CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-196
`
`
`
`MEDICAL REVIEW S
`
`
`

`

`CLINICAL Irnvnazw1
`
`505 b (2) NBA
`Application Type
`Submission Number 22196
`
`Submission Code
`
`000 .
`
`Letter Date November 20, 2007
`Stamp Date November 20, 2007
`_
`PDUFA Goal Date September 19, 2008
`
`June Cai, MD
`Reviewer Name
`Review Completion Date August 6, 2008
`
`Established Name Zolpidem tartrate
`(Proposed) Trade Name ZolpiMistTM Lingual Spray
`Therapeutic Class Hypnotics
`Applicant NovaDel Pharmaceuticals Inc.
`
`Priority Designation
`
`S
`
`Formulation Oral Spray
`Dosing Regimen
`5mg per spray:
`-Adults: 10mg immediately before
`bedtime
`
`-Elderly: 5mg
`-With hepatic impairment: 5mg
`.
`Indication Short-term treatment of insomnia
`
`Intended Population Adults and elderly
`
`lTkneleNDAmicwmflnuinppliedtothisrwiewaimmwd.
`
`

`

`Clinical Review
`June Cai, M.D.
`NDA 22196 5-0“)
`
`Table of Contents
`
`1
`
`RECOMMENDATIONS/RISK BENEFIT ASSESSMENT
`
`W4
`
`1.1
`1.2
`1.3
`1.4
`1.5
`
`Recommendation on Regulatory Action..........................................................................................4
`Risk Benefit Assessment ............................................................................
`
`Recommendations for Postmarketing Risk Management Activities...
`
`Recommendatiom for other Pom Marketing Study Commitments ........
`Other Phase IV Commitments ............................................................
`
`2
`
`INTRODUCTION AND REGULATORY BACKGROUND...........................
`
`
`
`“......4
`
`2.1
`2.2
`2.3
`
`2.4
`2.5
`
`* Product Information..................................................................................................................................4
`Availability of Proposed Active Ingredient in the United States..............................................................5
`Currently Available Treatments for Proposed Indication and Important Safety Issues with Consideration
`5
`Summary of Preeubmission Regulatory Activity Related to Submission..................................................6
`Other Relevant Background Information ...................................................................................................6
`
`3
`
`ETHICS AND GOOD CLINICAL PRACTICES..................m..................._..-....«........................'...7
`
`Submission Quality and Integrity ...................
`.... ..
`........................7
`
`
`...............
`. ..
`..
`..
`Compliance with Good Clinical Practices...
`
`Financial Disclosures........................................................................................................................7
`
`3.]
`3.2
`3.3
`
`4
`
`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED 1'0 OTHER REVIEW DISCIPLINES ......7
`
`5
`
`6
`
`7
`
`4.1
`4.2
`4.3
`4.3.1
`4.3.2
`
`Chomstry' Manufacturing and Controls ....u........................7
`
`Preclimcal' Pharmacology/row.....................
`
`Clinical Pharmacology .......................................
`
`Pharmacodymics .................................................................
`Pharmacokinctics.............................................................................................................8
`
`
`WW~MW9
`
`SOURCES OF CLINICAL DATA
`
`5.1
`5.2
`5.3
`
`Table of Clinical Studies .........................................................................
`.....
`.........................9
`
`Review Strategy.......................................
`.
`....
`.........9
`Discussion of Individual Studies ............................................................................................................ lo
`
`
`emmmmlmemmammeemmmemlmumummua1l
`
`REVIEW OF EFFICACY
`
`REVIEW OF SAFETY
`
`MIOWWWW1 l
`
`7.1
`
`Methods ................................................................................................................................................. ll
`7. i. 1
`Clinical Studies Used to Evaluate Safety.....
`. .
`.
`
`7. l .2
`Adequacy ofDan.............................................................................. 12
`7.1.3
`Pooling Data Across Studies to Estimate and Compue Incidence................ .............. 12
`7.2
`Adequacy of Safety Assessments.................. ....
`................_............................. ................
`.................13
`7.2.1 mamawmmmafiurm
`Explaatiorn for Dose Response ........................................................................................13
`7.2.2
`SpecialAnimaland/oranitro’I’eetiag......................................................................13
`7.2.3
`Ramble Clinical Tampa...”................................................................................. 13
`7.2.4 Metabolic, Chance, and Interaction Workup ..........................................................14
`7.2.5
`Evaluation forPotentialAdverseEvutsforSimichrupian; Class ................................ 14
`7.3
`Major Safety Results .............................................................................................. 14
`7.3.1 Deans.................................................................................... 14
`
`...-.............................. 14
`7.3.2 Noam! Serious Adverse Evens ......
`
`7.3.3 Dropoutsmd/or Discontinuaione..- ................................................................................................14
`(idler Significant Adverse Evans”:............................................................................14
`7.3.4
`
`

