CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-030
`
`SUMMARY REVIEW
`
`

`

`Deputy Division Director Memorandum
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date
`
`October 23, 2008
`
`
`From
`
`George S. Benson, MD
`
`
`Sub'ect -
`De 11 Division Director Review
`
`
`NDA#
`
`
`000
`Su 7o lement#
`
`A. nlicant _
`Date of Submission
`PDUFA Goal Date
`
`
`
`
`
`
`
`Proprietary Name/
`
`Dosa_e forms/Strenth
`Proposed Indication
`
`
`
`
`
`
` Recommendation
`
`
`
`‘
`
`Toviaz/
`
`
`
`4 m_ and 8 m_ extended-release tablets
`Treatment of overactive bladder with symptoms of urge
`
`urina
`incontinence, ur_enc , and urina
`fre- uenc
`
`_
`
`
`Cross Divisional Team Leader
`
`
`
`Medical Officer
`Chemist Team Leader
`Chemist Reviewer
`
`‘
`
`Clinical Pharmacolo
`
`Team Leader
`
`Clinical Pharmac0103 Reviewer
`Pharmacolo 3 ltoxieolo 3 Team Leader
`Pharmacolo 3 /toxicolo 3 Reviewer
`Biometrics Team Leader
`
`Chief Reulato Pro’ect Mana_er
`Reulato Pro'ect Mana-er
`
`
`
`’
`
`
`
`
`
`
`
`
`
`
`

`

`wwsewewnr
`
`Introduction
`
`Background
`CMC
`
`Nonclinical Pharmacology/Toxicology
`Clinical Pharmacology
`Clinical Microbiology
`Efficacy/Statistics
`Safety
`Advisory Committee Meeting
`. Pediatrics
`
`. Other Relevant Regulatory Issues
`. Labeling
`. Decision/Action/Risk Benefit Assessment
`
`1.
`
`Introduction
`
`‘
`
`Anticholinergic drugs (muscarinic antagonists) have been a mainstay of overactive
`bladder therapy for decades. Fesoterodine fumarate1s a muscarinic receptor antagonist
`agent whichIS proposed for the indication “treatment of overactive bladder with
`symptoms of urge urinary incontinence, urgency, and fiequency”1n NDA 22-030.
`Currently approved oral agents in this drug class for the'overactive bladder indication
`include oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (Vesicare), darifenacin
`(Enablex), and trospiurn (Sanctura). The mechanism of action of these drugs1s blockade
`of cholinergic (muscarinic) receptors in the bladder detrusor muscle and, therefore,
`inhibition ofbladder contractility. Fesoterodine1s rapidly and extensively metabolized to
`an active metabolite (5-hydroxytolterodine) whichIS also the major active metabolite of
`the approved drug tolterodine (Detrol).
`
`2. Background
`
`NDA 22~O30 was originally submitted on March 17, 2006, and received an “approvable”
`action on January 25, 2007. The single major deficiency identified in the “approvable”
`letter was:
`
`“Pre—approval Inspection (PAI) of your active pharmaceutical ingredient (API)
`manufacturing facility, Schwarz Pharma Ltd., located in Shannon, Ireland, could not be
`conducted because the site has not been available for PAI during this review cycle, as
`stated in your letter, dated July 20, 2006. Satisfactory inspection of your API
`manufacturing facility, Schwarz Pharma Ltd., located in Shannon, Ireland, is required
`before this application may be approved.”
`
`In addition to the manufacturing facility inspection, “labeling remains unresolved.”
`
`The sponsor submitted a complete response to the “approvable” action on May I, 2008.
`The safety update in the complete response included updated safety data from three long-
`
`

