CENTER FOR DRUG EVALUATION AND RESEARCH
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER:
`22-525
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`
`
`APPLICATION NUMBER:
`
`22-525
`
`SUMMARY REVIEW
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`SUMMARY REVIEW
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`June 13, 2010
`
`Director
`Division of Neurology Products/HFD-120
`
`
`
`File, NDA 22-525
`
`MEMORANDUM
`
`DATE:
`
`FROM:
`
`
`
`TO:
`
`SUBJECT: Action Memo for NDA 22-525, for the use of Namenda XR
`(memantine hydrochloride) extended release capsules
`
`NDA 22-525, for the use of Namenda XR (memantine hydrochloride) extended
`release capsules, for the treatment of moderate to severe dementia of the
`Alzheimer’s type (AD), was submitted by Forest Laboratories, Inc., on 8/20/09.
`Namenda (immediate release) tablets are currently approved for patients with
`moderate to severe AD at a maximum dose of 10 mg BID. The application
`contains the results of a single placebo controlled trial of the XR formulation in
`patients on stable doses of an acetylcholinesterase inhibitor (AChEI), that
`purports to demonstrate the effectiveness of a single daily dose of 28 mg, as well
`as safety data from this trial, from open-label trials in patients with AD, and from
`trials in non-AD patients of the immediate release Namenda at doses greater
`than 20 mg/day. The sponsor has also submitted the requisite CMC and
`pharmacokinetic data.
`
`The application has been reviewed by Dr. Ranjit Mani, medical reviewer, Dr. Julia
`Luan, statistician, Dr. Sherita McLamore, chemist, Dr. Irene Chan, Division of
`Medication Error Prevention and Analysis (DMEPA), Dr. Antoine El-Hage,
`Division of Scientific Investigations (DSI), Dr. Xikui Chen, DSI (Bioequivalence
`Branch), Drs. Huixia Zhang, and Hao Zhu, Office of Clinical Pharmacology. The
`team recommends that the application be approved.
`
` I
`
` agree.
`
`
`As described in detail by Drs. Mani and Luan, Study 50 randomized 677 patients,
`with 661 included in the primary intent-to-treat population, to receive either
`Namenda XR 28 mg, once a day, or placebo, for 24 weeks. The study was
`conducted at 83 centers in the US, Mexico, Argentina, and Chile. Patients were
`started on 7 mg/day for a week, and were titrated up by 7 mg/day each week,
`until the target dose of 28 mg given once a day. The primary outcomes were the
`mean change from baseline on the Severe Impairment Battery (SIB), the
`cognitive measure used in the trials supporting approval for immediate release
`Namenda, and the CIBIC-plus, also a standard measure in these trials. The
`comparisons between placebo were statistically significant for both outcomes (LS
`mean difference of 2.8, p=0.001 and mean difference of 0.3, p=0.008, for the
`contrasts on SIB and CIBIC-plus, respectively).
`
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`1
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`0.8
`3.0
`1.5
`3.3
`
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`As Drs. Mani and Luan note, there was a difference in the estimate of the
`treatment effect on the SIB between countries.
`
`Specifically, there were 38 (46% of the total) centers in the US, 23 in Argentina,
`and 11 each in Chile and Mexico. There were 170/661 (26% of the total) patients
`in the US. As Dr. Luan notes, the estimate of the treatment effect (the difference
`in mean change from baseline between drug and placebo) on the SIB by country
`were as follows:
`
`
`US
`Mexico
`Chile
`Argentina
`
`The sponsor suggested analyses that included additional covariates to attempt to
`address (correct for) this “imbalance”. Dr. Luan notes that the results of these
`analyses do not differ materially from the protocol-specified analyses.
`
`Regarding safety, there were no unexpected adverse events noted, nor any
`unacceptable increased frequencies of any adverse events known to be
`associated with Namenda. It is worth noting that the 24 hour AUC of Namenda
`XR, given as 28 mg once a day is about 1.3 times that of immediate release
`Namenda, 10 mg BID, and the steady-state Cmax of the XR is about 1.5 times
`that of the immediate release tablet given as 10 mg BID.
`
`The OCP review notes a moderate dose-dumping effect on all dose strengths of
`20% v/v alcohol at 2 hours, and a pronounced effect at 40% v/v ethanol at 30
`minutes.
`
`Finally, the sponsor has performed a bioequivalence study to compare the
`clinically studied XR formulation to the to-be-marketed formulation. Dr. Chen of
`the Bioequivalence Branch of DSI noted that the inspection of that study
`revealed:
`
`“The integrity and validity of all standard curves used in the analysis of study
`subject plasma samples in Study MEM-PK-17 cannot be confirmed as the source
`records related to the preparation of calibration standards were not maintained at
`Forest Research Institute and were not available for FDA audit (see discussion in
`483 Item1).”
`
`The sponsor responded to the deficiencies noted in the 483 with an explanation
`of how the plasma standard curves were prepared, and that all steps except the
`last step in their preparation were documented in the Sponsor’s notebooks.
`Chromatograms for the standard curves were available. The OCP reviewers find
`this response acceptable.
