CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`PHARMACOLOGY REVIEW(S)
`
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Applicant:
`Review Division:
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`NDA 202788
`EDR Original Serial 000
`3/4/11
`Received date: 3/4/11; Submit date: 3/14/11
`Fentanyl Sublingual Spray
`Management of breakthrough cancer pain in
`patients
`
` who are already receiving and
`who are tolerant to opioid therapy for their
`underlying persistent cancer pain
`Insys Therapeutics, Inc.
`Division of Anesthesia, Analgesia and Addiction
`Products (DAAAP)
`Elizabeth A. Bolan, Ph.D.
`Reviewer:
`R. Daniel Mellon, Ph.D.
`Supervisor/Team Leader:
`Bob Rappaport, M.D.
`Division Director:
`Kathleen Davies
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202788 are owned by Insys Therapeutics, Inc. or are
`data for which Insys Therapeutics, Inc. has obtained a written right of reference.
`Any information or data necessary for approval of NDA 202788 that Insys Therapeutics,
`Inc. does not own or have a written right to reference constitutes one of the following:
`(1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed
`drug, as reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`202788.
`
`Reference ID: 3051871
`
`1
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`(b) (4)
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`

`

`NDA 202788
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 5
`1.1
`INTRODUCTION.................................................................................................... 5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 5
`1.3 RECOMMENDATIONS............................................................................................ 5
`INDICATIONS AND USAGE .......................................................................................... 6
`
`INDICATIONS AND USAGE .......................................................................................... 6
`
`2 DRUG INFORMATION ............................................................................................ 9
`2.1 DRUG................................................................................................................. 9
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 9
`2.3 DRUG FORMULATION ......................................................................................... 10
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 10
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 10
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 14
`2.7 REGULATORY BACKGROUND .............................................................................. 14
`3 STUDIES SUBMITTED.......................................................................................... 14
`3.1
`STUDIES REVIEWED........................................................................................... 14
`STUDIES NOT REVIEWED ................................................................................... 14
`3.2
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 15
`4 PHARMACOLOGY................................................................................................ 15
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 15
`
`6 GENERAL TOXICOLOGY..................................................................................... 15
`
`7 GENETIC TOXICOLOGY ...................................................................................... 15
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) WITH
`7.1
`.......................................................................................................... 16
`8 CARCINOGENICITY ............................................................................................. 18
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 18
`
`SPECIAL TOXICOLOGY STUDIES................................................................... 19
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 19
`
`APPENDIX/ATTACHMENTS............................................................................. 20
`
`10
`
`11
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`12
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`Reference ID: 3051871
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`NDA 202788
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`Table of Tables
`
`Table 1. Levels and Acceptability of Fentanyl Sublingual Spray Excipients................. 10
`Table 2. Specifications of Fentanyl Base Drug Substance Impurities .......................... 12
`Table 3. Specifications of Fentanyl Sublingual Spray Drug Product
`Impurities/Degradants ................................................................................................... 13
`Table 4. Studies Reviewed........................................................................................... 14
`Table 5. Positive Controls ............................................................................................ 17
`Table 6. TA97a Colony Count Data.............................................................................. 17
`Table 7. TA98 Colony Count Data ............................................................................... 17
`Table 8. TA100 Colony Count Data.............................................................................. 18
`Table 9. TA1535 Colony Count Data............................................................................ 18
`Table 10. TA102 Colony Count Data............................................................................ 18
`
`
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`
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`Reference ID: 3051871
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`NDA 202788
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`Table of Figures
`
`Figure 1. Structure of Fentanyl Base.............................................................................. 9
`Figure 2. Structures of Fentanyl Drug Substance Impurities (reproduced from NDA).. 11
`Figure 3. Structure of
` (reproduced from NDA)...................................... 13
`
`
`Reference ID: 3051871
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`

