CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER”:
`
`22-030
`
`PHARMACOLOGY REVIEW; S!
`
`

`

`SUPERVISORY MEMO 3
`
`FOOD AND DRUG ADMINISTRATION
`
`
`
`Division of Reproductive and Urologic Products
`Center for Drug Evaluation and Research
`
`Date:
`
`Reviewer:
`
`September 24, 2008
`
`LyImda Reid, Ph.D.
`Supervisory Pharmacologist
`
`NDA #lSS#/date:
`
`22-030 (N000) May 1, 2008
`
`Sponsor:
`
`’
`
`-
`
`Pfizer
`
`Drug Product:
`
`Fesoterodine fumarate (Toviaz®)
`
`Indication:
`
`_
`
`Overactive bladder
`
`MHT Labeling Consult
`RE:
`
`
`Introduction: This NDA was originally filed on March 17, 2006. It received an
`approvable action pending satisfactory inspection of the manufacturing facility on
`January 25, 2007. Labeling negotiations were, for the most part, completed at that time.
`The submission received on May 1, 2008 contained the Sponsor’s final proposed label.
`A consult was sent to the Maternal Health Team (MHT) on June 27, 2008. The DRUP
`Pharm/Tox team filed their completed reviews with recommended pregnancy labeling on
`September 16, 2008. On September 19, 2008, the Division received the MHT review of
`the Pregnancy section containing labeling recommendations in non-PLR and PLR
`formats.
`
`The Toviaz labeling agreed to by the Sponsor and DRUP is consistent with other
`antimuscarinic drug labels. The reproductive and developmental findings for
`fesoterodine are similar to all other antimuscarim'c products. The recommended changes
`proposed by thevMHT would make the Toviaz label significantly different than the other
`drugs of this class and may unfairly penalize it. In addition, the recommended division of
`the nonclinical data into summary and detailed observations is considered cumbersome
`and confusing in the non-PLR labeling format.
`
`Regulatory Action: We recommend that the labeling format proposed by the Sponsor
`be retained. At the time this label is converted from non—PLR to PLR formatting, we will
`incorporate the recommended changes as appropriate.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Lynnda Reid
`9/25/2008 02:58:16 PM
`PHARMACOLOGIST
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`PRODUCT:
`
`22-030
`
`010
`
`‘01 May 2008
`Fesoterodine
`
`INTENDED'CLINICAL POPULATION:
`
`Men and women with overactive bladder with
`
`symptoms of urinary urgency, fi'equency and/or urge
`incontinence
`
`SPONSOR:
`
`Schwartz Pharma
`
`DOCUMENTS REVIEWED:
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
`
`‘
`
`i
`
`>
`Electronic File
`Division of Reproductive and Urologic Products
`
`Laurie McLeod—Flynn, Ph.D., D.A.B.T.
`Lynnda Reid, Ph.D.
`Scott Monroe, M.D.
`
`PROJECT MANAGER:
`
`Celia Peacock, MPH, RD
`
`Date of review submission to Division File System (DFS): 09/11/08
`
`

`

`TABLE OF CONTENTS _
`
`EXECUTIVE SUMJVIARY ...................................................................................-. .......... 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................... 7
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY................................................................... 7
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS ................................................. 9
`
`

