050 mg (0:0.0] 7), and 0. 075 mg (p=0.0035). No significantp-values were
`observedfor the 0.025 mg dose versus placebo.
`'
`
`In the pivotal study, for the proposed indications, significant benefit over placebo was not shown
`for any dose level during the time interval 24 to 72 hours, since all p—values exceeded thepre-set
`adjusted significance levels.
`
`1.3.3
`
`Safety
`
`('0) (4)
`
`.
`>
`.
`.
`;afety database 18 comprised of safety data fiom 1952 subjects
`The palonosetron PONV;
`enrolled in four clinical trans, in which 1520 patients received palonosetron. In addition to safety
`information from pivotal and supporting studies, information on the effects of palonosetron on
`cardiac conduction (QTc) was submitted in thorough QT study PALO-03-11.
`
`No new safety findings emerged from the PONV development program or post marketing
`surveillance which changes the risk profile of palonosetron since original FDA approval of the
`drug in 2003.
`
`The most common adverse reactions were constipation, flatulence, abdominal pain, headache
`and dizziness. Incidences of these events were similar across all palonosetron dose groups, and
`comparable to placebo, except headache, whose incidence was higher in the highest dose group
`(>0.075 mg), a dose level not used in the Phase 3 trials.
`
`Thorough QT/QTc (tQT) study PALO-03-ll showed that palonosetron is not associated with
`significant QT prolon ation at doses up to 2.25 mg, thus providing a 30-fold safety margin for
`the proposed PONV (b) (4)dose, 0.075 mg, and a 9-fold safety margin for the FDA approved
`CINV dose, 0.25 mg. Information from the ECG analysis performed in association with Phase 3
`PONV trials showed no differences in ECG parameters between palonosetron and placebo-
`treated subjects, further supporting the tQT findings
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21-372/S—008
`Palonosetron, Aloxi®W
`
`The most commonly reported adverse events that were possibly or probably related to treatment
`were constipation and headache, followed by QT prolongation, bradycardia and pruritis.
`Constipation was seen in 3% of patients receiving palonosetron 0.025 mg, 4% of patients
`receiving palonosetron 0.050 mg, 2% of patients receiving palonosetron 0.075 mg, and 3% of
`patients receiving placebo. Likewise, headache was noted in 5% ofthe 0.025 mg dose group, 4%
`of the 0.050 mg dose group, 3% ofthe 0.075 mg dose group, and 4% of the placebo group. In
`summary, a clear cut dose response or differences between palonosetron and placebo was not
`seen. Further analysis of QT data is included in section 7.1.9 of this review.
`
`Overall, the clinical data submitted in this efficacy supplement appear to support the safe use of
`palonosetron as a one-time dose to prevent post-operative
`(b) (4)nausea and
`vomiting for up to 24 hours after surgery.
`
`1.3.4 Dosing Regimen and Administration
`
`The doses of palonosetron selected for Phase 3 PONV studies were based on results of Phase 2
`dose-ranging studies 2500 and 2502._In Study 2500, a single I.V. dose of palonosetron was
`administered to surgical patients at one of five dose levels (0.1 ug/kg, 0.3 rig/kg, 1 pig/kg, 3
`rig/kg or 30 ug/kg) or placebo. In Study 2502, surgical patients were administered a single oral
`dose of palonosetron at one of five dose levels (0.3 rig/kg, 1 pg/kg, 3 pg/kg, 10 ug/kg or 30
`rig/kg) or placebo.
`
`Prior studies in healthy volunteers demonstrated that palonosetron was well tolerated, had
`generally dose proportional pharmacokinetics, and a mean half-life on the order of 40 hours.
`Phase 2 studies showed antiemetic effects in PONV patients (at doses ranging from 0.1 ug/kg to
`30 ug/kg), and provided information for dose selection and additional safety support for
`continued Phase 3 development.
`b
`4
`The proposed PON\
`(
`) ( )narket dose for I.V. palonosetron, 0.075 mg, is more than 3-fold
`lower than the currently approved CINV dose, approximately 80-fold lower than the highest dose
`(90 pg/kg) used in Phase 2 CINV study 2330, and approximately 28-fold lower than the
`maximum dose (30 pg /kg) used in Phase 2 studies in the target PONV patient population. A
`dose of 2.25 mg, used in thorough QT study PALO-03-11, is 30 fold greater than the proposed
`PONV (b) (4)iose.
`
`1.3.5 Drug-Dru g Interactions
`
`The time to recovery during surgery was collected and analyzed in the two Phase 3 trials PALO-
`04-06 and PALO—04-07 to provide a clinical indication of whether palonosetron might have an
`interaction with anesthetic agents. In study PALO-O4—06, the mean (SD) recovery time for
`placebo patients was 9.8 min (10.2), while that of the palonosetron treated patients was 11.8 min
`(12.2), 9.4 min (12.8) and 12.4 min (16.7), after 0.025 mg, 0.050 mg and 0.075 mg, respectively.
