CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022328Orig1s000
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`MEDICAL REVIEW(S)
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`CLINICAL REVIEW
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`Application Type NDA (Complete Response)
`Application Number(s) 022328
`Priority or Standard Class 1 Resubmission
`
`Submit Date(s) 9/27/11
`Received Date(s) 9/27/11
`PDUFA Goal Date 11/27/11
`Division / Office DNP / ODE1
`
`Reviewer Name(s) Christopher D Breder, MD PhD
`Review Completion Date 25 Oct 2011
`
`Established Name Zolpidem tartrate lozenge
`(Proposed) Trade Name Intermezzo
`Therapeutic Class Sedative Hypnotic
`Applicant Transcept Pharmaceuticals
`
`Formulation(s) sublingual lozenge
`Dosing Regimen x 1 qMiddle of the Night
`(MOTN) PRN
`Indication(s) Treatment of insomnia
`following MOTN awakening
`Insomnia patients
`
`
`
`Intended Population(s)
`
`Template Version: March 6, 2009
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`Reference ID: 3038263
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`

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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 5
`1.1 Recommendation on Regulatory Action ............................................................. 5
`1.2 Risk Benefit Assessment.................................................................................... 5
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 5
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 5
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 5
`2.1 Summary of Presubmission Regulatory Activity Related to Submission ............ 5
`3 SIGNIFICANT ISSUES RELATED TO OTHER REVIEW DISCIPLINES ................. 8
`3.1. Pharmacokinetics ............................................................................................... 8
`4 REVIEW OF EFFICACY......................................................................................... 11
`Efficacy Summary...................................................................................................... 11
`4.1
`Indication .......................................................................................................... 11
`4.1.1 Methods ..................................................................................................... 11
`4.1.2 Demographics............................................................................................ 11
`4.1.3 Analysis of Primary and Key Secondary Endpoint(s)................................. 11
`4.1.4 Analysis of other Secondary Endpoints(s) ................................................. 12
`4.1.5 Other Endpoints ......................................................................................... 14
`5 REVIEW OF SAFETY............................................................................................. 16
`Safety Summary ........................................................................................................ 16
`5.1 Methods............................................................................................................ 16
`5.2 Supportive Safety Results ................................................................................ 16
`5.2.1 Common Adverse Events .......................................................................... 16
`5.3 Other Safety Explorations................................................................................. 18
`5.3.1 Time Dependency for Adverse Events....................................................... 18
`6 APPENDICES ........................................................................................................ 20
`6.1 Additional PK Investigations by Medical Reviewer .............................................. 20
`6.1.1 Analysis of Postdose Zolpidem Concentrations by Gender and Dose.............. 20
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Table of Tables
`
`Table 1 Mean Intermezzo Pharmacokinetic Parameters after Single Dose of Intermezzo
`3.5, 1.75, and 1.0 mg in Females and Males (Study ZI-05-009) ...................... 8
`Table 2 Mean (SD) Plasma Concentration at 3, 4, and 5 hours in Females Following the
`1.75 mg dose and in males Following the 3.5 mg Dose................................... 9
`Table 3 The Predictive Probabilities of Exceeding Threshold Plasma Concentration
`Values (female subjects).................................................................................. 9
`Table 4 Predictive Probabilities of Exceeding Threshold Plasma Concentration Values
`(male subjects)............................................................................................... 10
`Table 5 Mean (%CV) Intermezzo 3.5 mg Cmax and Plasma Levels at 3, 4, and 5 hours
`in males ......................................................................................................... 10
`Table 6 Adverse Events for Females (1.75 mg) and Males (3.5 mg) from the ZI-10
`Study.............................................................................................................. 16
`Table 7 Adverse Events at the 3.5 mg Dose Level from the ZI-12 Study...................... 17
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Table of Figures
`
`Figure 1 Cumulative % of Patients Asleep (After MOTN Awakening) at Sequential 10-
`Minute Intervals by PSG (Study ZI-06-010) ................................................... 12
`Figure 2 LPS Post MOTN Awakening in Females by Dose Group................................ 13
`Figure 3 LPS Post MOTN Awakening in Males by Dose Group.................................... 15
`Figure 4 Distribution of Plasma Zolpidem Concentrations 3 hours Post-dose by Gender
`and Dose ....................................................................................................... 21
`Figure 5 Distribution of Plasma Zolpidem Concentrations 4 hours Post-dose by Gender
`and Dose ....................................................................................................... 22
`Figure 6 Distribution of Plasma Zolpidem Concentrations 5 hours Post-dose by Gender
`and Dose ....................................................................................................... 23
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`Approval is recommended.