`

`Reviewer: Laurie McLeod-Flynn
`
`NDA No. 22030
`
`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`. A. Recommendation on approvability: There is no impediment to approval of this
`NDA from a phannacology/toxicology perspective
`
`B. Recommendation for nonclinical studies: No new studies are recommended.
`
`C. Recommendations for labeling
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`No evidence of drug-related carcinogenicity was found in 24-month studies with oral
`administration to mice and rats. The highest tolerated doses in mice (females45 to
`60 mg/kg/day, males 30 to 45-mg/kg/day) correspond to 11- to 19-fold (females) and 4—
`to 9-fold (males) the estimated human AUC values reached with fesoterodine 8 mg,
`which is the Maximum Recommended Human Dose (MRHD). In rats, the highest
`tolerated dose (45 to 60 mg/kg/day) corresponds to 3- to 8—fold (females) and 3- to 14-
`fold (males), the estimated human AUC at the MRHD.
`
`Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome
`aberration tests) or in vivo (mouse micronucleus test).
`
`Fesoterodine had no effect on reproductive function, fertility, or early embryonic
`development of the fetus at non—maternally toxic doses in mice. The maternal No~'
`Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early
`embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure
`was 0.6- to 1.5~fold higher in mice than in humans at the MRHD, whereas based on peak
`plasma concentrations, the exposure in mice was 5— to 9—fold higher. The Lowest-
`Observed—Effect Level (LOEL) for maternal toxicity was 45 mg/kg/day.
`
`Pregnancy
`
`Pregnancy Category C
`
`Reproduction studies have been performed in mice and rabbits. No dose-related
`teratogenicity was observed at oral doses up to 75 mg/kg/day in mice (6 to 27 times the
`expected exposure at the MRHD based on AUC and greater than 77 times the expected
`Cmax) and up to 27 mg/kg/day in rabbits (3— to 11- fold by AUC and 19- to 62-— fold by
`Cmax) or at subcutaneous doses up to 4.5 mg/kg/day in rabbits (9- to 11- fold by AUC and
`43 to 5 6-fold by Cmax). In mice treated orally with 75 mg/kg/day (6- to 27-times the
`expected exposure at the MRHD based on AUC and greater than 77-times the expected
`Cmax), increased resorptions and decreased live fetuses were observed. One fetus with
`cleft palate was observed at each dose (15, 45 and 75 mg/kg/day), at an incidence within
`the background historical range. In rabbits treated orally with 27 mg/kg/day (3 to 11— fold /
`by AUC and 19 to 62- fold by Cmax), ”N— incompletely ossified
`stemebrae (retardation of bone development) were observed in fetuses. In rabbits treated
`by subcutaneous (sc) administration with 4.5 mg/kg/day (9 to 11- fold by AUC and 43 to
`
`b(4l
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`NDA No. 22030
`
`53- fold by CW), maternal toxicity and WW incompletely ossified
`stemebrae were observed in fetuses (at an incidence within the background historical
`range). At 1.5 mg/kg/day s.c., (3—fold by AUC and 11 to 13— fold by Cm“), decreased
`maternal food consumption in the absence of any fetal effects was observed. Oral
`administration of30 mg/kg/day fesoterodine to 7 \ mice in a pre- and postnatal
`development study resulted in decreased body weight of the dams and delayed ear
`opening of the pups. No effects were noted on mating and reproduction of the F1 dams
`-~ gon the F2 offspring.
`
`There are no adequate and well-controlled studies using Toviaz in pregnant women.
`Therefore, Toviaz should be used during pregnancy only if the potential benefit
`outweighs the potential risk to the fetus.
`
`M4)
`
`II.
`
`Summary of nonclinical findings
`
`’A. Brief overview of nonclinical findings
`
`Exaggerated pharmacological effects (including mydriasis, increased heart rate, and
`neurological effects) were the primary limiting toxicity for both mice and dogs. No
`treatment related histopathological changes were observed after treatment for 6 months in
`mice or 9 months in dogs.
`
`Although a clearly defined effect on QT prolongation was not observed in dogs
`administered oral fesoterodine, effects were observed in dogs exposed intravenously to
`greater than 10 times the expected clinical exposure.
`
`Fesoterodine was negative for genotoxicity and/or mutagenicity in a battery of in vitro