`

`term open—label extension studies, an ongoing 12—week, open label study, and five new
`Phase 1 studies.
`.
`
`3. CMC
`
`The CMC reviewer concluded that “this NDA has provided sufficient CMC information
`to assure the identity, strength, purity, and quality of the drug product. All facilities
`involved are in compliance with the cGMP, and labels have adequate information as
`required. Therefore, from a CMC perspective, this NDAis recommended for “Approval.”
`
`The drug substance manufacturing site in Shannon, Ireland, received an “acceptable”
`inspection (June, 17,2008) The lack of this facility being available for inspection was
`the primary basis for the‘‘”approvable action taken during the first review cycle.
`
`The requested shelf life of 24 months for the 4 and 8 mg tablets packaged in bottles with
`desiccant and in aluminum/aluminum blister was granted.
`
`4. NonclinicalPharmacology/Toxicology
`
`' No new non—clinical data were submitted in the complete response. All required
`nonclinical studies were submitted in the original NDA submission and included
`subchronic toxicology studiesn1 mice, rats, and dogs, 6 and 9month chronic toxicology
`studies1n mice and dogs, respectively, reproductive and developmental studiesin mice
`and rabbits, full battery of genotoxicity studies, 2--year carcinogenicity studiesin mice
`and rats, evaluation of skin and eye irritation potential, and in vitro assessment of
`phototoxicity.
`
`The nonclinical reviewers believe that the “non-clinical data support an approval.”
`
`5. Clinical Pharmacology
`
`The clinical pharmacology review stated that “The Office of Clinical
`Pharmacology/Division of Clinical Pharmacology 3 finds the resubmission for NDA 22-
`030 for fesoterodine acceptable from a Clinical Pharmacology perspective.”
`
`Fesoterodine is a new molecular entity but its metabolite SPM 7605IS the same as the
`active metabolite of the approved drug tolterodine. Fesoterodine undergoes rapid
`deesterification to its hydroxy metabolite, SPM 7605. Following oral administration, the
`parent compound fesoterodine can not be detectedin plasma and fesoterodine’ s
`pharmacokinetics (PK) is descn'bed by its active metabolite SPM 7605. CYP2D6 and
`CYP3A4 are the two major metabolic enzymes responsible for the metabolism of SPM
`7605.
`
`Important clinical pharmacology conclusions and labeling recommendations include:
`
`

`

`The results of a “thorough QT study” (SP686) demonstrated that fesoterodine 4 and 28
`mg/day for 3 days did not appear to have a significant effect on the QTc interval.
`Fesoterodine causes a dose dependent increase in heart rate.
`
`Sex, age, and race have no significant effect on the PK of fesoterodine.
`
`Hepatic impairment: Moderate liver impairment increases the Cmax and AUC of SPM
`7605 by 1.4 and 2.] fold, respectively. The clinical pharmacology reviewer believes that
`no dose adjustment is needed in patients with moderate hepatic impairment. The effect of
`severe hepatic impairment has not been evaluated. Fesoterodine is not recommended for
`use in patients with severe hepatic impairment because of the potential for increased drug
`exposure in this group of patients.
`
`Renal impairment: In patients with mild renal impairment, Cmax and AUC were 1.3 and
`1.6 fold higher, respectively, than in patients with normal renal function. In patients with
`moderate renal impairment, Cmax and AUC values were 1.5 and 1.8 fold higher than in
`patients with normal renal function. In subjects with severe renal impairment, Cmax and
`AUC values were 2.0 and 2.3 fold higher than in subjects with normal renal function. The
`clinical pharmacology reviewer recommends no dose adjustmentin patients with mild
`and moderate renal impairment and agrees with the sponsor’s proposal to limit patients
`with severe renal impairment to doses no greater than 4 mg/day. I agree.
`
`CYP2D6 poor metabolizers: CYP2D6 PMs have Cmax and AUC values that are
`approximately 2-fold higher than CYP2D6 EMS. In limited data from phase 3 trial
`SP584, CYP2D6 PMs did not have higher baseline corrected heart rates than EMS.
`Although side effects of dry mouth and constipation were higher in the 8 mg dose group -
`compared to the 4 mg dose group, no significant safety problems were encountered in
`both the CYP2D6 EM and PM patient populations. The safety risk of this two—fold
`increase in exposure appears to be low. The clinical pharmacology reviewer does not
`recommend a dose adjustment in CYP2D6 PMs.
`
`Concomitant food intake causes a mean increase in Cmax of 19-30% and AUC by 18-19%.
`These small increases are not thought to be clinically significant.
`
`CYP3A4 inhibition: The concomitant administration of fesoterodine and ketoconazole
`increased SPM 7605 Cmax by 2.0-2.1 fold and AUC by 2.3-2.5 fold. Administration of
`fesoterodine to patients who are CYP2D6 PMs who are also taking ketoconazole 200 mg
`twice daily resulted in increases of 5.69 and 4.48 fold in AUC and Cmax of SPM 7605,
`respectively, compared with CYP2D6 EMS with no concomitant CYP3A4 inhibitor. The
`clinical pharmacology reviewer recommended that the fesoterodine dose be restricted to
`no more than 4 rug/day when given to a patient taking a strong CYP3A4 inhibitor.
`
`Concomitant administration of fesoterodine with an oral contraceptive containing
`ethinylestradiol and levonorgestrel did not significantly affect the plasma levels of
`ethinylestradiol and levonorgestrel.
`
`