`
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`
`2
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`

`
`There were no new toxicology studies submitted in this application. However, we
`had been aware of a report in the literature of a single dose study of the
`combination of memantine and donepezil that resulted in extensive “Olney”-type
`lesions. Though memantine, by itself, was known to have caused these lesions,
`the pathology in the combination study was more extensive than had occurred
`with memantine alone, and occurred at a lower dose of memantine when given
`alone. Because of this finding, we had asked the sponsor to perform a 28 day
`combination study. This study detected the lesion, but the pathology appeared to
`be considerably less severe and extensive than the results of the single dose
`combination study. For this reason, it was postulated that the lesion may, in fact,
`be more severe after a single dose than after repeated dosing. Because of this,
`Drs. Freed and Hawver have recommended that the sponsor repeat the single
`dose combination study (the first study had significant flaws), and this will be
`made a post-marketing requirement (PMR).
`
`Comments
`
`The sponsor has submitted a single controlled trial that they conclude provides
`substantial evidence of effectiveness for Namenda XR as a treatment for patients
`with moderate to severe AD. In addition, they have submitted safety experience
`in patients receiving Namenda XR 28 mg, given once a day, from this trial as well
`as from extended, open-label studies. Further, they have provided evidence of
`safety from studies with the immediate release Namenda at doses greater than
`the approved 20 mg/day (10 mg given BID). This data is presumed necessary
`because the Namenda XR 28 mg dose gives an AUC about 1.3 and a Cmax
`about 1.5 times greater than the 10 mg BID dose of the immediate release
`Namenda.
`
` agree that the data submitted establish the effectiveness of Namenda XR. I
`acknowledge, of course, the finding that the estimate of the treatment effect is
`smaller in the US than in other countries, but this poses no bar to approval in my
`view. As Dr. Mani notes, such disparate estimates of a treatment effect in
`different countries is not particularly unusual, and inspections of two sites in
`Argentina revealed no important irregularities.
`
`The sponsor has proposed that Namenda XR be approved as a treatment for
`patients with moderate to severe AD. This would mirror the current indication for
`immediate release Namenda. However, immediate release Namenda was
`studied as monotherapy and adjunctive therapy with AChEIs; this supported the
`“global” claim it now has. Namenda XR has been studied only as adjunctive
`therapy.
`
`Despite the fact that Namenda XR has been studied only as adjunctive therapy, I
`believe it is reasonable to grant it a “global” claim, as with the immediate release
`product. We come to the current application with the established fact that
`
` I
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`3
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`memantine is an active moiety in the treatment of AD, both as mono- and
`adjunctive therapy. The purpose of requiring a controlled trial with Namenda XR
`is to establish that memantine remains effective with this new pattern of
`absorption provided by the XR formulation. We have concluded that this has
`been shown, for the reasons given above. Although it is true that we do not have
`information about the comparative effectiveness of these formulations (although,
`as has been also shown, the exposure with the XR formulation is greater than
`with the 10 mg BID dose of the IR formulation, suggesting that the XR should be
`at least as effective as the IR), and we do not have empirical evidence of the XR
`formulation’s effectiveness when given as monotherapy, I believe it is perfectly
`reasonable to conclude that it will be effective as monotherapy, given the “proof
`of principle” of its effectiveness as a product, obtained in the adjunctive study.
`
` also agree that the safety of Namenda XR has been established. The data from
`the controlled trials at the proposed dose are quite re-assuring, despite the fact
`that the exposures are greater than that produced by the current approved dose
`of immediate release Namenda. The safety experience from controlled trials at
`higher doses than 10 mg BID of the immediate release Namenda, although
`admittedly obtained in populations less fragile than patients with AD, is also
`somewhat supportive of the safety of the proposed XR dose.
`
` I
`
` I
`
` am somewhat concerned about the dose-dumping effect of alcohol on
`Namenda XR, especially at higher concentrations of alcohol. However, both the
`OCP reviewer and Dr. Mani are reassured that the safety of Namenda XR is still
`assured if the entire dose was absorbed rapidly. Further, it is unlikely that the
`population for whom the product is intended will frequently ingest alcohol. For
`these reasons, the in vitro dose dumping effect should not preclude approval, nor
`need there be specific language in labeling warning against ingesting alcoholic
`beverages.
`
` I
`
` also agree with the OCP reviewer that the conclusion reached by DSI about the
`bioequivalence study need not preclude approval; that is, I agree that the
`sponsor has adequately addressed DSI’s concern.
`
`Finally, Dr. Chan has numerous comments pertaining to requested changes in
`the carton and container labeling. These have been discussed with the sponsor
`and they have made the requested changes.
`
`For the reasons described above, then, I will issue the attached Approval letter
`with agreed-upon product labeling.
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`4
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`Russell Katz, M.D.
`Russell Katz, M.D.
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`5
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`Application
`Type/Number
`--------------------
`NDA-22525
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`FOREST
`LABORATORIES
`INC
`
`------------------------------------------
`NAMENDA XR(MEMANTINE
`HCL)ER CAPSULES
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RUSSELL G KATZ
`06/21/2010
`
`