`and in viva assays.
`
`Two-year carcinogenicity bioassays were conducted in rats and mice up to a maximally
`tolerated dose of fesoterodine. There was adequate exposure to each of the major human
`metabolites. No treatment related increases in the type or incidence of neoplastic and/or
`hyperplastic lesions were observed.
`
`Reproductive toxicology:
`
`In a mouse fertility study (oral), at 45 mg/kg/day, no effect on male fertility or the male
`reproductive system was observed. In females, numbers of corpora lutea, implantation
`sites, live fetuses, and uterine weight were decreased at this dose. At 15 mg/kg/day (about
`equal to the expected clinical expoSure), no effects on female fertility, the female
`reproductive system, or early embryonic development were observed.
`
`In a mouse embryo/fetal study (oral), at 75 mg/kg/day (about 6—30 times the expected
`clinical exposure of an 8 mg dose via AUC), one dam died, and body weight, gravid
`uterine weight, and the number of live fetuses were decreased. Resorptions were
`increased. At 45 mg/kg/day, one dam died, but no effect on body weight was observed.
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`NDA No. 22030
`
`The number of live fetuses appeared to be decreased, but did not reach statistical
`significance. Lack of significance for resorptions in the mid dose group may have been
`due to the decrease in implantation sites seen in this group. At the lowest dose of 15
`mg/kg/day (about equal to the expected clinical exposure), the number of resorptions was
`increased and the number of live fetuses was decreased. In addition, 1 fetus with cleft
`palate was observed in each of the treated groups, but not in the control group.
`
`In a rabbit embryo/fetal study (oral), at 27 mg/kg/day (about 4-12 times the expected
`clinical exposure of an 8 mg dose via AUC), one dam died following dosing. Resorptions
`were increased at this dose and the total number of live fetuses was decreased. No
`malformations were observed, but the number of fetuses with incompletely ossified
`stemebrae were increased. At 9 mg/kg/day (about 0.2 times the expected clinical
`exposure), one dam aborted and was sacrificed. Although, the number of fetuses with
`incompletely ossified stemebrae appeared to be increased, statistical significance was not
`reached. A no effect level for maternal and fetal toxicity was not clearly identified in the
`study.
`
`Although an increase in litter incidence'of incompletely ossified stemebrae was not
`observed due to a high incidence in the control, this effect appears to be dose related and
`significant when fetal incidence is also considered.
`
`Dams dosage (mg/kg/day)
`___—_
`
`Stemebrae incompletely ossified or reduced
`
`
`82** (84.5%)
`83 (71.6%)
`76 (69.1%)
`68 (63.1%)
`.
`_fetal incidence (percent)
`19 (100%)
`18 (94.7%)
`18 (94.7%)
`16 (80.0%)
`litter incidence (percent) .
`
`
`In a rabbit embryo/fetal study (subcutaneous), at 4.5 mg/kg/day by subcutaneous
`administration (about 10-12 times the expected clinical exposure of an 8 mg doSe via
`AUC of the active entity SPM 7605), mortality was observed in dams in conjunction with
`clonic convulsions, dyspnea, miosis, and a decrease in body weight and food
`consumption. No effects on number of corpora lutea, implantation sites, resorptions,
`placental and fetal weights, or number of live fetuses were observed. No external or
`skeletal malformations were observed. No treatment related external or skeletal variations
`were observed. No treatment related skeletal retardations were observed except
`incomplete ossification of the stemebrae. At 1.5 mg/kg/day (about 3~4 times), no
`maternal or fetal effects were observed except for a decrease in maternal food
`consumption. At 0.5 mg/kg/day, no maternal or fetal effects were observed.
`
`Although an increase in litter incidence of incompletely ossified stemebrae was not
`observed due to a high incidence in the control, this effect appears to be dose related and
`significant when fetal incidence is also considered.
`
`
`Oral administration
`Dams dosage (mg/kg/day)
`_ 0-5
`1-5
`
`
`Incomplete ossification of the stemebrae
`
`_fetal incidence
`,
`
`litter incidence
`
`.
`
`46*
`16
`
`
`
`32
`14
`
`31
`14
`
`33
`12
`
`