`

`NDA 202788
`
`Elizabeth A. Bolan, Ph.D.
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`Insys Therapeutics, Inc. has submitted NDA 202788 for Fentanyl Sublingual Spray
`(FSS), a formulation of fentanyl base intended for sublingual delivery for the treatment
`of breakthrough cancer pain. Fentanyl Sublingual Spray is packaged as a unit dose
`spray device that delivers one actuation per vial. Each actuation delivers
`“‘4’ with
`100, 200, 400, 600 or 800 mcg of fentanyl. Doses of 100, 200, 400, 600, 800, 1200,
`and 1600 mcg of fentanyl are intended to be used.
`
`This application was submitted via the 505(b)(2) regulatory pathway and the Applicant is
`relying on the Agency’s findings of safety and efficacy and the pharmacology,
`pharmacokinetics, and toxicology information in the label of Actiq (NDA 20747).
`
`1.2
`
`Brief Discussion of Nonclinical Findings
`
`The pharmacology and toxicology of fentanyl have been well characterized. No
`nonclinical toxicology studies were deemed necessary to characterize the safety of
`fentanyl for this product unless abnormalities arose during monitoring of pulmonary
`function in the clinical studies. No abnormalities in pulmonary function were noted in
`the clinical studies therefore, no nonclinical studies with fentanyl were conducted.
`
`The excipients used in the FSS formulation are all found at higher levels in drugs
`previously approved by FDA and do not pose any toxicologic concerns. Extractable and
`leachable assessments were conducted with the
`“M" material from the FSS
`container closure system. Drug Master File
`"’m’ for the
`"m"
`is referenced by the Applicant. The
`"M are used in over 150 approved drugs,
`many with similar aqueous formulations to F88. The Agency’s previous finding of
`safety for the
`"m" material will be relied on in order to support its safety.
`
`The impurities/degradants in the drug substance and drug product are controlled at
`acceptable levels. A structural alert for mutagenicity was identified in the drug product
`degradant
`"’m’ (
`"M" The Applicant conducted an Ames Assay which
`showed a negative result for mutagenicity, therefore “m" can be regulated as a typical
`non-genotoxic impurity according to ICH QBB(R2). The drug product specification set
`for “m in this NDA is acceptable.
`
`There are no unique nonclinical issues associated with this product compared to the
`referenced fentanyl product. There are no outstanding concerns with this NDA that
`would preclude approval. The recommendation from Pharmacology/Toxicology is that
`NDA 202788 be approved with no post-marketing requirements.
`
`1.3 Recommendations
`
`1 .3.1 Approvability
`
`Reference ID: 3051871
`
`

`

`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 202788
`
`The recommendation from Pharmacology/Toxicology is that NDA 202788 be approved
`with no post-marketing studies.
`
`1.3.2 Additional Non Clinical Recommendations
`None
`
`1.3.3 Labeling
`The table below contains the draft labeling submitted by the Applicant, the changes
`proposed by the reviewer and the rationale for the proposed changes. For the final
`version of the label, please refer to the Action Letter. Note: The recommended changes
`from the proposed labeling are in red or strikeout font.
`
`Applicant’s proposed labeling
`
`Reviewer’s proposed changes
`
`Rationale for
`changes
`
`Reference ID: 3051871
`
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`(b) (4)
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`2 Page(s) of Draft Labeling has been Withheld in
`Full as B4 (CCI/TS) immediately following this page
`
`

`

`Elizabeth A. Bolan, PhD.
`
`
`
`(M(4)
`
`l
`
`NDA 202788
`
`2
`
`Drug Information
`
`2.1
`
`Drug
`
`CAS Registry Number
`437—38—7
`
`Generic Name
`
`Fentanyl base
`
`Code Name
`
`NA
`
`Chemical Name
`
`N-phenyl-N-[1-(2-phenylethyl)—4-piperidinyl] propanamide; N-(1-phenethylpiperidin-4-yl)-
`N-phenylpropionamide
`
`Molecular FormulaIMolecular Weight
`CDH23N20; MW=336.47 (free base)
`
`Figure 1. Structure of Fentanyl Base
`
`CH3 CH2 CONCN—CHZ CH2<©
`
`Pharmacologic Class
`Opioid Agonist (FDA Established Pharmacologic Class)
`
`2.2 Relevant INDs, NDAs, and DMFs
`
`IND/NDA/MF
`drug/compound
`Sponsor Division/Office
`status
`IND 72411
`Fentan ISuinnual S-ra
`Ins s
`DAAAP
`active
`
`ade o uate
`
`D
`
`N A 20747
`
`Actiq (referenced drug)
`
`Cephalon
`
`M
`
`DAAAP
`
`ON DQA
`
`ON DQA
`
`eff/20,3?
`
`adequate
`
`Reference ID: 3051871
`
`