`

`Clinical Review
`June Cai, MD.
`NDA 22196 8-000
`
`ZolpiMist
`
`_
`
`
`
`' Submission Specific Primary Safety Concerns...................................................................................14
`7.3.5
`Supportive Safety Results............................................................. 15
`7.4
`Common Adverse Events"
`................... 15
`74. 1
`Special Safety Studies....................... 17
`7.4.2
`lmmmmeity ............................
`......................................... 17
`7.4.3
`Other Safety Exploration ............................................................
`.....17
`7.5
`Doee Dependency for Adverse Evens........................................................
`.....17
`7.5.1
`Time Dependency for Adverse Events ...............................................
`.....18
`7.5.2
`Drug-Demographic Interactions”................................
`.
`.......
`....18
`7.5.3
`7.5.4 Dug-Disease Interactions...............
`.
`.......
`............
`.....18
`
`Drug-Drug interactions................
`..................... 18
`7.5.5
`........
`.....18
`7.6
`Additional Safety Explorations......
`
`Human Carcinogenicity ..................................
`............. 18
`7.6.1
`Human Reproduction and PregnaneyData... . ..
`..18
`7.6.2
`Pediatrics and Effect on Growth ..............................
`...........
`..18
`7.6.3
`
`Overdose, Drug Abuse Potential, Withdrawal and Rebomd.................
`1.8
`7.6.4
`Additional Submissions ............................................................................................................... l9
`7.7
`
`POSTMARKETING EXPERIENCE mmmmwmwo
`
`. .
`
`
`
`mmmmwo
`APPENDICES
`Literature Review/Reference: ...-.........................................................................................................20
`
`.................21
`Labeling Recommenduions ..............
`
`Advisory Committee Meeting .................
`.
`.
`.....22
`
`9.1
`9.2
`9.3
`
`8
`
`9
`
`Appears This Way
`On Original
`
`

`

`Clinical Review
`June Cai, MD.
`NDA 22196 8.000
`ZolpiMist
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`From clinical perspective, I recommend the Division taking an approval action for this NDA
`supplement if other aspects of data are sufficient, including inspection fiom the Agency Division ‘
`of Scientific Inspection.
`
`1.2 Risk Benefit Assessment
`
`Despite potential risks, this application appears to demonstrate sufficient benefit outweighing
`risks ifthe data quality and reliability are sufficient
`
`1.3 Recommendations for Postmarketing Risk Management Activities
`
`In addition to Medication Guide, periodic poshnarketinn surveillance for adverse events and
`
`abuse potential
`
`
`11(4)
`
`19.)
`
`em..."rm" :seeaistm‘legitimise
`
`1.4 Recommendations for other Post Mariana: Study Comments
`
`None from clinical point of view. -
`
`1.5 Other Phase IV Commitments
`
`None from clinical point ofview.
`
`2
`
`Introduction and Regulatory Background
`
`2.1 Product Information
`
`ZohiMist‘n' isamdosnpmdfosmulntioncfaolpidemtutmflAmbienMWRkhehanH
`. name is MMG—trinwtltyl—ZynolylimidueflJ-a] pyridine~34cemide L-(+)-tarttate (2:1), a non-
`benaodiuapine hypnotic ofthe imidazopyridine class.
`
`ItmametersddoscoralspraydelivcrysystmthatdeliversaS-mgmeofaolpidemtamate
`halOOuLspnthspmsormMmcmdtwoofmionsonolmedecd
`wmmwnhtheideOmgAmbimtahmmindicnfionfwdikpodmnforflie
`shofl-tumWofinmnnhclmacwizedbydifilculdeswhhsbepinnistion.
`
`