`

`Reviewer: Laurie McLeod-Flynn
`
`NDA No. 22030
`
`In a mouse developmental study, at 60 mg/kg/day, one dam was found dead during the
`lactation period and decreased maternal body weight and food consumption were
`observed. Decreased litter weight and developmental delay (time to ear opening) were
`observed in the F1 generation. At 30 mg/kg/day, decreased maternal body weight was
`observed. A decrease in litter weight did not reach statistical significance at this dose, but
`developmental delay (time to ear opening) and increased activity level (not significant,
`but present at 60 mg/kg/day) were observed in the F1 generation. At 10 mg/kg/day, no
`effects on dams or the F 1 generation were observed. No effects on reproductive
`performance of the F1 generation were observed nor any effects on the F2 generation, at
`any dose.
`
`' There was adequate exposure to each of the major human metabolites in reproductive
`studies.
`
`B. Pharmacologic activity
`
`Fesoterodine and its hydrolysis product SPM 7605 are specific but non-selective
`muscarinic receptor antagonists. In vivo, fesoterodine is rapidly and extensively
`metabolized to SPM 7605, which is much more inhibitory at muscarinic receptors than
`fesoterodine. SPM 5509, another major human metabolite is far less potent than SPM
`7605. The pharmacology of the metabolites SPM 7789 and SPM 7790 were not studied.
`
`C. Nonclinical safety issues relevant to clinical use
`
`Exaggerated pharmacological effects (including mydriasis, increased heart rate, and
`neurological effects) were the primary limiting toxicity for both mice and dogs. An
`increase in QT interval was also observed at high doses in intravenous studies in dogs.
`The risk of these effects has been evaluated in clinical studies.
`
`Low multiples of the expected clinical exposures were observed for some reproductive
`effects of fesoterodine in animals (oral studies); however, there is a history of similar
`effects in animals for anti-muscarinic drugs for overactive bladder, including tolterodine
`which produces the same primary active metabolite as fesoterodine. Several of the effects
`reported in animals, such as cleft palate in mice, are reported to be associated with stress
`during the gestational period. Although fesoterodine is not used at doses which are
`expected to cause stress in humans, labeling should recommend that it should not be used
`during pregnancy unless the potential benefit justifies the potential risk to the fetus. ‘ /
`
`m\
`
`

`

`Reviewer: Laurie McLeod~Flynn
`
`'
`
`NDA No. 22030
`
`2. 6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22030
`Review number: 2
`
`Sequence number/date/type of submission: 010/ 01 May 2008
`Information to sponsor: Yes ( ) No (x)
`Sponsor and/or agent: Schwartz‘Pharma
`Manufacturer for drug substance: Schwartz Pharma
`
`Reviewer name: Laurie McLeod—Flynn
`Division name: Division of Reproductive and Urologic Products
`HFD #: 580
`
`Review completion date: 9/9/08 .
`
`Drug:
`
`Trade name: Toviaz
`Generic name: Fesoterodine
`Code name: SPM 8272
`
`Chemical name: 2—((R(+))-3_-diisopropylarnino-l-phenylpropyl)-4-
`(hydroxymethyl)-phenylester hydrogen fumarate
`Molecular formula/molecular weight: C30H41N07/ 527.66
`Structure:
`'
`
`
`
`Relevant lNDs/NDAs/DMFS: IND # 51232:
`
`Drug class: anti-muscan'nic
`
`Indication: overactive bladder with symptoms of urinary urgency, frequency and/or urge
`incontinence
`
`Clinical formulation: 4- and 8-mg sustained—release tablets
`
`Route of administration: oral
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`'
`
`NDA No. 22030
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS
`
`Conclusions: There is no impediment to approval of this submission from a
`phannacology/toxicology perspective. -
`
`Unresolved toxicology issues: No. issues are considered to be unresolved.
`
`Recommendations: There are no recommendations for further nonclinical studies.
`
`Suggested labeling: see detailed suggestions on page 3 (Executive Summary).
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Laurie McLeod
`9/16/2008 09:33:35 AM
`PHARMACOLOGIST
`
`Lynnda Reid
`9/16/2008 11:44:50 AM
`PHARMACOLOGIST
`
`