`

`I agree with the clinical pharmacology reviewer’s labeling recommendations.
`
`6. Clinical Microbiology
`
`There are no outstanding issues and the “microbiological attributes” are considered
`“adequate.”
`
`7. Efficacy/Statistics
`
`To support efficacy for the overactive bladder indication, the sponsor reported the results
`'of two phase 3 trials (Trial SP583 conducted in Europe and Trial SP584 conducted in the
`United States). Both trials were randomized, double—blind, placebo-controlled, fixed-
`dose, parallel arm studies comparing fesoterodine 4mg/day, fesoterodine 8 mg/day, and
`placebo for a treatment interval of 12 weeks in a well—defined population of patients with
`overactive bladder.
`
`Entry criteria included:
`
`0 Greater than 18 years of age
`
`0 Minimum 6-month history of symptoms of OAB or urge incontinence
`
`0 Completion of a voiding diary for 3 consecutive days during the week prior to
`randomization
`'
`~
`
`0 Minimum of 3 urge incontinence episodes and 8 micturitions/24hrs during the
`above diary period
`
`Primary endpoints:
`
`Primm Endpoint:
`
`The primary endpoint for the two phase 3 trials (SP-583 and SP-584) is change in number
`of micturitions (frequency) per 24 hours (fiom baseline to the end of 12 weeks of
`treatment).
`
`Co-Prirnm Endpoint:
`
`Change in number of urge incontinence episodes per 24 hours (from baseline to the end
`of 12 weeks of treatment).
`
`The two primary endpoints are currently standard primary endpoints for overactive
`bladder trials.
`
`In study SP-583 a total of1135 patients were randomized and 1132 were treated: 279
`with placebo, 265 With fesoterodine 4mg/day, 276 with fesoterodine 8mg/day and 283
`
`

`

`with an active comparator (tolterodine 4mg/day). Most patients (>80% in any treatment
`group) completed the full 12 weeks of treatment. Most of patients (81%) were females
`with a mean age of 57 years and an overall age range of 19 to 86 years.
`
`In study SP-S 84 a total of 836 patients were randomized and 832 patients treated: 266
`with placebo, 267 with fesoterodine 4mg/day and 267 patients with fesoterodine
`8mg/day. Most patients (>80% in any treatment group) completed the full 12 weeks of
`treatment. The majority (76%) of patients were females, with a mean age of 59 years and
`an overall age range of 21 to 91 years. A total of 9% of patients were poor metabolizers
`for CYP2D6.
`
`The results for the two co-prirnary endpoints in the two phase 3 studies (SP—5 83 and SP—
`584) are shown in Tables 1 and 2.
`
`Table 1. Incontinence episodes per 24_hours
`
`
`
`
`
`
`
`
`
`
`
`Stud SP-583
`Feso 4mg
`n=199
`3-8 3-4
`1.8 2-9)
`-—2.06(2.7)
`
`P=0.001
`
`Feso 8mg
`n=223
`
`
`
`Placebo
`(n=205
`
`Stud SP-584
`Feso 4mg
`n=228
`
`Feso 8mg
`n=218
`39(33)
`
`-2 27(2.4)
`
`—1.0(2.7)
`
`-1.77(31) —2.42(2.8)
`
`P<0.001
`
`P=0.002
`
`P<0.001
`
`
`
`
`
`
`
`
`
`Placebo
`n=211
`
`Change from —1.20(3.3)
`baseline
`
`P-value for
`change from
`baseline vs.
`- lacebo
`
`Mean (SD) - Sample size reflects number of patients at baseline
`Analysis reflects baseline to endpoint using LOCF.
`
`Only those patients who experienced urge incontinence at baseline were included for the
`analysis of number of urge incontinence episodes per 24 hours: In Study 1, the number of
`these patients was 211, 199, and 223 in the placebo, fesoterodine 4 mg/day and
`fesoterodine 8 mg/day groups, respectively. In Study 2, the number of these patients was
`205, 228, and 218, respectively.
`
`