`
`1.2 Risk Benefit Assessment
`
`A primary concern with the Sedative Hypnotic class is the potential for residual effects.
`The zolpidem products carry a risk of having elevated plasma levels in females. This
`Medical Officer believes the Sponsor has adequately mitigated these risks by lowering
`the female dose to 1.75 mg per dosing and by recommending not to dose with less than
`four hours of sleep time remaining.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`This Medical Officer does not believe a REMS is needed for this application. I agree
`with the Sponsor’s plan to issue a Medication Guide and Patient Instructions for Use
`that focus on the proper dosing and potential hazards of next-day sedation.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`A principle concern with this drug is whether patients will follow the dosing guidance, as
`dosing with insufficient sleep time remaining, may lead to high residual drug levels. The
`Division had communicated their desire for the Sponsor to conduct a form of actual use
`study in the second Complete Response cycle; however, both parties agreed that the
`data would be difficult to collect in the setting of a controlled clinical trial. This Medical
`Officer would like the Sponsor to conduct a study in the setting of the drug being
`marketed that would provide this information.
`
`The Sponsor should conduct the necessary studies to comply with the PREA
`requirement (e.g., ages 6-17).
`
`2 Introduction and Regulatory Background
`
`2.1 Summary of Presubmission Regulatory Activity Related to Submission
`
`NDA 23-238/S0036 for the use of Intermezzo® 1.75 and 3.5 mg for the treatment of
`insomnia following middle of the night (MOTN) awakening was submitted 9/30/08. The
`Sponsor received two Complete Responses (CRs), 28 Oct 2009 and 14 JUL 2011. In
`the action letter for the second CR, the Division of Neurology Products (DNP) had
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`several concernsrelated to characterization of the pharmacokinetics and to the potential
`morning plasma levels of Zolpidem:
`
`e anecessary first step in addressing DNP’s concerns about residual morning
`levels of zolpidem from Intermezzo would be a more thorough characterization of
`the distribution of blood levels that can occur the morning after dosing;
`e to address the concernthat zolpidem levels were not safe, the Sponsor
`should...pursue strategies to decrease morning Zolpidem levels from Intermezzo,
`particularly levels at the high endofthe distribution (e.g. through modification of
`dose, time, patient selection, etc.);
`e depending on the residual zolpidem levels that might result after mitigation
`strategies are implemented, it might be necessary for you to demonstrate, in an
`adequately powered study with demonstrated assay sensitivity, that the levelsstill
`present do not present an unacceptable risk of next-day impairment.
`
`In addition to these issues and potential mitigations, DNP noted that they had a concern
`about whether subjects would comply with dosing instructions, possibly taking the drug
`with less than 4 hours of sleep time remaining. The Sponsor asserted that obtaining an
`accurate assessmentof this compliance would be difficult in a controlled trial setting.
`DNP agreed, since even in a controlled environment (e.g., Study Z-12), deviations were
`noted. In lieu of the requested actual use study, DNP commentedthat it would be
`reasonable to estimate that patients would take this drug with 3 or 3.5 hoursleft to sleep
`and that this consideration should be taken into account wheninterpreting and
`assigning meaning to results of safety studies (e.g., Z-18, the “Driving Study”) or
`pharmacokinetic studies (e.g., ZIl-05-009).
`
`A Type C meeting was held 16 September based on materials supplied by the Sponsor
`on 23 AUG 2011 and 07 SEP 2011. The primary focal points of the meeting were
`discussionsof:
`e the Sponsor’s proposal to lower the recommendeddosefor females to 1.75 mg,
`since there was a gendereffect giving rise to plasma levels approximately 40%
`higherin this population;
`
`e the characterization of pharmacokinetics, and particularly, the variability and
`levels present in African —American subjects.
`
`DNP and the Sponsoragreed that the Complete Response should focus on these
`issues.
`
`The Sponsor’s Complete Response submission of 27 SEP 2011 contains:
`e An |l-page summary of evidence supporting Transcept's proposal for dosing
`recommendations in males and females,
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`Reference ID: 3038263
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`

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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`e Analysis datasets for subgroup analyses supporting the resubmission.
