CENTER FOR DRUG EVALUATION AND
`
`, RESEARCH
`
`APPLICA TION NUMBER:
`
`21-774
`
`' MEDICAL REVIEW! SQ
`
`

`

`MEMORANDUM
`
`DATEzAugust 31, 2005
`
`FROM:
`
`Director
`
`Division of Neurology Products/HFD-120
`
`TO:
`
`File, NDA 21-774
`
`SUBJECT: Action Memo for NDA 21—774, for the use of Ambien CR (zolpidem
`tartrate extended-release tablets) in patients with insomnia
`
`Sanofi-Synthelabo Inc. submitted NDA 21—774, for the use of Ambien CR
`(zolpidem tartrate extended-release tablets) in patients with insomnia on June 8,
`2004. Ambien immediate release tablets are currently approved for the
`treatment of insomnia. The application was submitted to HFD-170, the division
`responsible at that time for sedative/hypnotic drug products.‘ The application
`consisted of the results of two randomized controlled trials, each of 2 weeks
`
`duration. Study 29, in non-elderly adults, compared the effects of a 12.5 mg
`dose to placebo; Study 30 compared the effects of a 6.25 mg dose to placebo in .
`elderly adults. HFD-170 issued an Approvable letter on April 8, 2005, informing
`the Sponsor that, “The data in‘this application are inadequate to establish the
`efficacy of Ambien CR for the treatment of sleep maintenance insomnia”, and
`asking the sponsor to perform at least one additional study, _“...that supports not
`only an early treatment effect over a reasonable period during the night, but a
`reasonable degree of durability of that effect as well.”.
`
`Presumably, these conclusions were based on the division’s view that Study 29
`in non-elderly adults did not adequately demonstrate an effect on sleep
`maintenance after the first two nights of treatment. This conclusion was based
`on the fact that the protocol—specified outcome, PSG WASO over hours 0-8 on
`nights 15 and 16, did not reach statistical significance.
`
`Briefly, the protocol-specified primary outcome in this study was PSG WASO
`from hours 0-8 on nights 1 and 2. By protocol, if this outcome reached statistical
`significance on an ANOVA (which it did), the same outcome was to be tested on
`- nights 15 and 16'. This comparison, however, failed to reach statistical
`significance. Further analyses of these data revealed that there were highly
`significant results at nights 15 and 16 from hours 0—6; based on this observation,
`the protocol-specified outcome in Study 30 was changed to PSG WASO from
`hours 0-6.
`In this second study, this outcOme did reach statistical significance on
`nights 1 and 2, and also at nights 15 and 16.
`
`Further, because the results of the WASO on nights 15 and 16 were not
`significant in Study 29, the protocol prohibited an examination of other secondary
`outcomes on these nights, including especially measures of sleep latency.
`
`

`

`The sponsor responded to this letter with a submission dated 5/31/05." In this
`submission, they argue that it is more appropriate to rely on ANCOVA for the
`WASO measurements(utilizing the baseline value of the measurement in
`question as the covariate because of baseline differences in these measures;
`such an analysis was included in the protocol to be utilized if there were baseline
`imbalances, and the prior record suggests that the Agency actually requested an
`ANCOVA), and further, that it is also appropriate to rely on the contrasts in Study
`29 (in non-elderly adults) on WASO hours O-6,-as was done prospectively for
`Study 30.
`In addition, they argue that subjective assessments of sleep were in
`favor (some reaching statistical significance) of Ambien CR on nights 15 and 16.
`
`Examination of the results reveals a number of findings of interest.
`
`Study 30 is unequivocally "positive" on WASO 0-6 hours on nights 1 and 2 and
`nights 15 and 16. Examination of WASO hour by hour reveals significant
`differences in favor of drug on hours 2—6 on nights 1 and 2, and in favor of drug
`on hours 2-4 on nights 15 and 16. On hour 8 on nights 15 and 16, the direction
`of the effect reverses. Further, analyses of sleep latency on nights 1 and 2
`clearly reached statistical significance, as it did on. nights 15 and 16.
`
`In Study 29, although the results of the analyses of P86 WASO over hours 0-8
`do not reach significance on nights 15 and 16, the study is clearly “positive” on its
`primary outcome (WASO over hours 0-8 on nights 1 and 2). Analyses of WASO
`over hours 0-6 (the primary outcome in Study 30) on nights 15 and 16 is also
`clearly nominally significant (p<0.0001 by ANCOVA; similar results on ANOVA).
`Examination of WASO hour by hour reveals significant differences favoring drug
`on hours 1—7 on.nights 1 and 2, and for hours 2-5 on nights 15 and 16. On hours
`7 and 8, the direction of effect reverses on nights 15 and 16. Further, sleep
`latency is clearly significant on nights 1 and 2 (p<0.0001 by ANCOVA; p=0.04 by
`ANOVA) and nights 15 and 16 (p=0.034) by ANCOVA, but only on nights 1 and 2
`by ANOVA.
`-
`
`.
`
`In both studies, differences on subjective measures generally favored drug over
`placebo both on nights 1 and 2Iand nights 15 and 16, although nOt all statistically
`significantly (see, for example, Dr. Buenconsejo's statistical review, page 45).
`Mean change in patients’ overall global impression reached significance at all
`time points in both studies.
`
`COMMENTS
`
`Although HFD-170 issued an Approvable letter for this application, they had
`concluded that Study 29 did not demonstrate the (persistent) effectiveness of
`Ambien CR in improving sleep maintenance, and, that, therefore, the sponsor
`needed to perform an additional trial to demonstrate this effect.
`I have a different
`View.
`
`