`

`_ SUPERVISORY MEMO 2
`
`.
`
`FOOD AND DRUG ADMINISTRATION
`
`Division of Reproductive and Urologic Products
`Center for Drug Evaluation and Research
`
`Date:
`Reviewer:
`
`September 15, 2008
`I Lynnda Reid, Ph.D. ‘
`Supervisory Pharmacologist
`
`NDA #/SS#/date:
`
`22-030 (N010) May 1, 2008
`
`Sponsor:
`
`.
`
`Schwartz Pharma
`
`Drug Product:
`
`Fesoterodine fumarate (Toviaz®)
`
`Indication:
`
`Overactive bladder
`
`Approval
`Recommended Action:
`
`
`Drug History: Fesoterodine fumarate, hereafter referred to as fesoterodine, is a new
`molecular entity being developed for the treatment of overactive bladder (OAB) with
`symptoms of urge urinary incontinence, urgency and urinary frequency. Fesoterodine is
`a muscarinic receptor antagonist and belongs to the antimuscafinic class of agents.
`Antimuscarinic drugs act by antagonizing the acetylcholine—induced stimulation of
`postganglionic muscarinic receptors. In the bladder, muscarinic receptors are thought to
`mediate the detrusor contractions responsible for normal voiding and the primary portion
`of the contraction1n OAB associated with urgency and urge incontinence.
`
`NDA 22—030 was initially filed on March 17, 2006. The original nonclinical data was
`reviewed by Dr. Laurie McLeod-Flynn. All required nonclinical studies were submitted
`including subchronic toxicology studies in mice, rats and dogs, 6 and 9 month chronic
`toxicology studies in mice and dogs,'respectively, reproductive and developmental
`studies in mice and rabbits, full battery of genotoxicity studies, 2—year carcinogenicity
`studies1n mice and rats, evaluation of skin and eye irritation potential, and1n Vitro
`assessment of phototoxicity.
`
`The original NDA received an approvable action pending satisfactory inspection of the
`manufacturing facility. Supplement N010 contains no new nonclinical data and the
`original recommendation that the nonclinical data supported an approval still stands.
`
`I concur with the labeling recommendations made by Dr. McLeod-Flynn1n her review
`filed September 16,2008.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Lynnda Reid
`9/16/2008 11:47:39 AM
`PHARMACOLOGIST
`
`

`

`Comments on NDA 22-030 Fesoterodine fumarate
`From A. Jacobs 9/11/08
`
`I concur that there are no outstanding pharm/tox issues.
`
`I concur with the proposed pregnancy category: C
`
`Perhaps concurrence with the carcinogenicity results (no drug-related effects) by the
`exec-cac should be referred to somewhere.
`
`I have discussed this with the pharm/tox reviewer and supervisor.
`
`

`

`------——--------—-___---------__n--.--------n---------.--------——--—---------u.-----.---—---------——-------------——--
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`‘
`
`Abby Jacobs
`9/11/2008 08:10:18 AM
`PHARMACOLOGIST
`
`

`

`PHARMACOLOGY/TOXICOLOGY RESUBMISSION MEMO
`
`NDA Number: 22030
`
`Applicant: Pfizer
`
`Stamp Date: 19 May 2008
`
`Drug Name: Toviaz
`
`NDA Type: resubmission
`
`section of the NDA indexed and
`
`paginated in a manner allowing
`substantive review to begin?
`
`
`
`
`
`
` Content Parameter
`
`On its face, is the
`
`phannacology/toxicology
`section of the NDA organized
`(in accord with 21 CFR 314 and
`
`current guidelines for format and
`
`content) in a manner to allow
`substantive review to begin?
`
` Is the pharmacology/toxicology
`
` On its face, is the pharmacology/
`
`toxicology section of the NDA
`
`
`legible so that substantive review
`
`can begin?
`
`
`
`
`Are all required (*) and
`The Pharmacology/Toxicology review is
`
`in DF S. There are no new issues from a
`requested IND studies (in accord
`
`
`P/T perspective.
`with 505 bl and b2 including
`
`
`referenced literature) completed
`
`
`and submitted in this NDA
`
`(carcinogenicity, mutagenicity*,
`
`
`
`teratogenicity*, effects on
`
`
`
`fertility, juvenile studies, acute
`
`
`and repeat dose adult animal
`
`studies*, animal ADME studies,
`
`safe
`o_harmacolo , etc ?
`
`
`
`
`
`If the formulation to be marketed X
`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).
`On its face, does the route of
`administration used in the animal
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`