`(Section 5.3.5.3)
`
`e Updates to labeling components for consistency with revised dosing
`recommendationsand instructions.
`
`Oo PackageInsert, Medication Guide, and Patient Instructions for Use
`(Section 1.14.1.3)
`Annotated Package Insert, Medication Guide, and Patient Instructions for
`Use (Section 1.14.1.2)
`Carton and container labels (Section 1.14.1.1)
`Updatedfiles for the proposed labeling in Structured Product Labeling
`(SPL) format.
`
`This review focused on these materials, study reports by the Sponsor, as well as prior
`reviews by the DNP including:
`e Complete Response Action letter of 14 JUL 2011
`e DNP Director Memosof 14 JUL 2011 and 26 OCT 2009
`Cross Discipline Team Leader (CDTL) Memos of 03 SEP 2009 and 20 JUL 2011
`Medical Reviewer's Clinical Reviews of 03 SEP 2009 and 12 JUL 2011
`Statistical Review and Evaluations of 19 JUN 2009 and 08 JUL 2011
`Clinical Study Reports submitted by the Sponsor
`o ZI-06-10 A Randomized, Double-blind, Placebo-controlled, Crossover
`Study of the Efficacy and Safety of Sublingual Zolpidem tartrate lozenge in
`Adult Patients with Insomnia Characterized by Difficulty Returning to
`Sleep after Middle-of the-Night (MOTN) Awakening
`ZI-12 A Randomized, Double-Blind, Placebo-Controlled, Parallel Group
`Study Of The Efficacy And Safety Of The Zolpidem Tartrate Sublingual
`Lozenge In Adult Subjects With Insomnia Characterized By Difficulty
`Returning To Sleep After Awakening In The Middle-Of-The-Night (MOTN)
`ZI-18 Assessment of Next-Morning Driving Performance after Middle of
`the Night Administration of Zolpidem Tartrate Sublingual Tablet 3.5 mg in
`Healthy Adult Volunteers: Single-Center, Double-Blind, Randomized,
`Placebo-Controlled, Four-Way Crossover Study
`
`2.5.1 Other Regulatory Activity
`
`The Intermezzo (Zolpidem tartrate) partial waiver/deferral plan was reviewed by the
`PeRC PREA Subcommittee on September 02, 2009. The Division recommendeda
`partial wavier from 0 {years because the disease/condition does not exist in children
`and a deferral from 6 °®years because the productis ready for approvalin adults. The
`PeRC agreed with the Division to grant a partial waiver because the disease/condition
`doesnotexist in children age 08 years. The PeRCis requesting an application
`certification of deferred studies and the required dates prior to the Division taking an
`approval action.
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`3 Significant Issues Related to Other Review Disciplines
`
`3.1. Pharmacokinetics
`
`The principle focus of the pharmacokinetic analysis was the support of the mitigation
`strategy lowering female dosing to 1.75 mg.
`
`Sponsor’s Analysis: The pharmacokinetic data to support the Intermezzo 1.75 mg
`dose in females and 3.5 mg dose in males is derived from the PK PD (ZI-05-009) study.
`This study investigated the pharmacokinetics and pharmacodynamics of Intermezzo
`doses of 1.0, 1.75, and 3.5 mg in 11 females and 13 males.
`
`Plasma levels were approximately 45% higher in females than males. Higher levels in
`females are mostly attributed to lower apparent clearance (Table 1). The lower
`clearance in females is not explained by body weight, since the difference is still evident
`after normalization for body weight. Intermezzo mean Cmax, AUC, and the 3-, 4-, and 5-
`hour plasma levels changed linearly with dose in females and males in the study.
`
`Table 1 Mean Intermezzo Pharmacokinetic Parameters after Single Dose of
`Intermezzo 3.5, 1.75, and 1.0 mg in Females and Males (Study ZI-05-009)
`
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`
`The 3-, 4-, and 5-hour plasma data from six Intermezzo pharmacokinetic studies was
`pooled by the sponsor to gain a better understanding of the distribution of zolpidem
`plasma levels at these time points (Table 2). The pooled data suggests that the average
`4-hour plasma levels in females, following the 1.75 mg dose, are in a range similar to
`the 4-hour levels in males, following the 3.5 mg dose.