`

`The Agency had agreed that examining PSG WASO from hours 0-6 (in Study 30)
`was a clinically appropriate measure of Ambien CR’s ability to improve sleep
`maintenance.
`In this study, there were clearly significant findings on nights 1 and
`2 as well as on nights 15 and 16.
`.
`
`A post-hoc analysis of this measure in Study 29 showed a highly nominally
`statistically significant effect favoring drug on this outcome on nights 15 and 16,
`with a-p-value of <0.0001 (recall that this outcome was already clearly'positive on
`nights 1 and 2). Further, an examination of the hour to hour results out to Hour 5
`on nights 15 and 16 (analyses we asked the sponsor. to perform) yields highly
`significant treatment differences favoring drug (p-values typically <0.001).
`Although we would not typically accept as definitive the results of a' post hoc
`analysis, in this case it seems to me to be reasonable to do so. Although the
`sponsor presumably chose this duration as primary for Study 30 based on the
`' retrospective examination of the Study 29 data, the Agency's acceptance of this
`time period as being clinically meaningful was clearly independent of the specific
`findings. That is, the Agency agreed to accept hours 0-6 as a clinically
`meaningful period on which to base a conclusion about Ambien CR’s
`effectiveness as a sleep maintenance drug not because of any specific results, ,
`but based on an independent judgement that this had clinical meaning (for
`example, had retrospective analyses of Study 29 revealed nominal significance
`only on Hours 0-2, the Agency would not have accepted this as a primary
`outcome measure for Study 30, because it would not have been clinically
`appropriate as a measure of sleep maintenance). Once this point is accepted,
`the question then becomes whether or not the (retrospective) finding on this
`measure in Study 29 is acceptable.
`
`l_be|ieve it is, despite the fact that it is post hoc, primarily because of the
`robustness of the finding. Specifically, the p—value for the overall Hours 0-6
`- contrast is highly significant (p<0.001), and the p-values for the hour by hour
`analyses are of a similar magnitude.
`I believe that these highly robust results, on
`a measure independently considered to be meaningful (and which show similarly,
`though actually somewhat less, robust results in Study 30, in which they were
`prospectively designated and are considered unequivocally “positive”), support
`the conclusion that Study 29 has demonstrated an effect on sleep maintenance
`at nights 15 and 16. Further, examination of the record suggests that the Agency
`required the sponsor to establish an effect on WASO beyond Hour 3; this was
`shown in both studies out to nights 15 and 16.
`
`It is true that with increasing duration of treatment, the effect seems to diminish,
`and at the last hour(s) of the night, the effect reverses. Experts consider the
`panoply of effects seen here to represent what may be called “consolidation” of
`sleep, in which effects on sleep are essentially ”shifted to the left” (that is,
`'
`patients fall asleep faster and stay asleep better during the night, with a slight
`“rebound” in the early morning hoUr(s), giving rise to better sleep quality for most
`
`