`

`PHARMACOLOGY/TOXICOLOGY RESUBMISSION MEMO
`
`
`
`studies appear to be the same as
`the intended human exposure
`route? If not, has the sponsor
`submitted a rationale to justify
`the alternative route?
`
`Has the sponsor submitted a
`statement(s) that all of the
`pivotal pharm/tox studies have
`been performed in accordance
`with the GLP regulations (21
`CFR 58) g an explanation for
`an significant deviations?
`Has the sponsor submitted all
`special
`studies/data requested by the
`Division during pre—submission
`discussions with the s onsor?
`
`Are the proposed labeling
`sections relative to
`
`pharmacology/toxicology
`appropriate (including human
`dose multiples expressed in
`either mg/mZ or comparative
`serum/plasma levels) and in
`accordance with 201.57?
`
` If this NDA is to support a Rx to
`
`10
`
`If there are any impurity - etc.
`issues, have these been
`addressed?
`(New toxicity
`studies may not be needed.)
`11 Has the sponsor addressed any
`'
`abuse potential issues in the
`submission?
`
`'
`
`.
`
`OTC switch, have all relevant
`studies been submitted?
`
`Any Additional Comments:
`
`This will be a labeling review from a P/I‘ perspective, unless a new safety issue is identified by
`the review team during the course of an NDA review.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Laurie McLeod
`6/6/2008 04:44:44 PM
`PHARMACOLOGIST
`
`Lynnda Reid
`6/9/2008 11:17:28 AM
`PHARMACOLOGIST
`
`

`

`Comments on NDA 22-030 Fesoterodine filmarate
`From A. Jacobs 1/22/07
`
`I concur that there are no outstanding pharm/tox issues.
`
`I concur with the proposed pregnancy category: C
`In the labeling under pregnancy, consideration should be given to not including the
`increased incidences of fetuses with delayed ossification, since the incidence of litters
`(the preferred comparator) with delayed of ossification is not significantly increased.
`
`1 have discussed this with the pharm/tox supervisor: ‘
`
`

`

`This is a representation of an electronic record that was signed electronically and}
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Abby Jacobs
`1/22/2007 03 :24 :00 PM
`PHARMACOLOGIST
`
`