`Table 2 Mean (SD) Plasma Concentration at 3, 4, and 5 hours in Females Following
`the 1.75 mg dose and in males Following the 3.5 mg Dose.
`
`
`The predictive probability of a subject being exposed to a high zolpidem blood level at 3,
`4, and 5 hours following a dose of Intermezzo was also assessed. The analysis
`indicated that the predictive probability of Intermezzo 1.75 mg producing a plasma level
`of 40 ng/ml or higher in females at 3, 4, and 5 hours post-dose is lower than that of 10
`mg zolpidem measured at 6 and 8 hours post-dose (Table 3).
`
`Table 3 The Predictive Probabilities of Exceeding Threshold Plasma
`Concentration Values (female subjects)
`
`
`
`
`In males, the predictive probability of Intermezzo 3.5 mg producing a plasma level of 40
`ng/ml or higher at 3, 4, and 5 hours post-dose is similar to or lower than that of 10 mg
`zolpidem measured at 8 hours post-dose. The probabilities at other concentrations are
`shown in Table 4.
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`
`Table 4 Predictive Probabilities of Exceeding Threshold Plasma Concentration
`Values (male subjects)
`
`
`
`
`Covariate analysis of the pooled 3-, 4-, and 5-hour plasma levels in non-elderly females
`and nonelderly males indicated that age, body weight and race (African-Americans and
`non-African- Americans) did not significantly influence Intermezzo plasma levels (Table
`5). The data pooled from all 3.5 mg Intermezzo pharmacokinetic studies suggests that
`mean Cmax, and the 3-, 4-, and 5-hour plasma levels were similar among Caucasians,
`African-Americans and the subgroups.
`
`Table 5 Mean (%CV) Intermezzo 3.5 mg Cmax and Plasma Levels at 3, 4, and 5
`hours in males
`
`
`Medical Reviewer’s Analysis and Comments: The Sponsor has proposed lowering
`the dose in females to 1.75 mg to mitigate the concern of elevated zolpidem plasma
`levels. Each demonstration of the Sponsor’s data (i.e., Tables 1-5) suggests that by
`lowering the females’ dose to 1.75 mg, the probability of the more worrisome levels
`seen in the female 3.5 mg group is reduced. This is also demonstrated in the Medical
`Reviewer’s analysis of the ZI-05-009 data set assessing zolpidem concentration
`
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`distribution by gender and dose (Figure 4). In this analysis, no female subjects at 3hr
`post-dose had levels greater than 40 ng/ml in the 1.75 mg group, while almost half had
`levels between 35 and 92 ng/ml in the 3.5 mg group. In summary, this Medical
`Reviewer believes the dose reduction in females mitigates the concern about the
`potential residual morning zolpidem levels.
`
`Based on the data from Table 5 this reviewer does not believe that the variance of the
`PK of African –American males is sufficiently different to warrant specific labeling.
`
`4 Review of Efficacy
`Efficacy Summary
`This review will not reanalyze prior findings of efficacy but will highlight and
`independently verify the Sponsor’s supporting statements for the use of 1.75 mg in
`female subjects.
`
`4.1 Indication
`
`Intermezzo® is to be indicated for the treatment of insomnia following MOTN
`awakening.
`
`4.1.1 Methods
`
`The efficacy support for Intermezzo 1.75 mg dose in females is derived from the sleep
`laboratory study (ZI-06-010). This study was a double-blind, placebo-controlled clinical
`crossover study which evaluated the safety and efficacy of 1.75 mg and 3.5 mg doses
`of Intermezzo in adults with a history of middle-of-the-night awakening. Latency to
`persistent sleep (LPSMOTN) and Total Sleep Time (TSTMOTN) after a scheduled MOTN
`awakening were the primary and the principal secondary endpoints of the study.
`
`4.1.2 Demographics
`
`82 patients (58 female, 24 male) were randomized and analyzed for efficacy.
`
`4.1.3 Analysis of Primary and Key Secondary Endpoint(s)
`
`Sponsor’s Analysis: Statistically significant improvements compared to placebo were
`observed in both genders at their respective doses of 1.75 mg for female patients and
`3.5 mg for male patients.