`

`in these studies, as a general matter, patients considered the
`of the night).
`overall effects on sleep to be superior on drug compared to placebo, even on
`nights 15 and 16.
`
`Dr. John Feeney, Neurology team leader, concludes that the application should
`not be approved until the observation of the early morning change in the direction
`of the WASO findings is better understood.
`
`I agree that the genesis of this finding may not be completely understood at this
`time, and that the finding is of some concern, but I do not believe that this
`undermines the conclusion that the treatment is useful. Patients clearly
`considered the treatment useful overall, including out to nights 15 and 16.
`addition, patients did not experience early morning “hangover” or cognitive
`impairment; it is possible that, had the drug’s sleep-inducing effects persisted out
`to hour 8, patients would have been more likely to suffer early morning negative
`symptoms. The sponsor also performed additional analyses that demonstrated
`that early morning wakefulness was correlated with improvements in sleep
`latency and middle of the night sleep, independent of treatment; because drug
`induced greater improvements than placebo in these latter measures, drug-
`treated patients had more wakefulness in the early morning compared to placebo
`patients.
`In this sense, there appears to be a “trade-off” of drug effects, a trade-
`off that, in my view, the data suggest was preferable to patients.
`
`in
`
`Further, the very short duration of the studies is also of some concern (had the
`development program been initiated today, we would require longer studies;
`however, there are many areas of drug development in which similarly evolving
`standards are not imposed on sponsors whose development under older
`standards has been largely complete at the time of submission of their
`application).
`In any event, I believe that the sponsor has demonstrated
`effectiveness on sleep latency and maintenance in two studies for up to 2 weeks,
`and that the specific issues discussed above (short duration of the studies,
`diminishing of the effects over time, and'early morning reversal of effect) can,
`and should, be clearly described in labeling.
`
`For these reasons, I willIssue the attached Approval letter, with appended
`agreed-upon labeling
`
`. Russell Katz, M.D.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Russell Katz
`
`9/9/2005 02:12:59 PM
`MEDICAL OFFICER
`
`

`

`MEMORANDUM
`
`NDA 21-774 Ambien CR (zolpidem tartrate extended-release tablets)
`
`FROM:
`
`John Feeney, M.D.
`Neurology Team Leader
`
`SUBJECT: Response to Approvable Letter; July 6, 2005
`
`DATE:
`
`August 31, 2005
`
`On April 8, 2005, an Approvable Letter was sent to the sponsor for Ambien CR for the
`’ treatment of insomnia. The letter was sent by‘ the Division of Anesthetic and Critical
`Care Drug Products; subsequently responsibility for the sedative/hypnotic drug group
`was transferred to the Division of Neurology Products. In the Approvable Letter, the
`sponsor was asked to perform another clinical study to demonstrate “...not only an early
`treatment effect (on sleep maintenance) over a reasonable period during the night, but a
`reasonable degree of durability of that effect as well.”
`
`In support of the original application, the sponsor had performed 2 clinical studies. The
`first included non-elderly adult patients with chronic insomnia. The protocol—specified
`primary outcome was wake-time after sleep onset (WASO) from 0-8 hours on nights 1,2
`post-randomization. Using a stepdown approach, if the outcome at nights 1,2 was
`statistically significant, the same outcome was to be assessed at nights 15,16.
`
`The WASO 0-8 hours was statistically significant at nights 1,2. However, it was not
`statistically significant at nights 15,16.
`
`As a post hoc analysis, the sponsor investigated the WASO from 0-6 hours and found
`the result nominally significant at nights 1,2 and at nights 15,16.
`
`The second clinical study included elderly adult patients with chronic insomnia. Based
`on the outcome from the non-elderly study described above, the sponsor prospectively
`defined the primary outcome to be WASO 0-6 hours in this study. Again the timing of
`the primary outcome assessment was to be nights 1,2. Using a stepdown procedure, if
`the outcome at nights 1,2 was statistically significant, the same outcome would be
`assessed at nights 15,16.
`-
`
`The WASO 0-6 hours was statistically significant at both nights 1,2 and nights 15,16.
`
`Subsequent to the Approvable Letter, there was internal discussion about the clinical
`relevance of a drug product that might improve sleep maintenance for only the first 6
`hours of the night. The quote from the Approvable Letter in the above first paragraph
`suggests that the agency was willing to consider variable periods of time for
`assessment of the WASO in support of a sleep maintenance claim (“.-..over a
`
`