`

`
`
`
`
`
`Table 2. Micturitions per 24 hours
`
`_
`
`
`
`Stud SP-583
`
`Feso 4mg
`(n=265
`
`Stud '
`
`
`
`
`
`Placebo
`Feso 4mg
`Feso 8mg
`Feso 8mg
`Placebo
`n=279
`(n=267)
`n=276)
`(n=267)
`n=266)
`
`12.06 7)
`12.909)
`11.993)
`12 0(3 3)
`12.2(3.7)
`
`
`
`
`10.9(4.2)
`11.2(3_.4)
`101(3.2)
`-10.0(4.4)
`11.0(3.6)
`9.8(3.1)
`
`
`
`
`
`-1.86(3.6)' —1.94(3.0)
`-1.02(3.4)
`Change from _—1.02(3.0) —.1.74(2.7) —1.94(3,1)
`
`
`
`
`
`
`
`baseline
`
`
`P-value for
`
`
`P=0.032
`
`
`
`
`
`
`
`
`P<0.001
`
`'
`
`P<0.001
`
`change from
`baseline vs.
`
`‘nlacebo
`
`Mean (SD) — Sample size reflects number of patients at baseline
`Analysis reflects baseline to endpoint using LOCF.
`
`Statistical review:
`
`The statistician’s‘review of the efficacy data concluded that “based on the efficacy data
`submitted fiom the two Phase 3 studies, our analysis showed that at Week 12, compared
`with placebo, both doses of fesoterodine (4 and 8 mg) significantly (p<.05) reduced the
`average number of mictun'tiOns and urge incontinence episodes.”
`
`The primary medical officer during the first cycle review concluded that “fesoterodine
`results are similar in magnitude of improvement for change in the number of the
`mictun'tions per 24 hours, urge incontinence episodes per 24 hours and volume voided
`regardless of patient’s age, gender or race.”
`
`Efficacy summary:
`
`The results from both randomized, placebo-controlled primary phase 3 studies
`demonstrated that fesoterodine 4 mg and 8 mg administered once daily for 12 weeks
`imprOved the primary efficacy variables compared to placebo. The results were dose-
`responsive and statistically significant. The medical reviewers believe that the
`recommended dosing regimen should be a starting dose of 4 mg in all patients. If
`tolerability allows, and efficacy necessitates, patients may be titrated up to an 8 mg/day
`dose. Despite the lack of a placebo~controlled, dose—titration efficacy study, the medical
`reviewers support the recommended dose-titration scheme because the 4 mg dose is
`efficacious and safety will be enhanced. Ilsupport this recommendation. No adequately
`designed and controlled studies have been performed to compare the efficacy of
`fesoterodine to other approved anticholinergic agents for the treatment of overactive
`bladder.
`'
`
`8.
`
`Safety
`
`