`

`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 202788
`
`
`2.3 Drug Formulation
`Fentanyl Sublingual Spray is packaged as a unit dose spray device that delivers one
`actuation per vial. Each actuation delivers a volume of
` containing 100, 200,
`400, 600 or 800 mcg of fentanyl. Doses of 100, 200, 400, 600, 800, 1200, and 1600
`mcg are intended to be used. The two highest doses of 1200 and 1600 mcg require
`actuation of two units of the 600 mcg and 800 mcg strengths, respectively.
`
`Fentanyl Sublingual Spray is labeled to be used at a maximum of four doses per day.
`The two highest doses of 1200 mcg and 1600 mcg require actuation of two units to
`achieve the dose therefore the maximum number of units actuated per day is eight.
`With
` per actuation for eight actuations,
` will be used as the total daily
`volume of drug product consumed. The excipient levels and leachable assessments
`will be based on the volume of
` per day. The maximum daily dose (MDD) of
`the fentanyl drug substance for this product is 6.4 mg (1600 mcg x 4 doses).
`
`
` Total daily intake of
`excipients as well as the amount of the excipient in drugs previously approved for
`sublingual, buccal or oral use as listed in the FDA Inactive Ingredients Guide is outlined
`in Table 1. With the use of
` of FSS, total levels of all excipients are below
`levels previously approved by FDA and are therefore considered acceptable.
`
`
`
`
`Table 1. Levels and Acceptability of Fentanyl Sublingual Spray Excipients
` TDI, mg Amount in IIG*, mg
`Acceptable?
`Excipient
`Dehydrated alcohol
`196
`YES
`Propylene glycol
`52
`YES
`L-Menthol
`10
`YES
`Xylitol
`72
`YES
`*FDA Inactive Ingredients Guide
`2.4 Comments on Novel Excipients
`There are no novel excipients in FSS.
`
`2.5 Comments on Impurities/Degradants of Concern
`
`Impurities in the drug substance
`The MDD of fentanyl (6.4 mg) is < 2 g/day, therefore the qualification threshold
`according to the ICH Q3A(R2) guideline for impurities in the drug substance is 0.15% or
`1 mg/day intake, whichever is lower. The Applicant is obtaining the fentanyl base drug
`substance from
` (DMF
` The specifications for the drug
`substance impurities are listed in Table 2 and the structures are presented in Figure 2.
`
`
`Reference ID: 3051871
`
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`NDA 202788
`
`Elizabeth A. Bolan, Ph.D.
`
`The A licant has set the s ecifications in the dru substance for—,
`at
`, which are considered acceptable
`
`a e
`
`.
`
`
`
`contain moieties which are considered structural alerts for muta enICI
`
`our Impurl Ies In
`
`e rug su stance o ained from1
`
`.
`
`should be set for genotoxic or
`Specifications to reflect NM
`po en Ially genotoxic residual interme Ia es Impurities. For a MDD of 6.4 mg of
`fentanyl, the specifications set by the Applicant for the impurities containing structural
`alerts would yield a total daily intake of <1.5 mcg of each impurity and are therefore
`considered acceptable (Table 2).
`
`Figure 2. Structures of Fentanyl Drug Substance Impurities (reproduced from NDA)
`
`Reference ID: 3051871
`
`