`

`reasonable period of time during the night...”). From these discussions, a consensus
`emerged that a 0-6 hour effect was clinically relevant. Given this evolution of thinking
`within the agency, the sponsor was informed at a June 28, 2005 meeting that, with
`agreement on labeling, Ambien CR could be approved without the conduct of an
`additional clinical trial.
`
`The sponsor submitted labeling on July 6, 2005.
`
`Dr. Elizabeth McNeil reviewed the clinical data from the original NDA and has reviewed
`the new labeling in the context of recent meetings. I should note that this is the first
`review that l have written about Ambien CR, having only come to the project in the past
`two months.
`-
`
`Basis for Approval
`
`A. In her current review, Dr. McNeil concludes that Ambien CR should now be approved
`based on the results of the 2 clinical trials discussed above. In both trials, she argues,
`the primary protocol-specified outcome measure was statistically significant. In the first
`trial, this was the WASO 0-8 hours on nights 1,2. In the second trial, this was the WASO
`0-6 hours on nights 1,2. Given the new consensus that a 0-6 hour maintenance effect
`(the primary outcome in the elderly study) was clinically relevant, she believes Ambien
`CR should be approved.
`
`' Because the nights 15,16 outcome was not a primary outcome in either trial, she does
`not believe the failure of the WASO at nights 15,16 in the non-elderly study should
`preclude approval. She believes this finding should be described in labeling.
`
`[While not clearly reflected in the previous record for this application, I believe that a
`failure on the primary outcome at nights 15,16 for a treatment for chronic insomnia
`would be viewed by others involved in the review of sedative/hypnotics as a critical flaw
`that should prevent approval.]
`
`B. There is a view of this application different from Dr.McNeil’s view and, again, it is one
`not clearly reflected in the previous record. In my discussions'with others who attended
`recent meetings about this application, I believe the sentiment arose that, once
`agreement was reached that a 0—6 hour maintenance effect was clinically relevant, it
`was appropriate to abandon the protocol—specified outcome in the first, non-elderly
`study (the 0-8 hour WASO) in favor of a more—appropriate 0-6 hour WASO. At first
`glance, this seems like a reasonable evolution of thinking about this application. While
`unusual to look at post hoc outcomes, there is agency precedent for doing this when the
`originally stated primary outcome was viewed as less relevant or less appropriate.
`
`If the 0-6 hour WASO is adopted as the outcome of interest in the non-elderly study, the
`outcome is statistically significant both at nights 1,2 and nights 15,16. This essentially
`reproduces the finding on the 0-6 hour WASO in the elderly study at nights 1,2 and
`
`

`

`_
`nights 15,16. It is with this body of evidence that the sponsor was told at the June 28,
`2005 meeting with the agency that the application could be approved once labeling was
`negotiated.
`'
`
`C. I believe the review team has identified a stumbling block with this last approach. In
`their first-cycle reviews, Dr.McNeil and Dr.Joan Buenconsejo, the statistician, discuss
`the WASO results for each hour of the night. Reproducibly in both studies, wake time is
`greater for patients treated with Ambien CR in hours 7 and 8 of nights 15,16. The
`margin of difference is not trivial and approaches the best effect in favor of drug seen at
`earlier hours in the night.
`'
`
`I do not think that l have a complete enough understanding of the phenomenon at this
`point in time to recommend an approval action. The traditional teaching is that most
`people require 8 hours of sleep per night. The pattern of the data in the 2 controlled
`trials in this NDA suggest that Ambien CR re-distributes WASO to the last 2 hours of
`an 8 hour night. Such a consolidation of‘sleep toward the beginning of the night seems
`to represent a phenomenon beyond a simple sleep maintenance claim. This
`phenomenon has not been fully characterized. In particular, giVen the emergence of this
`paradoxical effect after 2 weeks of treatment, one has to wonder what will happen after
`longer periods of treatment.
`
`Miscellaneous Labeling Issue/Pregnancy Category
`
`During the review of the original NDA for Ambien CR, the pharm/tox reviewers
`considered the pregnancy category for Ambien. Although, previous reviews of the data
`had resulted in a Category — in labeling, reconsideration resulted in the
`recommendation that a Category C be implemented. Although not directly discussed in
`the Approvable Letter, the draft labeling that accompanied the letter included this
`change. The Supervisory Pharm/Tox Memo in DFS from the first-cycle review period
`explains in detail the rationale for the change.
`
`In the response to .the approvable letter, the sponsor changed the category back to —
`without further discussion. I contacted the sponsor by phone and explained the
`background for the recommended change, based on the available Pharm/Tox review.
`The sponsor has subsequently agreed to the change.
`
`Recommendation
`
`| recommend that an Approval Action be postponed pending further discussion of the
`above issues. A simple claim for sleep maintenance may be misleading to patients and
`prescribers given the pattern of WASO data observed in these 2 trials after 2 weeks.
`
`