`

`In the original NDA submission, safety data were drawn from total of 2288
`patients with overactive bladder (OAB) who received fesoterodine in phase 2 and 3 trials
`during the drug development program. This includes 858 (38%) patients exposed to
`fesoterodine for >6 months, 570 (25%) patients exposed for >12 months and 162 (7%)
`patients exposed for >18 months-There were also 489 patients who received fesoterodine
`during Phase 1 trials.
`'
`
`The safety update submitted in the complete response to approvable (May 1, 2008)
`contained updated safety data from three long-term open-label extension studies, an
`ongoing 12-week, open label study, and five new Phase 1 studies. These updated
`additional safety data include >500 patients exposed to fes‘oterodine for at least 2 years
`and >100 patients exposed for at least 3 years.
`
`Deaths occurring in placebo and active controlled phase 3 studies:
`
`Six deaths were reported from all placebo and active controlled studies. None of the
`deaths was judged by the investigators to be related to the use of fesoterodine.
`
`Of the six patients who died during the drug program development, one
`patient (#10672) in study SP582 died from cerebrovascular accident, the second
`patient (#10527) in study SP 583 died from myocardial infarction, the third patient
`(#10943) in study SP738 died fiom to metastastases to the liver, the fourth patient
`(#11184) in study SP738 died due to “sudden death,” the fifth patient (#10618) died
`several months after completing study SP 583 due to unknown causes, and the sixth
`patient died of “natural causes.” Five of the six deaths were considered by the ,
`investigators to be unrelated to festerodine. The “sudden death” case was considered
`unlikely related to the trial medication.
`
`The primary medical officer reviewed the narratives of these six cases and agreed with
`the investigators that none of the six deaths was related to the use of fesoterodine.
`
`Serious adverse events (SAE’s 1:
`
`In the original NDA submission, SAE‘s were reported in patients treated with placebo,
`fesoterodine 4mg, 8mg, lng/day; or the active comparator tolterodine 4mg/day in 2%,
`4%, 3%, 6%, and 2% of patients in these treatment groups. The primary medical officer
`concluded that Serious AE's in all treatment groups occurred across multiple body
`systems with no obvious trends. During long-term open—label treatment, SAE's occurred
`in 9% of patients. Serious AEs reported by more than 2 patients during open-label
`treatment were myocardial infarction in 4 (<1 %) patients, and breast cancer, bronchitis,
`knee arthroplasty, and cholecystectomy which were each reported by 3 patients.
`
`The narratives non-fatal SAE’S from phase 3 trials SP-583 and SP-584 are summarized in
`Tables 3 and 4.
`~
`
`

`

`Table 3: Non-fatal SAE’s-In' SP 583:
`
`Dose/Day
`
`Intensity
`
`
`
`
`
`Age/
`Gender
`
`54/F
`
`SP583
`Patient #
`
`10048
`10055
`10125
`10258
`10288
`10339
`10472
`10480
`10527
`
`Causality
`
`
`
`
`
`Moderate Not related
`Femoral neck fracture
`4mg
`
`
`
`
`4mg
`Moderate
`
`
`
`Hip arthroplasty
`8mg
`Severe
`Not related
`QT prolongation on ECG - 8mg
`Mild
`Possible
`
`\] 000(50%
`Unstable Angina
`2/F
`
`Mi
`8/F
`Tibia fracture
`0mg
`Severe .
`W
`m-
`70/F
`
`
`
`
`
`
`
`
`
`Bronchitis
`
`Severe
`
`Not related
`
`Mild
`
`.
`
`.
`
`
`
`000000000000
`
`10535
`
`60/F
`
`QTc prolongation on
`
`
`
`Fracture Patella
`Depression
`
`
`Death
`
`
`
`10618
`
`8
`
`2/F
`
`10700
`10715
`
`to"E
`30/F
`
`63/M
`
`
`
`.
`
`'
`
`
`
`
`
`Severe
`Severe
`
`Not
`
`assessed
`
`
`
`Not related
`Not related
`Not related
`
`
`
`Severe -
`
`
`
`
`
`—_—E_——
`11048
`75/F
`Arthalgia
`0mg
`Moderate Not related
`
`54/F
`
`
`
`
`
`
`
`