`

`NDA 202788
`
`Elizabeth A. Bolan, PhD.
`
`Table 2. Specifications of Fentanyl Base Drug Substance Impurities
`
`"’""
`
`Acce . table
`
`
`
`
`
`
`
`YES
`
`YES
`
`YES
`
`YES
`
`YES
`
`*structural alert for mutagenicity
`
`Impurities in the drug product
`The MDD of fentanyl of 6.4 mg in the FSS drug product is <10 mg/day, therefore the
`qualification threshold according to the ICH Q3B(R2) guidelines for
`impurities/degradants in the drug product is 1.0% or 50 mcg TDI, whichever is lower.
`The Applicant has identified
`"M" (
`“M" as the only degradant (Table 3).
`
`(b) (4)
`
`(b) (4)
`
`The Applicant considered "'""’ a potential structural alert and conducted
`a computational toxicology analysis using the MultiCase and Leadscope modeling
`programs (see reports in section 3.2.P.5.5 of NDA). The Applicant’s analysis predicted
`that
`“m" did not show potential for mutagenicity in either program. The Applicant
`evaluated several other parameters (i.e. clastogenicity and DNA damage) in the
`computational toxicology analysis but those parameters have not been validated and
`the results will not be discussed in this review.
`In 2009, an internal computational
`toxicology analysis using two programs was conducted by the FDA Informatics and
`Computational Safety Analysis Staff (ICSAS) for the potential for genotoxicity of
`"’""
`The ICSAS analysis found that the MultiCase (MC4PC) program predicted negative
`mutagenicity for Salmonella and E. coli and the MDL—QSAR program predicted a
`positive result for Salmonella mutagenicity and a negative result for E. coli mutagenicity.
`Other endpoints were analyzed in the ICSAS report, but only results relevant to
`Salmonella and E. coli mutagenicity will be discussed here.
`In order to be certain that
`the most current computational toxicology databases were used, the structure of
`“m"
`was resubmitted in 2011 to ICSAS for evaluation of mutagenicity. The Salmonella
`mutagenicity endpoint was analyzed by ICSAS using four different programs. No
`structural alerts for
`“m" were identified using DEREK for Windows and negative
`predictions were obtained with MultiCase (MC4PC) and Leadscope programs. The
`negative predictions with the MultiCase and Leadscope programs are consistent with
`the negative result from the 2009 ICSAS analysis. The SciQSAR program predicted a
`positive result for Salmonella mutagenicity which replicated the positive result from the
`MDL—QSAR in the 2009 ICSAS analysis. The names MDL-QSAR and SciQSAR refer to
`the same program and the name was changed to current SciQSAR when the program
`was sold to a new company. For the 2011 ICSAS analysis, the overall call of positive
`
`Reference ID: 3051871
`
`1 2
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`

`

`NDA 202788
`
`Elizabeth A. Bolan, Ph.D.
`
`“M" was made by the director of ICSAS, Dr. Daniel
`for Salmonella mutagenicity for
`Benz. Below is an excerpt from the 2011 ICSAS report.
`
`“Based on the OMB mandate for us to maximize sensitivity (avoid false
`negatives), we have predicted that
`“M will be positive for
`Salmonella mutagenesis based solely on a moderately positive call by
`only one of the four programs we used.”
`
`The Division considered “m to be potentially mutagenic and requested that the
`Applicant either reduce the specification to reflect a TDI of NMT
`“m" or conduct
`an Ames Assay. The Division held a tcon with the Applicant on 8/9/11 to discuss the
`positive prediction of the computational toxicology analysis for
`"m" The Division
`explained to the Applicant that in an internal computational toxicology analysis by FDA
`ICSAS, the SciQSAR program predicted a positive result for Salmonella mutagenesis
`for the drug product degradant
`"M" The Division requested that the Applicant conduct
`an Ames Assay with W" in order to definitively define the potential for mutagenicity.
`Since there has been confusion in the past with different compounds being referred to
`as
`"’"" the Division clarified that the CAS number of W is
`W" The Applicant
`agreed to conduct an Ames Assay with "M" and submit it to the NDA.
`
`The Applicant has conducted an Ames Assay with the impurity
`study is reviewed below (Section 7.1) and found to be valid and negative.
`"m" can be considered to be adequately qualified for mutagenic potential and
`may be regulated as a standard impurity to levels set in ICH Q3B(R2). The Applicant’s
`current drug product specification for
`“M" is acceptable.
`
`"’m’ The
`
`Figure 3. Structure of
`
`(reproduced from NDA)
`
`(b) (4)
`
`(0) (4)
`
`Table 3. Specifications of Fentanyl Sublingual Spray Drug Product
`Impurities/Degradants
`
`Im . uri
`
`/de . radant
`
`Acce . table
`
`Stabili
`
`s . ecification
`
`Reference ID: 3051871
`
`1 3
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`

