CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER.-
`
`21-372/8008/8010
`
`SUMMARY REVIEW
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`____.._—.——-—-———-—-—-'—-——"————""—
`
`DATE:
`
`2/29/08
`
`FROM:
`
`Joyce A Korvick, MD, MPH
`DGP/ODE lll
`
`SUBJECT:
`
`Deputy Division Director Approval Recommendation
`NDA 21-372
`
`S—008: postoperative nausea and vomiting (PONV)
`(b) (4)
`_
`8—01 0: removal of QTc prolongation warning information from the
`Warnings and Precautions section
`
`APPLICANT:
`
`Helsinn Healthcare SA
`
`DRUG:
`
`Aloxi® (palonosetron HCl) Injection
`for Intravenous Use (0.075mg)
`
`DIVISION RECOMMENDATION:
`1 recommend approval of 8-008, and S-010,
`
`Regulatory History:
`The sponsor has applied for two indications:
`a.) (8—008) prevention of postoperative nausea and vomiting (PONV) for up to
`l
`(b) (4)
`
`The sponsor is also requesting removal of QTc prolongation warning information from
`the Warnings and Precautions section of the product labeling (8-010).
`
`Aloxi is currently approved for ClNV (Chemotherapy Induced Nausea and Vomiting)
`indications at a higher dose of 0.25 mg I.V. prior to chemotherapy. Since the terminal
`elimination half-life of Aloxi is longer than the other currently approved 5HT3 receptor
`antagonists (40 hours), it provides a potential advantage over the other compounds.
`Efficacy was sustained in the CINV indications for up to 120 hours. This duration is
`listed in the clinical trials section of the current label.
`
`('0) (4)1NDICATIONS:
`PONV (8-008)
`
`This current application (8-008:
`(b) (4)addresses two indications PONV
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`In two randomized, phase 3 clinical studies (PALO-04-O6 and PALO—04—07), at single
`doses of 0.025, 0.050 or 0.075 mg, palonosetron was compared with placebo for the
`prevention of PONV‘
`(b) (4)in 1090 patients undergoing laparoscopic abdominal or
`gynecological surgery (04- 06) or gynecological or breast surgery (04-07).
`Two co-primary endpoints were used for the PONV (b) (4)indications; complete
`response (CR) from 0 to 24 hours, and CR from 24 to 72 hours. Relevant secondary
`endpoints, which studied CR at additional time intervals, were also considered. A
`statistical analysis plan detailed the handling of multiplicity for the primary endpoints but
`not for the secondary endpoints, thus the information is descriptive at best (for further
`details refer to Statistical Review).
`
`The results are shown below for Study-06. Benefit was demonstrated for the 0.075 mg
`dose, which is the dose the sponsor is pursuing for approval. It is noted that this dose
`level failed to demonstrate statistical significance over placebo after from 24 to 72 hours.
`This is an important consideration I will return to later in this summary.
`
`
`Prevention of Posto crative Nausea and Vomiting: Complete Res onse (CR), Study 1, Palonosetron 0.075 mg Vs Placebo
`Palonosetron Vs Placebo
`Treatment
`
`
`
`
`ceb
`)
`
`
`Palonosetron
`67/138 (48.6%)
`Placebo
`55/135 (40.7%)
`* To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p<0.017.
`ADifl'erence (%): palonosetron 0.075 mg minus placebo
`
`Study — 07, originally designated as a pivotal study, was submitted as a supportive study
`due to potential unblinding of the first 130 patients (approx. 30% of study participants).
`The sponsor provided a sensitivity analysis with the full data set including these patients
`as well as excluding these patients. When these patients were excluded efficacy results
`were not statistically significant (see statistical review for full details). Therefore, this
`study was not relied upon in the determination of efficacy in a substantial way.
`
`The sponsor also provided a large phase two, double-blind, dose-ranging study (381
`patients in the ITT population). This study demonstrated that the lug/kg dose
`(approximately 0.075mg) was the lowest effective dose. This study was well conducted.
`
`For the PONV indication, Study—06, the Phase II dose-ranging study, and the CINV
`studies are the evidence upon which this indication will be granted. The pre—specified
`statistical analysis plan limits the proven efficacy to 24 hours post-surgery.
`It is
`important to note, that while not statistically significant, an analysis of 0-72 hours might
`be demonstrated if an additional study or studies were designed with an alternate
`statistical analysis plan. One hurdle associated with this strategy is the fact that most of
`the efficacy occurred in the first 24 hours; however, there may be patients at particular
`rick Fnr PONV which might demptpflapite benefit after 24 hours.
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The labeled indication was specifically written for 24 hour duration of efficacy:
`
`“the prevention of postoperative nausea and vomiting (PONV) for up to 24 hours
`following surgery. Efficacy beyond 24 hours has not been demonstrated.”
`
`The-Team Leader felt that it was important to Specify this in the indication since
`clinicians have already come to expect a longer duration of effect for prevention of NV in
`
`
`
`
`
`
`LABELING PONV (8-008): Thus, in labeling this drug we recommended approval of
`PONV as outlined above, with a description of the clinical trial which described the
`
` atients as abdominal la aroscopy “out-patients”‘
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`S—010: Requesting removal of QTc prolongation warning information from the
`Warnings and Precautions section of the product labeling.
`
`The sponsor supplied a thorough QT study and safety analysis which was reviewed by
`the CDER QT Team. This study was well designed and conducted. The CDER Team
`concluded that:
`
`“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 QTcI 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 (5.1 ms) and 1 ms (4.8
`ms). Similar results were observed for QTcF.”
`
`“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.”
`
`The team agreed with the final changes to the label regarding the QT wording (see final
`label attached to approval letter).
`
`PEDIATRIC PREA:
`
`We are waiving the pediatric study requirement for ages 0 to 1 month of age because
`necessary studies are impossible or highly impractical because there are too few children
`in this age group to study.
`We are deferring submission of the sponsor’s pediatric study for ages 1 month to 16 years
`for this application because the drug is ready for approval for use in adults and the
`pediatric studies have not been completed.
`
`The Deferred pediatric study is a Post-Marketing commitment as' follows:
`
`1. Deferred pediatric study under PREA to evaluate (1) the safety and tolerability of
`two doses of I.V. palonosetron for the prevention of postoperative nausea and
`vomiting, and (2) the efficacy of these two I.V. palonosetron doses to prevent
`postoperative nausea and vomiting.
`
`Final Report Submission: December 13, 2008
`
`DMETS REVIEW:
`
`Carton and Container labeling was reviewed and received very late in the review cycle.
`Discussions were held with the sponsor and it was agreed upon that they would make
`revisions accordingly, as outlined in the approval letter. One issue which was raised was
`the standardization of expression of palonosetron nomenclature and dosage strength.
`Proposed resolution is based upon the sponsors response dated February 29, 2008 in
`which they agreed to the following:
`- Resolve the expression of palonosetron nomenclature and dosage strength on the
`carton label, container label, and in the package insert to present the milligram
`
`

`

`strength consistent with the established name, similar to other FDA—approved
`product labels.
`-
`0 Include a “New Strength” banner on the principal display panel of the carton for
`period of up to approximately six months provided the you can exhaust product
`inventory which includes this banner which may take longer than 6 months.
`This plan was acceptable to us as well as DMETS review team (see approval letter).
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Joyce Korvick
`2/29/2008 07:31:01 PM
`MEDICAL OFFICER
`
`