`

`
`Table 4: Non-fatal SAE’s In SP584:
`
`
`
`SP584
`Dose/Day
`
`
`
`
`
`
`
`Patient #
`
`
` ' -_
`
`()0Ii00
`
`
`sP
`
`neumonia
`Chest Pain
`
`13017
`
`13066
`
`58/F
`
`Malignant Melanoma
`Abnormal LFT’s
`
`
`0mg
`4mg
`Ai00
`m
`4 g
`‘Omg
`
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A0%
`
`
`
`
`
`Severe
`
`Severe
`Severe
`Mild
`Severe
`
`4
`
`"(IQ(IQGO
`AB
`#00ii
`
` g(m
`
`so
`
`r _
`
`.
`
`Cataract
`
`
`'
`
`Severe
`Severe
`
`
`
`
`Not related
`Not related
`
`
`In addition to the above SAE’s, a case ofpancreatitis was reported in a 72-year-old
`woman who received fes'oterodine for 16 months during SP-739 tn'al (an open-label
`extension of trial SP584). The patient had a history of cholecystectomy and other co-
`morbid medical conditions and was also on other concurrent medications. The event was
`determined by the investigator as unlikely related to fesoterodine.
`
`The medical reviewers concluded that the serious adverse events reported in the phase 3
`trials did not raise significant safety concerns with fesoterodine use and I agree.
`
`Common Adverse Events:
`
`Table 5 lists adverse events, regardless of causality, that were reported in the combined
`Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in
`1% or more of patients treated with fesoterodine 4 or 8 mg once daily for up to 12 weeks.
`
`10
`
`

`

`Table 5 . Adverse events with an incidence exceeding the placebo rate and reported by 21% of
`atients from double-blind, lacebo—controlled Phase 3 trials of 12 weeks treatment duration
`
`
`
`
`
`
`Placebo
`
`
`
`
`
`N=554
`%
`
`
`
`
`Gastrointestinal disorders
`
`
`
`
`
`
`18.8
`Dry mouth
`
`
`4.2
`. Constipation
`
`
`1.6
`Dyspepsia
`
`
`Nausea
`0.7
`Abdominal ain uuer
`1
`
`34.6
`6.0
`.3
`.9
`
`2 1
`
`
`
`
`7.0
`2.0
`0.5
`1.3
`
`System organ class/Preferred term
`
`
`
`2 5
`
`3
`4
`— 1-8
`2 —
`
`.2
`
`
`
`
`
`
`
`Infections
`
`Urinary tract infection
`
`p er res-irate
`tract infection
`Eye disorders
`.
`
`3.1
`
`D 6 es
`
`Renal and urinary disorders
`
`-
`
`
`
`.7
`
`1.6
`1.4
`
`.9
`.3 -
`
`0 2
`
`1.2
`
`0
`
`.4
`
`1.2
`1.2
`
`-
`
`1.1
`
`4
`
`3
`1
`
`1
`
`1
`1
`
`0
`
`7
`
`2
`
`0
`
`1
`
`3
`
`-
`
`0.7
`0.2
`
`0.5
`0.4
`
`0.7
`
`4
`
`0.
`
`0.5
`
`
`
`
`Dysuria
`
`Urin
`
`Respiratory disorders
`
`retention
`
`Cough
`D ThrOat
`General disorders
`
`Edema Heriheral
`
`
`
`
`
`
`
`
`
`
`
`Musculoskeletal disorders -
`Psychiatric disorders
`-
`
`Back nain
`
`Insomnia
`
`Investigations
`ALT increased
`GGT increased
`
`V
`
`Skin disorders
`
`Rash
`
`
`
`5 4
`
`0 0 -
`
`7
`
`0.9
`0.4
`
`-
`
`0.5
`
`
`
`ALT=alanine aminotransferase, GGT=gaInma glutamyltransferase
`
`Most AE’s were mild or moderate in intensity. Severe AE’s were reported for 4%, 5%,
`and 8% of patients in the placebo, fesoterodine 4 mg/day, and fesoterodine 8 mg/day
`groups, respectively. Dry mouth was the AE most often rated as severe in intensity.
`Adverse events led to discontinuation in 3%, 5%, and 6% of patients in the placebo,
`fesoterodine 4 mg/day and fesoterodine 8 mg/day groups respectively. The most
`common adverse event leading to discontinuation was dry mouth. With long—term
`fesoterodine treatment in the open-label extension studies, in the original NDA, the
`profile of common AE’s was similar to that listed in Table 5 above. Similar to the
`
`11
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`