`

`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 202788
`
`2.6 Proposed Clinical Population and Dosing Regimen
`Fentanyl Sublingual Spray is indicated for the management of breakthrough cancer pain
`in patients
` who are already receiving and
`who are tolerant to opioid therapy for their underlying persistent cancer pain. Fentanyl
`Sublingual Spray is labeled to be used at a maximum of four doses per day.
`
`2.7 Regulatory Background
`A PIND meeting with Insys Therapeutics, Inc. for IND 72411 was held on 8/25/05. The
`Division determined that no additional nonclinical studies would be required to
`characterize the safety of the fentanyl drug substance unless abnormalities arose during
`monitoring of pulmonary function in the clinical studies. It was also communicated to
`the Applicant that the NDA submission should include the identification and toxicity
`information of potential leachables and extractable from the drug delivery system.
`Guidance regarding adequate qualification of drug substance and drug product
`impurities/degradants as well as submission of an NDA via the 505(b)(2) regulatory
`pathway were provided to the Applicant. The IND was submitted in early 2007 and the
`30-date safety date was 2/2/07. The proposed clinical protocol was allowed to proceed.
`End-of-phase 2 and PNDA meetings were held on 12/07/07 and 8/17/10, respectively.
`The comments regarding extractable/leachable evaluation and specifications of
`impurities were reiterated to the Applicant at these meetings. No abnormalities in
`pulmonary function were noted in the clinical studies, therefore, no nonclinical studies to
`characterize the safety of fentanyl were deemed necessary.
`
` 3
`
`
`
`Studies Submitted
`
`3.1 Studies Reviewed
`
`Study number
`158333
`TTP-IOX-M0026
`
`NA
`
`NA
`
`
`
`
`
`
`
`Table 4. Studies Reviewed
`eCTD
`Study Title
`location
`4.2.2.2 Bacterial Mutagenicity Test- Ames Assay (
`Safety Assessment of Extractables and Leachables from
`4.3
`
`3.2.P.5.5 Computational Assessment of Genotoxicity of
`with MC4PC
`3.2.P.5.5 Computational Toxicity Assessment Using the Leadscope FDA
`Model for Test Structure (
`
`
`
`3.2 Studies Not Reviewed
`All submitted studies have been reviewed.
`
`Reference ID: 3051871
`
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`

`Elizabeth A. Bolan, Ph.D.
`
`NDA 202788
`
`3.3 Previous Reviews Referenced
`No previous reviews are referenced.
`
`
`
` 4
`
`Pharmacology
`
`Fentanyl is a synthetic phenylpiperidine opioid analgesic which acts as an agonist on
`the mu opioid receptor. The analgesic properties of fentanyl are similar to that of
`morphine and other mu opioids. Fentanyl is more lipid soluble than morphine and is
`roughly 100 times more potent as an analgesic than morphine. Time to peak analgesia
`of fentanyl is rapid and the duration of action is short (Gutstein HB and Akil H, 2006).
`The safety concerns of fentanyl are similar to those of other potent opioids with the
`major concerns being respiratory depression and the potential for abuse.
`
` 5
`
`Pharmacokinetics/ADME/Toxicokinetics
`
`Mechanism of action: Fentanyl is an opioid agonist which exerts its analgesic effects
`primarily through the mu opioid receptor subtype.
`
`Drug activity related to proposed indication: Fentanyl is a potent opioid and with
`sublingual administration first-pass metabolism is avoided resulting in a higher
`bioavailability than orally administered fentanyl. Fentanyl is lipophilic and rapidly
`crosses the blood brain barrier resulting in a rapid onset of action, an important factor
`for the relief of breakthrough pain episodes in cancer patients.
`
` 6
`
` General Toxicology
`No general toxicology studies were required for this NDA and none were submitted by
`the Applicant.
`
` 7
`
` Genetic Toxicology
`Genetic toxicology studies with fentanyl are described in the label of the referenced
`product, Actiq. No new genetic toxicology studies with fentanyl were required for this
`NDA and none were submitted by the Applicant. It was determined through
`computational toxicology analysis that the fentanyl degradant
` contains a structural
`alert for mutagenicity. The Applicant conducted an Ames Assay with
` which is
`reviewed below. The degradant
` was found to be negative in the Ames Assay.
`
`Reference ID: 3051871
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`