`

`SUPERVISORY MEMO
`
`I
`
`V
`
`' FOOD AND DRUG ADMlNISTRATION
`
`
`
`Division of Reproductive and Urologic Products
`Center for Drug Evaluation and Research
`
`Date: 12/20/06
`
`Reviewer: Lynnda Reid, PhD.
`Supervisory Pharmacologist
`
`NDA #lSS#/date: 22-030 (N000) dated March 17, 2006
`
`Sponsor: Schwartz Pharma
`
`Drug Product: Fesoterodine furnarate
`
`Indication: Overactive bladder -
`
`
`
`Drug History: Fesoterodine furnarate, hereafter referred .to as fesoterodine, is a new
`molecular entity being developed for the treatment of overactive bladder (OAB) with
`symptoms of urge urinary incontinence, urgency and urinary frequency. Fesoterodine is
`a muscarinic receptor antagonist and belongs to the antimuscarinic class of agents.
`Antimuscarinic drugs act by antagonizing the acetylcholine-induced stimulation of
`pOStganglionic muscarinic receptors. In the bladder, muscarinic receptors are thought to
`mediate the detrusor contractions responsible for normal voiding and the primary portion
`ofthe contraction in OAB associated with urgency and urge incontinence.
`
`Fesoterodine is hydrolyzed'by nonspecific plasma esterases to the active phenol
`derivative SPM 7605, which is chemically identical to an active metabolite of tolterodine
`(the active component of Detrol, approved for OAB in 1998). Fesoterodine and SPM
`7605 both show potent specific, but non-subtype selective, antimuscarinic properties.
`
`Fesoterodine will be available as a sustained release (SR) tablet formulation based on a
`
`_
`_
`centaining 4 mg or 8 mg of the active fesoterodine fumarate, intended
`for once-daily oral administration. All inactive excipients are compendial.
`
`83W
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`Nonclinical data supporting approval of NBA 22-030: The nonclinical .data submitted
`to support development under IND 51,232 and submission of NBA 22-030 were
`reviewed in detail by Dr. Laurie McLeod-Flynn. Studies included subchronic toxicology
`studies in mice, rats and dogs; 6 and 9 month chronic toxicology studies in mice and
`dogs, respectively; reproductive and developmental studies in mice and rabbits; full
`battery of genotoXicity studies; 2—year Carcinogenicity studies in mice and rats; evaluation
`of skin and eye irritation potential; and in vitro assessment of phototoxicity. DoSe
`::..ll\-\
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`limiting findings in animals were related to exaggerated pharmacologic effects including
`mydriasis, increased heart rate, and neurological effects (e.g., ataxia, dyspnea).
`
`Toxicology Studies: In single dose toxicology studies in mice and rats, the NOEL (no
`observed effect level) doses were 100 mg/kg following oral administration and 10 mg/kg
`following intravenous administration in both species. Toxicokinetics were not
`performed, but based on body surface area, the oral doses are approximately 60 and 120
`fold higher, and the i.v. doses are approximately 6 and 12 fold higher in mice and rats,
`respectively, compared to the MRHD (maximum recommended human dose of 8
`mg/day).
`
`chronically for 6 months at doses up to 100 mg/kg/day in males and 125 mg/kg/day in
`females evinced piloerection starting at 75 mg/kg. Dose—related changes in body weight
`gain were observed at all doses (35 mg/kg): primarily decreased weight gain in males and
`increased weight gain in females. At the highest doses, small but statistically significant
`changes were observed in triglyceride (l) and urea (T) levels in male mice, glucose levels
`(T) in female mice, and platelet counts (1) in both sexes. Exposures at the highest doses
`tested were approximately 85 fold higher in male mice and 185 fold higher in female
`mice than the expected exposures at the MRHD (based on mean SPM 7605 AUC values
`of~' 45 ng-ml/hr in norm'al'patients). . When compared to exposure levels in poor '
`metabolizers and patients‘With moderate hepatic impairment, exposures in mice were
`approxirnately 43 and 29 fold higher in male mice, and 94 and 63 fold higher in female.
`mice, respectively (based on mean AUC values of~ 89 ng-ml/hr in poor metabolizers and
`~132 ng-ml/hr in patients with moderate hepatic impairment).
`
`weights and morphological changes (pericholangitis with mild bile duct proliferation).
`Urinalysis showed significantly increased pH values in both sexes at 75 mg/kg and
`increased urine volume and decreased specific gravity in females. Systemic exposures in
`rats at the highest dose tested ranged fiom 9 to 14 fold higher than in normal patients, 4.5
`to 7 fold higher than in poor metabolizers and 3 to 5 fold higher than in patients with
`moderate hepatic impairment. The NOAEL in rats was approximately equivalent to the
`MRHD in normal males and approximately 3 fold less than the MRHD in normal
`females.
`’
`‘I
`"
`'
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`Subacute dose range-finding studies (3 days) were performed in dogs at oral doses of l,
`3, 10 and 30 mg/kg. The NOAEL was determined to be 3 mg/kg/day while 30 mg/kg
`exceeded the MTD (maximum tolerated dose) as defined by ataxia, reduced motility,
`severe conjunctivitis and pale gingival, and decreased weight and food consumption. At
`310 mg/kg, changes in hematology and chemistry parameters were observed consisting
`ofincreases in red and white cell parameters, platelets, bilirubin, triglycerides, inorganic
`phosphate, ALT and LDH'.~ In the chronic 9-month study in dogs performed at doses of
`0.5, 2.5 and 12.5 mg/kg/day, the NOAEL was 0.5 mg/kg/day, a dose approximately 4 to 6
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`