`controlled studies, most adverse events of dry mouth and constipation were mild- to
`moderate in intensity, with only a few cases reported as severe.
`
`A modestly increased incidence of anticholinergic adverse effects in patients aged 75
`years and greater compared to patients younger than 75 years was noted and described in
`the medical team leader’s review. Of 1120 patients who received fesoterodine in the two
`Phase 3, 12—week, placebo-controlled, efficacy and safety studies, 373 (33%) were 65
`years of age or older, and 123 (11%) were 75 years of age or older. No overall
`differences in safety or effectiveness were observed between patients younger than 65
`years of age and those 65 years of age or older in these studies. The incidence of
`commonly reported anticholinergic adverse events (constipation, urinary tract infection
`and dizziness), however, was higher in patients 75 years of age and older as compared to
`younger patients. This information has been added to the label. The label recommends
`. starting all patients on 4mg daily and titrating up as tolerability allows and efficacy
`necessitates. This is acceptable for all patients, including geriatric patients.
`
`Summary of Clinical Laboratory Findings:
`
`According to the medical officer’s review, overall, there were no apparent trends in mean
`changes from Baseline to the end of treatment or in shifts of clinical relevance over time
`in any hematology, clinical chemistry, or urinalysis parameters. Examination of
`.
`individual clinically-relevant laboratory abnormalities showed that there was no clinically
`relevant pattern of laboratory abnormalities reported as AE’s that resulted in withdrawal.
`Likewise, while there were individual cases that exceeded the normal range for individual
`laboratory parameters, there were no trendsin occurrence of markedly abnormal
`laboratory findings.
`
`There were isolated cases of mild to moderate elevations in AST, ALT, and GGT.
`Similar proportions of patients in all treatment groups met the 2.5 X ULN criterion. No'
`fesoterodine-treated patient had an AST/ALT elevation above 2.5-3 .0 X ULN and a
`bilirubin above ULN.
`
`Review of the new safety data included in the complete response submission shows it to
`be consistent with previously reported data in the original NDA and the original 120 day
`safety update. (An overview of the final safety update can be found on pages 8 to 15 of
`the Cross Divisional Team Leader’s review). No new risks or safety issues were
`identified by the medical officer in the review of the complete responsesubmission.
`
`Safe
`
`summa
`
`In the medical officer’s review for the original NDA, the clinical review team drew the
`following conclusions about the safety of fesoterodine:
`
`0 The reported adverse clinical events for fesoterodine are similar to the known side
`effects of other approved anti-muscarinic drugs, including dry mouth,
`constipation, dry eyes, and urinary retention.
`
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`
`

`

`0 Most reported clinical adverse events were mild to moderate in severity and
`resolved without significant medical intervention.
`0 The anti—muscarinic adverse events observed in the pivotal trials (i.e., dry mouth,
`constipation and urinary retention) appeared to be dose-related.
`0 A thorough clinical review of a small number of serious adverse events (SAEs) in
`- Studies SP583 and SP5 84 revealed no probable association with the use of
`fesoterodine
`
`0 The thorough QT safety assessment from Study SP686 demonstrated no signal of
`any effect of fesoterodine on the QT interval at the clinical dose of 4mg once a
`day and at a supra—therapeutic dose of 28 mg once a day.
`0 No significant hepatotoxicity was reported in any trials of fesoterodine, although
`there were a few patients with mild increases in serum transaminase levels, but
`<3X ULN. There was no determination of a direct association between these
`increases in transaminase levels and fesoterodine.
`
`0
`
`In the Phase 3 studies, a slight dose-dependent increase in mean pulse rate from
`baseline to end of treatment occurred in all the fesoterodine treatment groups. In
`the thorough QT study, there was a mild-moderate increase in heart rate following
`treatment in the high dose group (the supratherapeutic dose of 28mg daily).
`
`9. Advisory Committee Meeting
`
`Fesoterodine is the sixth orally administered anticholinergic drug to be approved for the
`indication “treatment of overactive bladder.” Although fesoterodine1s a new molecular
`entity, the drug1s rapidly metabolized to the active metabolite 5—hydroxytolterodine
`whichIs also the major metabolite of the approved drug tolterodine Although no “head
`to head” adequately controlled trials have compared fesoterodine to other approved
`anticholinergic drugs, the efficacy appears to be roughly comparable and no new safety
`concerns have been identified. No advisory committee was convened.
`
`10. Pediatrics
`
`The Pediatric Review Committee (PeRC) agreed with the partial waiver for patients less
`than 5 years of age and deferral of patients 6 to / years, 11 months of age. The PeRC
`recommended that the Division add the dates for the protocol submission and the date the
`studies are due to the Approval letter. Overall, PeRC agreed with the deferral and overall
`pediatric plan.
`
`11(4)
`
`1 1. Other Relevant Regulatory Issues
`
`a. Division of Scientific Investigations (DSI):
`
`DSI concluded that inspection of 3 of the 4 clinical sites did not reveal any significant
`regulatory violations. Overall, “the data appear acceptable in support of the respective
`indication.” The inspection of the fourth site revealed deficiencies with diary entries
`for seven of 17 subjects. “Given the extent of these deficiencies, the review Division
`may wish to consider whether to exclude these data fiom its safety or efficacy
`
`l3
`
`