`
`Likewise in PALO-04-07 there were no significant differences between placebo and
`palonosetron treated patients in the time to recovery after surgery, and indicate that-a single dose
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21-372/S-008
`Palonosetron, Aloxi®
`
`.
`
`of palonosetron at 0.025 mg, 0.05 mg, or 0.075 mg would not be likely to interact with anesthetic
`agents or other drugs used intra- or perioperatively.
`'
`
`Drug interaction studies in healthy volunteers demonstrated that single doses ofpalonosetron do
`not significantly affect pharmacokinetic parameters ofmetoclopramide or dexamethasone, and
`vice-versa. Although less relevant for the PONY (b) (4)indications, metoclopramide and
`dexamethasone may be used, along with palonosuron, tor the prevention of CINV.
`
`In an interaction study of palonosetron and aprepitant, 0.25 mg ofpalonosetron was administered
`as an I.V. bolus alone or co—administered with aprepitant to healthy subjects. Aprepitant did not
`affect the AUCO-oo ofpalonosetron but did increase its Cmax by 15%, with the 90% CI of
`bioequivalence comparison being 61.8% to 157%, which is outside the bioequivalence
`acceptance criteria of 80% to 125%. Adverse events were similar in both treatments.
`
`The biopharmaceutics reviewer, medical reviewer, and sponsor conclude that co-administration
`of aprepitant with palonosetron is acceptable. From a safety perspective, the increase in Cmax
`does not appear to be clinically meaningfiil.
`
`In-vitro studies indicate that palonosetron is not an inhibitor ofCYP1A2, CYP2A6, CYP2B6,
`CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5, nor does it induce the activity ofCYP1A2,
`CYP2D6 or CYP3A3/4. Therefore, the potential for clinically significant drug interactions with
`palonosetron appears to be low.
`
`'Medical Ofi‘icer’s Comment:
`The drug—drug interaction studies are valuable in elucidating the activity ofpalonosetron with
`anesthetic agents, metoclopramide, dexamethasone, and aprepitant. The later three are drugs
`that may be used Wli/Z‘Qhaalamselronfor the prevention ofCINV, but would not be usedfor
`prevention ofPON 5
`(b) (4)
`
`1.3.6
`
`Special Populations
`
`Palonosetron has not been studied in pediatric populations, the approved label does not
`- recommend dose adjustments for special populations, and the current submission does not
`provide new information on the use of palonosetron in special populations.
`
`10
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21—372/3-008
`Palonosetron, Aloxi®
`
`2
`
`INTRODUCTION AND BACKGROUND
`
`2.1 Product Information
`
`Trade Name (established name): Aloxi® (Palonosetron Hydrochloride)
`
`
`
`Chemical name/em irical formula:
`
`. (3aS)—2-[(S)—1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo—
`leenz[de]isoquinoline hydrochloride
`. C19H24N20.HC1
`
`Proposed Indication:
`The prevention ofpostoperative
`to
`(b) (4)
`
`Proposed Age group: Adults 2 18
`
`(b) (4)1ausea and vomiting (PON\
`
`(b) (4)
`
`br up
`
`Pharmacologic Class: Selective serotonin subtype 3 (5HT3) receptor antagonist
`
`Route of administration, Description, and Formulation: Intravenous injection
`
`Proposed Treatment Regimen: 0.075 mg administered as a single dose injected intravenouSly
`as a bolus, over 10 seconds, immediately before the induction of anesthesia
`
`2.2 Currently Available Treatment for Indications
`
`Three drug products in the 5HT3 receptor antagonist class are available for the indication of post-
`operative nausea and vomiting (PONV). These include; ondansetron, granisetron and dolasetron.
`
`1]
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`
`Nancy F. Snow
`NDA 21-372/S-008
`Palonosetron, Aloxi®
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Palonosetron, initially approved for use in the United States in July 2003, is currently indicated
`for the prevention of acute chemotherapy induced nausea and vomiting (CINV) associated with
`highly and moderately emetogenic chemotherapy regimens, and delayed CINV associated with
`moderately emetogenic chemotherapy. Palonosetron is approved for use in 53 countries
`worldwide.
`
`2.4
`
`Important Issues with Pharmacologically Related Products
`
`In 2006 the FDA Division of Drug Risk Evaluation (DDRE) conducted a review of the Adverse
`Event Reporting System (AERS) for cases of selected cardiovascular events associated with
`ondansetron, granisetron, dolasetron, and palonosetron use. Based on those results, the DDRE
`concluded that cardiovascular AEs are adequately reflected in the labels for ondansetron,
`granisetron, dolasetron, and palonosetron.
`
`At a November 16, 2006 Pediatric Advisory Committee (PAC) meeting the FDA reported on the
`one year post—exclusivity AB review for ondansetron. In the report pediatric deaths pre and post
`exclusivity were examined. Of 14 unduplicated cases, 7 were excluded due to confounding or
`insufficient information, and 7 were confounded by serious underlying medical conditions. In the
`post-exclusivity period 1 death case had insufficient information to assess causality. Continued
`monitoring of ondansetron for adverse events in all populations was recommended.