`NDA 202788
`
`7.1
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`In Vitro Reverse Mutation Assay in Bacterial Cells (Ames) with
`
`Study title: Bacterial Mutagenicity Test- Ames Assay
`Study no.:
`158333
`Study report location:
`EDR 4.2.3.3.1
`Conducting laboratory and location:
`Date of study initiation:
`GLP compliance:
`QA statement:
`Drug, lot #, and % purity:
`
`8/26/11
`Yes
`Yes
`
` CAS#
`S813990; 100%
`
`
`
`; Lot#
`
`
`Key Study Findings
` is not mutagenic in S. typhimurium strains TA97a, TA98, TA100,
`TA102, and TA1535 in either the presence or absence of S9.
`
`Methods
`
`Strains: TA97a, TA98, TA100, TA102, TA1535
` Concentrations in definitive study: 0.0501, 0.158, 0.501, 1.582, 5.00 mg/plate
`Basis of concentration selection: dose range finding study
`Negative control: DMSO
`Positive control: see Table 5 (reproduced from NDA)
`Formulation/Vehicle: DMSO
`Incubation & sampling time:
`incubation time: 48-72 h
`
`
`Study Validity
`The study is valid. Suitable numbers of replicate plates and appropriate counting
`methods were utilized. The five strains utilized in this study are considered adequate
`for routine testing as per ICH S2A. The positive controls demonstrated clear increases
`in tester strain revertants while the vehicle control was within historical range for the
`tester strains for this vehicle.
`
`Methods
` in a bacterial mutagenicity assay based on the
`The Applicant evaluated
`method of Maron and Ames (Maron and Ames, 1983). Five concentrations of test
`article as well as DMSO vehicle and positive controls were plated in triplicate with
`overnight cultures of Salmonella typhimurium strains TA97a, TA98, TA100, TA102,
`TA1535 (Ames, et al., 1975) on selective minimal agar in the presence and absence of
`S9 prepared from Aroclor-induced rat liver using the plate incorporation method. The
`positive controls utilized were appropriate for each tester strain and metabolic activation
`condition (Table 5).
`
`Results
`
`Reference ID: 3051871
`
`16
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`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 202788
`
`No substantial reductions in the background lawns or precipitate were noted at any
`concentration of test article. For each strain, all five concentrations in the presence and
`absence of S9 were able to be evaluated. The colony count data for each strain in the
`presence and absence of S9 are presented in Tables 6 through 10 (reproduced from
`NDA). The fold increase of the mean test article colony count value over the mean
`vehicle control colony count value is presented in the column with the heading “FI”
`(Tables 6-10). All of the strains at all of the concentrations tested showed negative
`mutagenic responses in the presence and absence of exogenous metabolic activation
`with S9.
`
`Study outcome: It is concluded that under conditions of the assays conducted,
` is not mutagenic in S. typhimurium strains TA97a, TA98, TA100, TA102,
`and TA1535 in either the presence or absence of S9.
`
`Table 5. Positive Controls
`
`
`
`Table 6. TA97a Colony Count Data
`
`
`
`Table 7. TA98 Colony Count Data
`
`Reference ID: 3051871
`
`17
`
`
`
`
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`
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`NDA 202788
`
`
`
`Table 8. TA100 Colony Count Data
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`
`
`Table 9. TA1535 Colony Count Data
`
`
`
`Table 10. TA102 Colony Count Data
`
` 8
`
` Carcinogenicity
`No carcinogenicity studies were required for this NDA and none were submitted by the
`Applicant.
`
` 9
`
` Reproductive and Developmental Toxicology
`No reproductive toxicology studies were required for this NDA and none were
`conducted. Fentanyl is currently a Pregnancy Category C. It has been evaluated in
`several animal studies which appear in the label of the referenced product, Actiq.
`
`Reference ID: 3051871
`
`18
`
`