`

`Clinical Review
`June Cai, MD.
`NDA 22196 8-000
`
`ZolpiMist
`
`2.2 Availability of Proposed Active Ingredient in the United States
`
`Zolpidem We isthe active ingredientond itisan FDA approvedand marketed drugand
`readily available in the US.
`
`2.3 Currently Available Treatments for Proposed Indication and Imports-t Safety Issues
`with Consideration
`
`Below is a list ofproducts that have been approved for dais indication since 1970.
`
`Benzodiapapincs -EME- Paradoxical effect
`
`
`
`_rnm:- wimalooholandoromérCNs
`_t:z_ «MAmionandm
`Ambieu CR zolpidem
`disinhibitive behaviors, changesIn
`slow release
`
`-'“"‘°"°°"
`’Brand more manuficmring discontinued by he sponor, Abbott for cornrnercialtenors. V
`
`Chloral hydrate (one ofthe brand names is Noctec) has also been used from very old days for
`treannernofinsomniaaswellassedation. lthnbeenusedinbotlradultsardchildtethsmain
`
`issues include cardiac arrhythmias of all forms including prolonged QT, torsodes de points, and
`cardiac arrest when used in combination with other drugs that have the some cardiac toxicities,
`hallucinations or confirsion, and prolonged bleeding when interacting with comedin.
`
`Dependenceappearsmbeaconnnonptobkmforellofdusedmgsexceptkozem.
`
`Dougewisghisncommendeddratsmhgdosn-belowueddnewmnudsasifivitym
`sedetivelhypnotic drugs in elderly mid/0t debiliwedpoiients.
`
`Merry off-label treatments are also used clinically, such a antihistamines, certain entipsychotin,
`andsonreantidepreseems. MmyofdrnecnryvaionsimifiMsideefl'eemNoneofme
`avoilobletreonnentforproposed mdicationnasonlsprey fortnulation.
`
`

`

`Clinical Review
`June Cai, MD.
`NDA 22196 8000
`
`b 2
`
`.4 Summary of Presuhnsission Regulatory Activity Related to Salli-laden
`
`I
`
`The sponsor conducted studies under 1ND #71290. A pro-1ND meeting was held on August 31,
`2005. The meeting addressed the product development progran including issues of CMC, non-
`clinical and clinical pharmacology as well as labeling.
`
`For the clinical program, the Division informed the sponsor the following:
`0 Either strict bioequivalence or a bracketing appromh using the approved 5 and 10 mg
`doses ofAmbien with PK values that fall between the approved ranges at all times was
`
`0 Evaluation ofthe PK profile ofthe recommended dose (5mg) for the geriatric population
`is expected.
`'
`o For a claim of acute use for short-term insomnia, a single placebo—controlled study with
`a lower dose (3-4 mg) of zolpidem lingual spray should be considered, in which both
`subjective time to falling back to sleep at home and the objective time to fall back to
`sleep alter artificial awakening in the sleep lab arecvaluated simultaneously.
`O A standard evaluation ofthe next morning residual drug effects should also be conducted
`including evaluation ofefl‘ect on driving behavior, which could be achieved by measure
`of pre- and poa- treatment simulated driving eye-land coordination
`
`Additionally, the Agency informed the sponsor ofthe responsibility to look at combinations of
`drugs, specifically a study ofthou patients who take chronic medications for sleep maintenance,
`but with mid-insomnia. For this, our requests are as follows:
`.7
`'
`0 The lingual spray wouldbeusedtomanagethebreaktluough effects.
`0 Standardmeasuresofnext-dayresidual efl'ectsshouldbeincluded, esp.observationsfor
`potential residual effects on driving behavior, which could be evaluated by establishing
`the subjects’ simulated driving eyeolmrd coordination, then measuring it alter study drug
`treatment.
`
`0 This could possibly be approached a operhlabel safety study in outpatients ifa labeling
`claim for efficacy of sublingual zolpidem in combination is not considered.
`
`Afterwards, on Sept. 22, 2006, the Division. commie-wed some concerns regarding dosage used
`in non-clinical studiesandtiming ofexarnine aninrsloralmucosa, some issues intheClB, and
`revisions needed in clinical pharmacology perspective. The sponsor responded to the Division
`letterenNovember?‘,2006andagreedtoallelinicalconunents. No firrtherrelateddiscussion
`wasmadebetweenthen andNDA submission.
`
`1hisNDAnumberwasassignedonMeyl4,2007. Mwasnopre-NDAmeet'mg.
`
`2.5 mmmnumu-dm
`
`ThesponwreonfinneddmdrugahuepMenualwammedmtomeNDAappliesuonon
`0ct.25,2007.
`
`