`• In females, LPSMOTN was 15.70 min vs. placebo 27.73 min (p<0.0001); Sleep Onset
`Latency (SOLMOTN) was 28.43 min vs. placebo 38.54 min (p=0.0008); TSTMOTN was
`199.51 min vs. placebo 185.15 min (p=0.0028) and Subjective TST was 161.39 min vs.
`placebo 147.92 min (p=0.0330). All sleep variables are least square values.
`• In males, LPSMOTN was 12.74 min vs. placebo 29.03 min (p<0.0001); SOLMOTN was
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`21.92 min vs. placebo 37.97 min (p=0.0001); TSTMOTN was 207.02 min vs. placebo
`178.33 min (p<0.0001) and Subjective TST was 169.28 min vs. placebo 146.81 min
`(p=0.0422). All sleep variables are least square values.
`
`Figure 1 Cumulative % of Patients Asleep (After MOTN Awakening) at Sequential
`10-Minute Intervals by PSG (Study ZI-06-010)
`
`
`Medical Reviewer’s Analysis and Comments: The Sponsor has adequately verified
`that 1.75 mg is efficacious in females for the claim of treating LPS for MOTN
`awakening. This is verified by the Medical Reviewer’s independent analysis (Figure 2)
`In an ANOVA analysis of the LPS Post awakening in females, the 1.75 mg group mean
`was 23.1 min (90% CI:16.8, 29.3) and the Placebo arm was 37.2 min (90%CI:30.9,
`43.5). The difference was statistically significant (P< 0.004) using Dunnett’s test. The
`1.75 mg dose in females appears to have a similar effect as the 3.5 mg dose in males
`(see Figure 1). At each latency period, the responder rate appears to be with 10% of
`the other gender’s rate.
`
`4.1.4 Analysis of other Secondary Endpoints(s)
`
`Medical Reviewer’s Analysis and Comments: Parameters related to sleep
`maintenance, such as Wake (time) after Sleep Onset (WASO) and the Number of
`Awakenings (NAW) were analyzed for the 1.75 mg dose in Females using the identical
`methodology as described in Section 6.14. Neither endpoint (WASOPOST and
`NAWPOST) were significantly reduced relative to PBO in either the 3.5 or 1.75 mg dose
`groups. While this was not a specific claim of the Sponsor, the analysis was performed
`to more completely characterize the effects for females at 1.75 mg.
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Figure 2 LPS Post MOTN Awakening in Females by Dose Group
`
`
`
`
`
`Figure Legend
`
`This figure demonstrates the 95% confidence intervals (green diamonds) for the
`LPS (Y axis, in minutes) in females in the PBO, 1.75 mg, and 3.5 mg dose groups from
`the ZI-10 Study. The middle bar in each diamond represents the group mean. Individual
`data points are represented by the dots rising vertically in each dose group. The black
`horizontal line crossing through the 1.75 mg diamond represents the overall mean of the
`three groups. Descriptive statistics of dose group, N, mean standard error, and the 95%
`confidence limits. Statistical testing using the Dunnett’s Test with the PBO groups as a
`control arm is presented in the bottom panel.
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`4.1.5 Other Endpoints
`
`Medical Reviewer’s Analysis and Comments: While the efficacy in males was not at
`issue in this Complete Response, this Medical Reviewer examined the efficacy of 1.75
`mg in males as a means to test whether Intermezzo would be effective in a population
`that generally had lower plasma exposure than females. An ANOVA analysis of the ZI-
`06-10 dataset supplied by the Sponsor using LPS post MOTN awakening by treatment
`was performed. A test for statistical significance was performed using Dunnett’s test
`with the placebo arm as the control treatment. Both the 3.5 mg and 1.75 mg treatments
`were effective (Figure 3;p=0.03 for 1.75 mg, < 0.0001 for 3.5 mg). This lends further
`support that the 1.75 mg dose can be effective in females, since for a given dose, the
`plasma zolpidem concentrations are often higher than in males.
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Figure 3 LPS Post MOTN Awakening in Males by Dose Group
`
`
`
`Figure Legend
`This figure demonstrates the 95% confidence intervals (green diamonds) for the LPS
`(Y axis, in minutes) in males in the PBO, 1.75 mg, and 3.5 mg dose groups from the ZI-
`10 Study. The middle bar in each diamond represents the group mean. Individual data
`points are represented by the dots rising vertically in each dose group. The black
`horizontal line crossing through the 1.75 mg diamond represents the overall mean of the
`three groups. Descriptive statistics of dose group, N, mean standard error, and the 95%
`confidence limits. Statistical testing using the Dunnett’s Test with the PBO groups as a
`control arm is presented in the bottom panel.