`

`This is a representation of an electronic record that ’was signed electronically and
`this page is the manifestation of the electronic signature.
`
`John Feeney
`8/31/2005 06:01:33 PM
`MEDICAL OFFICER
`
`

`

`- CLINICAL REVIEW
`
`Application Type
`Submission Number
`Submission Code
`
`NDA 21-774
`
`014
`
`AZ
`
`Letter Date
`
`Stamp Date
`.
`PDUFA Goal Date
`
`July 6 2005
`July 6 2005
`September 6 2005
`
`Reviewer Name
`
`D. Elizabeth McNeil
`
`Review Completion Date
`
`August 09 2005
`
`Established Name
`
`(Proposed) Trade Name
`Therapeutic Class
`Applicant
`
`zolpidem tartrate _
`Ambien CR
`
`sedative/hypnotic
`sanofi-synthelabo
`
`Priority Designation
`
`S .
`
`Formulation
`
`controlled release tablets
`
`Dosing Regimen
`Indication
`
`Once daily before bed
`Insomnia
`
`Intended Population
`
`Adults
`
`

`

`Clinical Review
`
`D. Elizabeth McNeil, MD
`NDA 21—774, sNOl4
`Ambien CR, zolpidem tanrate
`
`Table of Contents
`
`1 EXECUTIVE SUMMARY .....................................................................................................................................3
`
`1.1 RECOMMENDATION ON REGULATORY ACTION ................................................................................................... 3
`1.2 RECOMMENDATION ON POSTMARKETING ACTIONS .......................................................................................... 3
`
`1.2.1 Risk Management Activity......................................................................................................................... 3
`1.2.2 Required Phase 4 Commitments ................................................................................................................ 3
`1.2.3 Other Phase 4 Requests .............................................................................................................................. 3
`
`2 INTRODUCTION AND BACKGROUND ............................................................................................................4
`
`2.1 PRODUCT INFORMATION ................................................................................ ; .................................................... 4
`2.2 CURRENTLY AVAILABLE TREATMENT FOR INDICATION ..................................................................................... 4
`2.3 AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ........................................................ 4
`2.5
`PRESUBMISSION REGULATORY ACTIVITY ...................................................................................................4
`2.6 OTHER RELEVANT BACKGROUND INFORMATION ............................................................................................... 5
`
`6 INTEGRATED REVIEW OF EFFICACY ........................................................................................................... 5
`
`7 INTEGRATED REVIEW OF SAFETY ................................................................................................................6
`
`9 OVERALL ASSESSMENT .................................................................................................................................... 6
`
`9.1 CONCLUSIONS .........................................................................................................................................i............ 6
`9.2 RECOMMENDATION ON REGULATORY ACTION ................................................................................................... 6
`9.3 RECOMMENDATION ON POSTMARKETING ACTIONS ............................................................................................ 6
`9.4 LABELING REVIEW .............................................................................................................................................. 6
`
`10 APPENDIX .................................... 10
`
`10.1 LINE-BY-LINE LABELING REVIEW ..................................................................................................................... 10
`
`

`

`.
`Clinical Review
`D. Elizabeth McNeil, MD
`NDA 21—774, sNOl4
`Ambien CR, zolpidem tartrate
`
`1 EXECUTIVE SUMMARY
`
`1.1 Recommendation on Regulatory Action
`
`I recommend an approval action.
`
`The proposed labeling should be revised to add information on morning somnolence and detail
`the findings from the clinical trials. The pregnancy category rating should be modified from - LO
`C in light of the preclinical data available for zolpidem tartrate. The indication for use should be
`modified to make it consistent with other recently approved hypnotics. Final labeling will be
`negotiated with the sponsor.
`
`1.2 Recommendation on Postmarketing Actions
`
`1.2.] Risk Management Activity
`
`No risk management activity is recommended.
`
`1.2.2 Required Phase 4 Commitments
`
`The sponsor will be required, as per PREA, to perform safety and efficacy studies of Ambien CR
`in the pediatric population.
`
`1.2.3 Other Phase 4 Requests
`
`There are no Phase 4 requests.
`
`