`

`Clinicid Review
`June Cai, MD.
`NDA 22l96 8-000
`
`ZolgiMist
`
`On Oct. 30, 2007, the sponsor communicated to the Agency regarding video submission fix oral
`irfitafionstudyhnrasaspatofflnefinalstudynpomhowever, itdidnotsatisfyflneAgency
`pharm-tox review (verbalcommunication with Melissa Banks, PhD) Further clarification was
`made'in the 74-day letter.
`
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality
`
`Generally speaking, the submission quality is acceptable.
`
`3.2 Compliance with Good Clinical Practices
`
`Review fi'om BS] is still pending (Please see 08] review for details.)
`
`3.3
`
`financialDiseioaun-es
`
`Thae'ns no financial disclosure for the two Principal Investigator, Luis Angles, M.D.
`(responsible for Study 001) and Evin Henderson Sides, III. MD. (responsible for Studies 002,
`003, and 004)- See Section 5.1 Table of Clinical Stndifi for details.
`
`4 Significant Efficacy/Safety Issues Related to Other Review Disciplines
`
`4.1 Chenktry Manufacturing and Controls
`
`There is no problematic issue fi'om chemistry point of view. For details, please see chemistry
`review conducted by the Agency Chemistry Reviewer, Shastri Bhamidipati, PhD.
`
`4,2 Preclinical Pharmacology/Toxicology
`
`Nonoclinical PK daa are mentially from three studies: MVRvMI, MVR-042, mm.
`
`For detniis, please m phamacology-toxieolofl review condncud by the Agency
`Phalnacology-Toxieoiogy Reviewer Melissa Banks, PhD.
`
`4.3 CWPhermacology
`
`Below are briefsnnnmayofpharmacodynmnicendphermaeokm information submitted by
`thesponsor. Fordetailednview,pleasembiophamecoiogynviewconductedbyflneAgency
`Biopharnaeeufieal Science Reviewer, Japeg Pnrepeily, PhD.
`
`