`
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`5 Review of Safety
`Safety Summary
`The safety has been evaluated in the previous Medical Reviewer and CDTL reviews.
`Comments from this MR will focus on materials sent in the Complete Response
`comparing adverse events in the 1.75 and 3.5 mg dose groups in females.
`
`5.1 Methods
`
`Adverse events for the ZI-10 and -12 studies were presented by the Sponsor. This
`Medical Officer specifically looked at
`• the incidence rate between females at 1.75 mg and males at 3.5 mg; and
`• the incidence rate between females at 1.75 and 3.5 mg.
`
`5.2 Supportive Safety Results
`
`5.2.1 Common Adverse Events
`
`Table 6 Adverse Events for Females (1.75 mg) and Males (3.5 mg) from the ZI-10
`Study
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Table 7 Adverse Events at the 3.5 mg Dose Level from the ZI-12 Study
`
`
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`Reference ID: 3038263
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`
`
`
`
`Medical Reviewer’s Analysis and Comments: The incidence and type of adverse
`events in the ZI-10 Study appear similar between the 1.75 mg dose group in females
`and 3.5 mg in males (Table 6). These data are, however, derived from relatively small
`studies, so the data may not be generalizable. The ZI-10 study is a crossover design, so
`the adverse event data may not be comparable to cohorts in the 3.5 mg group of the ZI-
`12 study because of prior drug exposure, particularly for subjects dosed first with 1.75
`mg in ZI-10 and because of the longer duration of dosing in the ZI-12 study.
`
`
`5.3 Other Safety Explorations
`
`5.3.1 Time Dependency for Adverse Events
`
`Medical Reviewer’s Analysis and Comments: The Sponsor proposed a second
`means of mitigating the concern over residual zolpidem plasma levels1 by proposing to
` While in principle, every labeling restriction
`
`
`1 In addition to lowering the dose for females to 1.75 mg
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`18
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`(b) (4)
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`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`could enhance safety; this reviewer finds the proposal essentially redundant with the 4
`hour anticipated sleep time labeling and without significant potential effect. The
`proposed labeling already contains a recommendation to only dose Intermezzo when
`
`there are at least 4 hours of sleep time remaining.
`
`
`
`
`. On the other hand, there may be
`
`an advantage in keeping
`the language of
`the labeling simpler in terms of not having
`potentially conflicting advise to the prescriber.
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`Reference ID: 3038263
`
`19
`
`

`

`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`
`6 Appendices
`
`6.1 Additional PK Investigations by Medical Reviewer
`
`6.1.1 Analysis of Postdose Zolpidem Concentrations by Gender and Dose
`
`
`
`Reference ID: 3038263
`
`20
`
`

`

`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Figure 4 Distribution of Plasma
`Zolpidem Concentrations 3 hours
`Post-dose by Gender and Dose
`
`
`Figure Legend
`Distribution plots for individuals
`(N on Y-axis) versus zolpidem plasma
`level (X-axis) at the 3 hr post dose
`interval. A box and whisker plot overlays
`each histogram.
`
`In the top plot, containing data for
`females in the 1.75 mg dose group, the
`range is (6.4-38.5 ng/ml), the mean is
`21.9 ng/ml (90%CI: 18.4,25.5).
`
`
`
`
`
`
` In the second plot, containing
`data for females in the 3.5 mg dose
`group, the range is (6.2-91.8 ng/ml, the
`mean is 39.0 ng/ml, (90%CI: 36.4,41.5).
`
`
`
`
`
`
`In the third plot, containing data
`for males in the 1.75 mg dose group, the
`range is (2.4-28.5 ng/ml, the mean is
`14.9 ng/ml, (90%CI: 12.4, 17.3).
`
`
`
`
`
`
`In the last plot, containing data
`for males in the 3.5 mg dose group, the
`range is (4.9-76.4 ng/ml), the mean is
`25.4 ng/ml, (90%CI: 23.8, 26.9).