`

`Clinical Review
`
`D. Elizabeth McNeil, MD
`NDA 21-774, sN014
`
`Ambien CR, zolpidem tartrate
`
`2 INTRODUCTION AND BACKGROUND
`
`2.1 Product Information
`
`Zolpidem tartrate is an imidazopyridine class hypnotic with an affinity for the benzodiazepine
`(BZl) receptor of GABAA. It is currently marketed as an immediate release formulation under
`the trade name Ambien (NDA 19-908) by Sanofi-synthelabo.
`
`Sanofi-synthelabo now proposes to market a modified release preparation of zolpidem as
`Ambien CR. The sponsor has developed a bilayer formulation which is intended to produce an
`immediate as well as a sustained release of zolpidem. This formulation is meant to maintain the
`same elimination half—life as the immediate release formulation but give slightly higher plasma
`concentrations during the middle of the night in order to improve sleep maintenance. The
`sponsor tried to preserve the elimination half-life from the immediate release formulation in
`order to try to prevent next—day residual effects.
`
`The sponsor has developed a 12.5 mg tablet for use in adults and a 6.25 mg tablet for use in the
`elderly.
`
`The sponSor proposes that this product,_Ambien CR, be used for the — . treatment of
`chronic insomnia, recommending one tablet be taken at bedtime. This medication is for use in
`the adult population, including the elderly. It has not been studied in pediatric patients.
`
`2.2 Currently Available Treatment for Indication
`
`Currently there are four FDA approved products indicated for the short—term treatment of chronic
`insomnia: Halcion (triazolam); Prosom (estazolam); Ambien (zolpidem); Sonata (zaleplon).
`
`'
`
`Lunesta (eszopiclone) and Rozerem (ramelteon) are approved for the treatment of chronic
`insomnia. The indication sections of their respective labels do not limit them to short term use.
`
`A number of other products are used off-label to treat chronic insomnia e.g. tricyclic
`antidepressants, anxiolytics, and antihistamines.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Zolpidem tartrate is currently being marketed by Sanofi-synthelabo as Ambien. There have been
`no major safety concerns or labeling changes for this product.
`I
`
`2.5 Presubmission Regulatory Activity
`
`On April 8 2005, the Agency took an ‘approvable’ action on the Ambien CR application.
`
`

`

`Clinical Review
`
`D. Elizabeth McNeil, MD
`NDA 21-774, sN014
`Ambien CR, zolpidem tartrate
`
`On May 10 2005, the Agency met with the applicant to discuss the approvable letter and clarify
`the requirements for the application to progress.
`'
`
`On June 28 2005, the applicant and the Agency met to discuss the planned complete response to
`the approvable letter. At that meeting, the Agency agreed to accept the two previously submitted
`studies in support of a sleep maintenance indication, with sleep onset as a key secondary
`endpoint. It was agreed that the complete response would consist of labeling informed by the
`labeling changes which had been previously suggested as part of the approvable letter dated
`April 8 2005.
`
`This current submission is a labeling supplement without new clinical data.
`
`2.6 Other Relevant Background Information
`
`When I reviewed the original submission for this product, I recommended an approvable
`action for this product. The sponsor has made the case that they upheld the letter, if not the spirit,
`of the original development plan. The primary endpoint in both studies was a decrease in WASO
`on nights 1 and 2, i.e. objective demonstration of an immediate effect. This criterion was met in
`both studies submitted so the demonstration of efficacy has been replicated; therefore an
`approval may be granted.
`
`As I stated originally, I concur that this product has a hypnotic effect and therefore may
`appropriately be used in the treatment of insomnia. Hypnotic benefits were clearly demonstrated
`in both studies on nights 1 and 2. The data from nights 15 and 16 were not as convincing. Since
`we do not have any measure of drug effectiveness at days 7/8, it is fair to say that there are
`immediate effects on sleep maintenance and latency to persistent sleep though persistence of that
`effect for 2 weeks has not been clearly demonstrated and the point at which the benefit begins to
`decline cannot be identified. There are some people who would benefit from the use of Ambien
`CR, since the immediate increase in sleep maintenance benefit may be expected to last up to 6
`(elderly) or 7 hours (adults). The clinical utility of this product when used for a 2 week period is
`uncertain since the sleep maintenance benefit, after a fortnight of use, decreases to 4 (elderly) or
`5 hours (adults).
`
`Since we realize that insomnia may be a chronic condition, it would have been good to have
`hypnotics demonstrate long—term efficacy but that may be a matter for future hypnotic
`development plans. In the label for this product, we can assure that the duration of benefit, a key
`component of a product intended for sleep maintenance, is clearly stated. As other products for
`sleep maintenance are developed, we shall attempt to make certain that the expected duration of
`benefit is clearly stated in those labels as well.
`
`6 INTEGRATED REVIEW OF EFFICACY
`
`No Integrated Review of Efficacy is needed as this supplement provides new labeling without
`additional clinical data beyond what was submitted to the original NDA.
`
`