`
`V
`Medical Officer ’3 Comment:
`The PAC addressedpediatric deaths associated with ondansetron, which is approvedfor
`pediatric use. Palonosetron is not approvedfor pediatric use at this time.
`
`2.5 Presubmission Regulatory Activity
`
`Syntex Laboratories, the original sponsor, filed the first IND for Palonosetron on 2 June 1992
`(IND 39.797) for the I ..V formulationr7777777777777777777777777
`
`(b) (4)
`(b) (4)
`
`‘
`
`(b) (4)Helsinn Healthcare SA assumed responsibilities for béfii"i"ii"’§fia"6féi“““““““““
`INDs on 3 August 1998. The following Table 1 (includedIn the sponsor’s sNDA submission)
`provides a brief overview of regulatory events pertaining to efficacy in the PONV program
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21-372/S-008
`Palonosetron, Aloxi®
`
`\ T
`
`able I
`
`Pre-NDA Meeting
`Dec. 7. 2006
`
`
`Palonosetron PONV Re ulato Histo
`
`
`Outcome of Meetin ~ Agreement
`
`
`
`End-Phase 2 Meeting 5/4/03
`Agreed that the two Phase 3 efficacy protocols, PALO-04-06 and
`
`
`
`PALO-04-07 appeared adequate to pivotally support a label claim for the prevention of
`
`
`PONV. Commented in end of phase 2 meeting minutes regarding the design of treatment
`
`
`allocation schemes and patient populations for these two trials and indicated that the
`
`
`
`
`overall planned design. objectives. efficacy endpoints, sample size and planned statistical
`anal sis were accetable.
`
`
`
`
`FDA SPA of Phase 3 efficacy
`
`
`FDA agreed that the overall protocol design. sample size, outlined execution, and
`
`
`
`protocols; FDA Letters dated Dec. 17,
`2004, March 7~8 2005
`analyses of these pivotal protocols were acceptable as presented.
`
`Teleconference:
`
`
`
`
`A subset of patients was potentially unblinded by an issue in clinical supply labeling. FDA
`Clinical supply label
`Janua
`2006
`
`
`
`agreed that totally replacing the potentially affected 130 patients in Study PALO-04-07
`was accetable.
`
`Teleconference:
`
`
`
`A second episode, identified after enrollment was complete, involved
`
`Potential unblinding at German sites
`
`Oct. 13, 2006
`misapplication of labeling to the drug accountability form at 12 German sites. FDA
`
`
`determined that PALO-O4—07 may serve as a supporting study for purposes of the
`
`
`
`planned PONV sNDA based on this potential unblinding. Further statements regarding the
`
`potential unblinding issue were obtained by a third party from affected sites. A sensitivity
`
`
`analysis on the primary efficacy endpoint has been performed and is included in the
`
`
`PALO-04-07 re-ort as discussed with FD .
`
`
`Based on preliminary Phase 3 efficacy results for pivotal trial PALO—04—06. confirmatory
`
`
`efficacy results from Phase 3 trial PALOvO4-07, and Phase 2 trial 2500. FDA concluded
`
`
`the NDA a n neared read for submission.
`
`
`
`
`
`
`
`
`
`Medical Officer’s Comment:
`The palonosetron regulatory history did not initiallv inphmio
`
`(b) (4)
`
`
`
` l
`
`2.6 Other Relevant Background Information
`
`N/A
`
`3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES
`
`3.1 CMC (and Product Microbiology, if Applicable)
`N/A
`
`13
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy F. Snow
`NDA 21-372/8-008
`Palonosetron, Aloxi®
`
`3.2 Animal Pharmacology/Toxicology
`
`Since palonosetron is already approved, no further pre—clinical studies were required. Animal
`Pharmacology/Toxicology studies are reviewed in the original NDA submission.
`
`4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY
`
`4.1 Sources of Clinical Data
`
`Clinical data is provided by the sponsor in a multiple volume paper submission. Further clinical
`data is derived from trials in support ofthe original NDA approval, and post-marketing safety
`
`4.2 Tables of Clinical Studies
`
`Table 2 provides a description of pivotal and confirmatory trials used to support this submission.
`Table 2; Table of Clinical Studies for NDA 21-372/s008, (b) (4)5010
`Table 8.8.2:] Controlled Clinical Trials
`
`No. ofSubjects:
`_
`
`(enrolledlnmdyzedll-‘AS‘IPP';
`Study Number
`Age Range”
`Study Data
`
`
`Sm: Distribution"
`Cum l ralur
`Sludv Dal n
`Stud Curlers
`m FAS‘ Pose Grow _s
`~
`‘
`..
`.
`--
`,.
`'
`--
`.
`:-'.‘,.-A :1 l’li/Mnl'mmisll‘fi‘iebcv. :‘liid‘Sx‘il'e'ri'FSrud‘v'é
`" :
`;
`':
`
`
`
`Placebo
`
`
`i154 i344
`PAID-04436
`Randomized,