`

`NDA 202788
`
`Elizabeth A. Bolan, PhD.
`
`10 Special Toxicology Studies
`
`The FSS device is a single-dose stoppered glass vial assembled into a delivery device
`to be used as a sublingual spray. The NDA references DMF
`“m" for
`the
`"m" material. This DMF has been reviewed by ONDQA and found to be
`adequate. The Applicant conducted extractable and leachable studies with the
`M". The DMF for the
`“m"
`“m" has been referenced
`
`(ll) (4)
`
`by many NDAs for products approved by FDA and no safety concerns with leachables
`have arisen.
`
`Fentanyl Sublingual Spray is labeled to be used at a maximum of four doses per day.
`The label reads: “Once a successful dose is found, patients should limit consumption to
`four or fewer doses per day”. The two highest doses of 1200 mcg and 1600 mcg
`require actuation of two units to achieve the dose. Each unit can be actuated only once.
`Therefore, with a maximum of four doses per day with the two highest doses requiring
`two actuations, the maximum number of units actuated per day would be eight. With
`W" per actuation for eight actuations,
`“M" is the total daily volume of drug
`product consumed. The volume of
`m“) will be used in the extractable and leachable
`assessments in order to calculate total daily intake of any identified compounds.
`
`An extractables assessment was conducted with the
`"M" were
`in the FSS device (report # TTP-lOX—M0026). Extractions with the
`performed with water and 100% ethanol. Several compounds were identified at very
`low levels. A leachable assessment with the
`“m" with the drug
`product was also conducted using 1-3 year stability samples (report # TlP-lOX—M0026).
`The most abundant leachable identified was
`“M (
`"’m’ at a level
`which would yield
`“m".
`W"
`
`used
`
`(5) (4)
`
`compounds were identified in the leachable study at very low levels. The
`"M" are used in over 150 approved drugs, many with similar aqueous formulations
`to FSS. We are unaware of any safety signals that have arisen for these products due
`to the use of the
`"M. The Agency’s previous finding of safety for the
`material will be relied on in order to support its safety.
`
`Several other
`
`(I!) (4)
`
`11
`
`Integrated Summary and Safety Evaluation
`
`Fentanyl is a well-characterized mu opioid. No pharmacology or toxicology data with
`fentanyl were required for this NDA and no data with fentanyl were submitted. The
`excipients used in the FSS formulation are all found at higher levels in drugs previously
`approved by FDA for sublingual, buccal or oral use and do not pose any unique
`toxicologic concerns. There are no concerns with extractables or leachables from the
`"M" material for this product. The impurities/degradants in the drug substance
`and drug product are controlled at acceptable levels. There are no outstanding
`concerns with this NDA that would preclude approval. The recommendation from
`Pharmacology/Toxicology is that NDA 202788 be approved with no post-marketing
`requirements.
`
`Reference ID: 3051871
`
`1 9
`
`

`

`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 202788
`
`12 Appendix/Attachments
`
`
`
`Reference List
`
`Ames BN, Mccann J and Yamasaki E (1975) Methods for detecting carcinogens and
`mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat Res
`31:347-364.
`
`Gutstein HB and Akil H (2006) Goodman and Gilman's The Pharmacological Basis of
`Therapeutics, (Laurence L.Brunton ed) McGraw-Hill, New York, NY.
`
`Maron DM and Ames BN (1983) Revised methods for the Salmonella mutagenicity test.
`Mutat Res 113:173-215.
`
`
`
`Reference ID: 3051871
`
`20
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELIZABETH BOLAN
`11/30/2011
`
`RICHARD D MELLON
`11/30/2011
`I concur.
`
`Reference ID: 3051871
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`NDA/BLA Number: 202-788 Applicant: Insys Therapeutics,
`Inc.
`NDA/BLA Type: 505(b)(2)
`
`Stamp Date: March 4, 2011
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`X
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`X
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`X
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`X
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` 6
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`Drug Name: Fentanyl
`Sublingual Spray
`
`On initial overview of the NDA/BLA application for filing:
`
`
`
`
`
`Content Parameter
`Yes
`No
`1 Is the pharmacology/toxicology section
`organized in accord with current regulations
`and guidelines for format and content in a
`manner to allow substantive review to
`begin?
`
`Is the pharmacology/toxicology section
`indexed and paginated in a manner allowing
`substantive review to begin?
`
`Is the pharmacology/toxicology section
`legible so that substantive review can
`begin?
`
`Are all required (*) and requested IND
`studies (in accord with 505 b1 and b2
`including referenced literature) completed
`and submitted (carcinogenicity,
`mutagenicity, teratogenicity, effects on
`fertility, juvenile studies, acute and repeat
`dose adult animal studies, animal ADME
`studies, safety pharmacology, etc)?
`
`If the formulation to be marketed is
`different from the formulation used in the
`toxicology studies, have studies by the
`appropriate route been conducted with
`appropriate formulations? (For other than
`the oral route, some studies may be by
`routes different from the clinical route
`intentionally and by desire of the FDA).
`Does the route of administration used in the
`animal studies appear to be the same as the
`intended human exposure route? If not, has
`the applicant submitted a rationale to justify
`the alternative route?
`7 Has the applicant submitted a statement(s)
`that all of the pivotal pharm/tox studies
`have been performed in accordance with the
`GLP regulations (21 CFR 58) or an
`explanation for any significant deviations?
`8 Has the applicant submitted all special
`studies/data requested by the Division
`during pre-