`

`. Clinical Review
`
`D. Elizabeth McNeil, MD
`NDA 21-774, sN014
`Ambien CR, zolpidem tartrate
`
`7 INTEGRATED REVIEW OF SAFETY
`
`No Integrated Review of Safety is needed as this supplement provides new labeling without
`additional clinical data beyond what was submitted to the original NDA.
`
`9 OVERALL ASSESSMENT
`
`9.1 Conclusions
`
`The applicant has submitted labeling for their new product, Ambien CR.
`
`This labeling is submitted as a complete response to the approvable letter that was sent from the
`Agency on April 8 2005. There is no new clinical data provided with this submission. The
`support for the labeling claims was previously submitted as part of the original NDA.
`
`The wording in the indication should be modified for clarity and consistency. I would agree that
`the
`,—
`may be removed from this section though the
`A
`V’
`should stand.
`
`The clinical trials section should provide details on the findings from the two studies conducted
`and I have modified the proposed language so that the details will be provided.
`
`The pregnancy rating should be changed from —-to C in light of the available data from animal
`studies.
`
`9.2 Recommendation on Regulatory Action
`
`This reviewer recommends an “approval” action be taken on this submisSion.
`
`9.3 Recommendation on Postmarketing Actions
`
`No postmarketing actions are recommended.
`
`9.4 Labeling Review
`
`I have provided general comments on the proposed labeling in this section. A line-by-line
`review, informed by the Agency’s comments in the approvable letter for this NDA issued on 8
`April 2005, may be found in the Appendix, with my additions to the text underlined.
`
`-
`Description:
`I made no changes to the proposed text.
`
`Clinical Pharmacology
`
`

`

`Clinical Review
`D. Elizabeth McNeil, MD
`NDA 21-774, sN014
`Ambien CR, zolpidem tartrate
`
`Reviewer ’5 note:
`
`While I made no changes to the proposed text, a pharmacokinetics consult was requested to
`review the figure and accompanying text in this section.
`‘
`
`Controlled trials supporting safety and efficacy:
`The sponsor proposed the following language:
`Adult outpatients (18—64 years) with primary insomnia (N=212) were evaluated in a double—
`blind, randomized, parallel—group, 3-week trial comparing Ambien CR 12.5 mg and placebo.
`Ambien CR was superior to placebo on objective measures (polysomnography recordings) of
`sleep induction (by decreasing latency to persistent sleep [LPS])
`,_.._..
`
`
`A...
`
`,during the first two nights and after two weeks of treatment.
`——-
`7 Ambien CR 12. 5 mg was shown to be superior to placebo
`on the patient’ 5 globalimpression regarding the aid to sleep
`x“.
`_.——
`
`Elderly outpatients (Z 65 years) with primary insomnia (N=205) were evaluated in a double—
`blind, randomized, parallel—group, 3—week trial comparing Ambien CR 6.25 mg and placebo.
`Ambien CR was superior to placebo on objective measures (polysomnography recordings) of
`
`sleep induction (by decreasing LPS)
`
`
`luring the first two nights and after two
`, Ambien CR 625 mg
`V"
`superior to placebo on the patient’ 5 global1mpression regarding the aid to
`
`weeks oftreatment.
`was
`“"
`sleep 3
`' _‘___
`
`Reviewer ’s note:
`
`1 modified these two paragraphs to more fully reflect the studies and the study results:
`Adult outpatients (18-64 years) with primary insomnia (N=212) were evaluated in a
`double-blind, randomized, parallel—group, 3-week trial comparing Ambien CR 12.5 mg
`andplacebo.
`--'—'
`-\
`
`u
`
`.1
`
`u
`
`./
`
`Ambien CR 12.5 mg was superior to placebo, on objective measures
`(polysomnography recordings) ofsleep induction (by decreasing latency to persistent
`sleep) durin