`fold lower than the MRHD. Adverse effects seen at ~22.5 mg/kg/day consisted of
`increased heart rates 4 hours post dosing, sometimes accompanied by an increase in
`systolic blood pressure; sporadic changes in urea (T in males), creatinine (l), and (x2-
`' glubulin (T); and decreases in gall bladder contractility. Conjunctivitis, occasionally
`accompanied by adhesions of the eyelid, was observed in all high—dose animals due to
`decreased lacrirnal secretion. Treatment with an artificial lacrimal fluid was effective in
`treating this response and examination of retinal tissue revealed no histopathological
`changes. Exposures in dogs (AUC of fesoterodine + SPM 7605) at the highest dose
`tested are approximately 80, '40 and 25 fold higher than exposures at the MRHD in
`normal metabolizers, poor metabolizers and in patients with moderate hepatic
`impairment, respectively.
`
`In acute local irritation studies, fesoterodine was classified as an ocular irritant but not a
`skin irritant. Fesoterodine producedno signs of sensitization in guinea pigs or effects on
`the immune system as tested in chronic toxicology studies and in the plaque forming
`colony assay in mice. SPM-7605 exhibited no signs of phototoxicity in vitro.
`
`Genotoxicifl and Carcinogenicity: Fesoterodine was negative in the standard battery of
`genotoxicity studies. In 2—year carcinogenicity studies in mice and rats conducted with .
`doses of 5, 15 or 45 mg/kg/day, there were no treatment-related increases in the type or
`incidence of neoplastic and/or hyperplastic lesions.
`
`Reproductive and Developmental Toxicigg: Fesoterodine was tested for effects on all
`stages of reproduction in mice, and for embryonic and teratogenic effects in rabbits.
`Administration of fesoterodine to male and female mice prior to mating resulted in no
`effects on fertility'in males at 45 mg/kg/day (the highest dose tested) and in females at 15
`mg/kg/day (a dose approximately equivalent to the MRHD for normal metabolizers).
`There were also no effects’on reproductive performance or fertility in offspring exposed
`in utero to doses up 60 mg/kg/day. Female mice exposed to 45 mg/kg/day prior to
`mating and through implantation had decreased numbers of corpora lutea, implantation
`sties and live fetuses.
`'
`
`Female mice exposed during the period of organogenesis to doses of 15, 45 or 75
`mg/kg/day demonstrated increased incidences of pre- and post-implantation loss
`including dose—related increase in resorptions, and dose-related increase in the number of
`live fetuses per litter; Fetal body weights‘were reduced starting at 45 mg/kg. There was
`aISO one fetus in each of the dosing groups with cleft palate. A pattern of increased
`resorptions and cleft palate is sometimes associated with maternal stress and has been
`seen with other muscarinic antagonists; In the multigenerational study in female mice
`exposed from implantation through weaning to doses of 10, 30 and 60 mg/kg/day, no
`incidences of cleft palate were observed. Offspring exposed in utero to 60 mg/kg/day
`had slight delays developmental parameters, i.e., ear opening, auditory startle reflex,
`passive avoidance response, mid-air righting reflex (also observed in the 30 mg/kg
`group), and open field tEStI (also observed in the 30 mg/kg group). There was a slight
`decrease in neonatal survival starting at 30 mg/kg. The NOAEL for developmental
`toxicity was 10 mg/kg/day.
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`Female rabbits were exposed during the period of organogenesis to oral doses of 3, 9 or
`27 mg/kg/day and subcutaneous doses of 0.5, 1.5 and 4.5 mg/kg. Systemic exposures
`were approximately the same at the 27 mg/kg/day p.o. dose and the 4.5 mg/kg/day s.c.
`dose (approximately 10 times the MRHD). Following oral administration, dose-related
`increases in the incidence of post-implantation loss, early resorptions, and incomplete
`ossification of sternebrae were observed and a NOAEL was not defined. Although the
`subcutaneous route was significantly more toxic to the dams, with deaths, clonic
`convulsions, dyspnea, miosis and deceased body weight and food consumption observed
`at 4.5 mg/kg, the only fetal effect at this dose was incomplete ossification of the
`stemebrae. The developmental NOAEL was 1.5 mg/kg (approximately 3-4 times the
`MRHD) following s.c. administration.
`,
`
`Conclusion/Recommendation: Nonclinical studies were limited by the exaggerated
`antimuscarinic pharmacological effects of fesoterodine, i.e., reduced GI motility, reduced
`secretion of the lacrimal gland, mydriasis, conjunctivitis, negative papillary reflex and
`changes in heart rate. Similar effects are seen with other muscarinic antagonists
`approved for the treatment of overactive bladder, and all effects are reversible upon
`cessation of treatment. Mice and dogs were-considered more relevant species since there
`were a number of metabolites in rats which were