`

`analyses.” The DRUP clinical review team and the Biometrics reviewer believe that
`the Phase 3 trials include so many patients and the statistical evidence is so
`compelling1n favor of the product that excluding the data from these 7 patients would
`have little impact on the overall efficacy conclusions.
`
`b. Division of Medication Error Prevention and Analysis (DMEPA):
`
`DMEPA “has no objections to the use of the proprietary name Toviaz for this
`product.”
`
`c. Office of Surveillance and Epidemiology (OSE):
`
`A pre-approval safety meeting with representation from OSE was held The safety
`data submitted1n the original NDA and the complete response submission were
`discussed Specifically, data relating to central nervous system, cardiac (including QT
`prolongation), hepatic, and skin (rash) events were reviewed. The overall safety
`profile of fesoterodine, as well as the safety profiles of other approved anticholinergic
`agents, were discussed. Labeling was also reviewed.
`
`No new safety concerns were identified and the labeling appears adequate for safe use
`of the drug. No post-marketing commitments were thought to be necessary. No
`specific safety data were identified which would require other than routine post-
`approval surveillance.
`I
`
`d.- Division of Drug Marketing, Advertising, and Communications (DDMAC):
`
`DDMAC was consulted to comment on product labeling from a marketing and
`advertising perspective. All DDMAC comments were considered and acted upon as
`deemed appropriate by DRUP.
`
`e. Financial disclosure:
`
`The financial disclosure information submitted in the original NDA submission was
`reviewed and found to be acceptable. No inappropriate financial arrangements
`relating to study investigators were identified.
`
`12. Labeling
`
`The label and patient package insert have been agreed upon with the sponsor.
`
`13. Decision/Action/Risk Benefit Assessment
`
`I agree with the recommendations of the cross divisional team leader, primary medical
`officer, clinical pharmacology reviewer, pharmacology/toxicology reviewer, CMC
`reviewer, and statistical reviewer that NDA 22—030 (fesoterodine for the treatment of
`overactive bladder) be approved.
`
`14
`
`

`

`Efficacy using accepted endpoints (incontinence episodes and urinary frequency) was
`demonstrated in two adequate, controlled phase 3 studies. Fesoterodine is an
`anticholinergic agent whose safety profile appears similar to other approved
`anticholinergic drugs, although no well designed or controlled comparative studies have
`been performed. No new safety concerns have been identified. Adverse events appear to
`berelated to the known pharmacology of anticholinergic drugs.
`
`No post-marketing studies are required.
`
`Labeling negotiations have been satisfactorily concluded.
`
`There are no outstanding issues related to this NDA, and I recommend approval.
`
`Appears This Way
`On Original
`
`15
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`George Benson
`10/23/2008 10:48:04 AM_
`MEDICAL OFFICER
`
`