`

`Clinical Review
`June Cai, MD.
`NDA 22196 $000
`
`zomiMist
`
`4.3.1
`
`Pharmacodynamies
`
`_—___—_———_—_—__————_—
`
`Zolpidem induces sleep through GABA—benzodiazepine receptor complexes. In pilot Studies
`001 and 2, ZolpiMist was evaluated with Stanford Sleepiness Sealer (SSS) and Digital Symbol
`Substitution Test (DSST) before and after treatments that showed similar sleep effect compared
`to that ofzolpidem; Study 003 and 004, DSST and Visual Analog Scale (VAS) were
`administered before and after neannents as assessment to show similar effect to that of zolpidem.
`
`4.3.2
`
`Pharmacokinetics
`
`After oral administration, zolpidem tablets absorbed rapidly and extensively and then undergoes
`hepatic first--pass embolism. The oral bioavailability ofzolprdemin human'rs reported as
`approximately 70%.
`
`The sponsor reports that the first pilot study (00]) demonstrated linearity of PK in the dose range
`of2.5m: to 10mg; The second pilot study (002) demonstrated that food delays absorption of
`ZolpiMist; The two definitive PK studies (003 and 004) demonstrated comparable PK
`parameters to those of zolpidem tablets, in both adults and elderly.
`
`The key PK parameters from definitive PK studies are displayed in the following table.
`
`Table 2. Comparisonof Key Pharmaeoklnetle Parameters of ZolpiMist
`in Young Versus Elderly Subjects (mbmitted by the sponsor)
`
`mess-mm-
`mm-—
`'
`_.39&60m§) marina)
`sinuses»
`
`WW
`
`Mm
`
`
`
`......
`
`'
`
`am-Imm-
`, 11.2“ “1.1411; ”momma,
`
`With ngardtomaaboliumZoipidanmissubmmflymetabolbedmainlyfiuuCYP
`3A4;mofitmflboifiuhuphmaeobfiedwfivifimmmm‘hvnrom
`metabolism smdieausingbunanfivermierosomesmdieaediatthebiomnsformafionof
`zolpidern by cytochrome P450 (CY?) isoenzymes mainly involves CYP3A4 isobrms, which
`appeartoaeeountforapproximflelyéfiofzolpidun chance. Amongotherisoforms,
`CWisesfinmdtoaeemmformofzolpidem elearanee, CYP1A2 for 14%,and
`CYPZDGandCYPZCl9forleesthn39fi.”
`
`

`

`Clinical Review
`June Cai, MD.
`NDA 22196 8-000
`29 iMist
`
`
`5 Sources of Clinical Data
`
`5.1 TableofClinieal Studies
`
`'l‘hctablcbelowpresentsthefourPKsmdieesubmittedforthisNDAwithatotalof96 subkcts.
`
`A Phase I study ofPK
`ofZolpidcm Lingual
`Spray compared tooral
`tablet
`
`'
`
`'
`
`.
`
`'
`
`'
`
`'
`
`..
`
`'
`
`2.5, 5, and 10
`mg ofzolpimist year-old)
`or10mg
`'
`Ambler:
`
`
`
`Dose ranging, open-label,
`A pilot PK study of
`5-way crossover, 5 dosing
`zolpidcm lingual spray
`compared to oral tablet with 7:3 days washout
`in healthy male
`period, in both fed and
`_
`volunteers:
`fastin conditions
`A definitive PK Study
`Dose ranging. randomized,
`ofzolpidcm lingual
`open-label, 4-way
`spray compared to oral
`crossover, 4 dosing with
`tablet in healthy male
`. 7:1:3 days washout period,
`and. female volunteers
`under fastin condition
`A PK study of
`Randomized, open-label, 2-
`. zolpidem lingual spray way, 2 single treatment
`compared to oral tablet with 7:3 days washout
`in healthy elderly
`period; under fasting
`vol
`V
`_
`'
`condition
`
`5 and 10 mg of
`zolpimist or 5
`and 10 mg
`Ambien tablets
`
`5 and 10 mg
`zolpimist or 5
`and 10 mg
`Ambien tablets
`
`14 (18-45
`year-old)
`
`.
`48 (18-45
`year—old)
`
`These studies evaluate PK parameters over the different Studied doses and abo provide safety
`and tolmbility infonnan‘on about administrations of ZolpiMiat 'm healthy volunteers. Among
`them, Studies 003 and 004 are the two definitivelpivotal studies.
`
`5.2mm
`
`Since this application mainly involves open-label PK- studies, the clinical review will focuson
`safetyofth‘isNDA, whiehwillbeachievedbymiewinsallfcwstudiesin Section7and
`focusinsmainlyondeath,SAEaanddropomaheeausctheyareallopcnlabelstudies.lwillalso
`MymmmmmmMmmmemamwof
`Efficacyanddiscuss individual studiasmore indcpth innextsuhseetion 5.3.
`
`