`
`
`
`Reference ID: 3038263
`
`
`
`21
`
`

`

`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Figure 5 Distribution of Plasma
`Zolpidem Concentrations 4 hours
`Post-dose by Gender and Dose
`
`
`
`Figure Legend
`Distribution plots for individuals
`(N on Y-axis) versus zolpidem plasma
`level (X-axis) at the 4 hr post dose
`interval. A box and whisker plot overlays
`each histogram.
`
`In the top plot, containing data for
`females in the 1.75 mg dose group, the
`range is (4.9-33.8 ng/ml), the mean is
`17.8 ng/ml (90%CI: 14.5, 21.2).
`
`
`
`
`
`
` In the second plot, containing
`data for females in the 3.5 mg dose
`group, the range is (3.9-71.5) ng/ml, the
`mean is 32.6 ng/ml, (90%CI: 30.4, 34.8).
`
`
`
`
`
`
`In the third plot, containing data
`for males in the 1.75 mg dose group, the
`range is (1.3-25.8 ng/ml, the mean is
`12.1 ng/ml, (90%CI: 9.7, 14.4).
`
`
`
`
`
`
`In the last plot, containing data
`for males in the 3.5 mg dose group, the
`range is (2.5-56.9 ng/ml), the mean is
`20.5 ng/ml, (90%CI: 19.2, 21.8).
`
`
`
`22
`
`Reference ID: 3038263
`
`

`

`Clinical Review
`Christopher D. Breder, MD PhD
`N022328 / 0046
`Intermezzo / zolpidem tartrate lozenge
`Figure 6 Distribution of Plasma
`Zolpidem Concentrations 5 hours
`Post-dose by Gender and Dose
`
`
`
`23
`
`Reference ID: 3038263
`
`
`
`
`
`Figure Legend
`Distribution plots for individuals
`(N on Y-axis) versus zolpidem plasma
`level (X-axis) at the 5 hr post dose
`interval. A box and whisker plot overlays
`each histogram.
`
`In the top plot, containing data for
`females in the 1.75 mg dose group, the
`range is (3.5-32.6 ng/ml), the mean is
`15.0 ng/ml (90%CI: 11.7, 18.3).
`
`
`
`
`
`
` In the second plot, containing
`data for females in the 3.5 mg dose
`group, the range is (205-69.0) ng/ml, the
`mean is 26.2 ng/ml, (90%CI: 24.0, 28.4).
`
`
`
`
`
`
`In the third plot, containing data
`for males in the 1.75 mg dose group, the
`range is (0.8-22.5 ng/ml, the mean is 9.8
`ng/ml, (90%CI: 7.8, 11.9).
`
`
`
`
`
`
`In the last plot, containing data
`for males in the 3.5 mg dose group, the
`range is (1.4-56.4 ng/ml), the mean is
`15.4 ng/ml, (90%CI: 14.1, 16.6).
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHRISTOPHER D BREDER
`11/02/2011
`
`RONALD H FARKAS
`11/15/2011
`
`Reference ID: 3038263
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`Complete Response
`
`
`Date
`7/1/2011
`From
`Ronald Farkas, MD, PhD
`/Subject|sd
`Cross-Discipline Team Leader Review
`NDA 22328, supplement #33
`
`Supplement#
`
`[Applicant=————S—S—SsTrransceptPharmaceuticalssid
`
`aQ
`Proprietary Name/
`Intermezzo/zolpidem tartrate
`Established (USAN) names
`Dosage forms/ Strength
`ProposedIndication(s
`
`1.75 mg / 3.50 mg
`Insomnia following middle-of-the-night awakening
`
`1. Introduction
`
`The original NDA application for Intermezzo received a Complete Response (CR)
`Letter on October 28, 2009. The Division agreed that efficacy for insomnia following
`middle-of-the-night (MOTN) awakening was adequately supported, but was
`concerned aboutthe safety risk from residual morning levels of drug, particularly if
`there was inadvertent re-dosing of Intermezzo in a single night, or inadvertent dosing
`with less than 4 hours of bedtime remaining. Both of these risks appeared potentially
`to be increased comparedto other Zolpidem products by the MOTN-dosing of
`Intermezzo.
`
`The Division indicated in the CR letter that it appeared necessary for the sponsorto
`demonstrate the following:
`1. That Intermezzo, when taken as directed, does not unacceptably impair
`