Medical Officer’s Review of NBA
`FesoterodineN.“
`NBA 22-030
`
`w)
`
`Date of Submission:
`
`NDA Goal Date:
`
`Target Action Date:
`Sponsor:
`
`March 27, 2006
`January 27, 2007
`January 26, 2007
`Schwarz Biosciences, Inc.
`
`Drug Name:
`Proposed Trade Name: '
`Proposed Drug Name:
`Pharmacologic Category:
`
`Phase 3 Studies Reviewed: '
`
`. w“?
`
`Fesoterodine
`
`_
`Anti-Cholinergic
`(Muscarinic Receptor Antagonist)
`SP584‘, SP583 & SP686
`
`Indication:
`
`Doses Used:
`
`Route of Administration
`
`Treatment of Overactive Bladder (OAB)
`4mg & 8mg once a day
`Oral
`
`

`

`TABLE OF CONTENTS
`
`1. Executive Summary.....................'. ........... page 3
`
`2. Integrated Summary of Efficacy (ISE)...........page 8
`
`3. Integrated Summary of Safety (ISS).............page 14
`
`4. Appendices"......................{ ....................page 33
`
`A. Medical Officer’s Review of Study SP583 ............ page 33
`’B. Medical Officer’s Review of Study SP584............page 61
`C. Medical Officer’s Review of Study SP686 ..........'..page 71
`
`Appears This Way
`On Original
`
`

`

`I. Executive Summary
`1.1.
`Recommendations
`
`In the opinion of this reviewer, from a clinical perspective, fesoterodine 4mg and 8mg
`tablets taken once daily should be approved for the Sponsor’s proposed indication
`“treatment of overactive bladder with symptoms of urge urinary incontinence,
`urgency and urinary frequency” in adult men and women.
`
`The evidence presented in the submission of this NDA is adequate in support of the
`effectiveness of fesoterodine. The adverse events profile of fesoterodine appears to be
`similar to other approved antimuscarinic drugs in its class. The safety evaluation exceeds
`the ICH guidance criteria for the number of patients exposed to fesoterodine and for the
`duration of exposure. Thorough QT safety assessment from study SP686 showed no
`signal of an effect at the clinical dose of 4mg and supra-therapeutic dose of 28mg once a
`day on ventricular repolarization or cardiac conduction.
`
`Summary of Clinical Findings
`1.2.
`' I.2.A. Brief Overview of Clinical Program
`Fesoterodine is a new chemical entity that belongs to the class of antimuscarinic agents.
`Fesoterodine has been developed as a sustained release (4mg & 8mg), once daily
`formulation for the proposed indication of treatment of overactive bladder with
`symptoms of urge urinary incontinence, urgency, and urinary frequency.
`
`. Fesoterodine is a non~selective muscarinic receptor antagonist. Following oral
`administration, fesoterodine is completely absorbed and de-esterified in Vivo to the active
`metabolite SPM 7605. Maximum plasma levels of SPM 7605 are achieved
`approximately 5 hours after administration of fesoterodine SR. Steady state is reached
`after 3 days and the major pathway for metabolism is via CYP2D6. Terminal half life of
`oral fesoterodine is approximately 7 hours. Hepatic metabolism and renal excretion
`contribute significantly to the elimination of SPM 7605. Approximately 70% of orally
`administered dose is recovered in urine as metabolite(s) and 7% is recovered in the feces.
`SPM 7605 is distributed widely in the body, as shown by the apparent volume of
`distribution of 519L after IV administration of fesoterodine. The metabolites of
`fesoterodine other than SPM 7605 have low or no in vitro binding to muscarinic
`acetylcholine receptors. In poor metabolizers of CYP2D6, exposure to SPM 7605 was
`approximately doubled. Inhibition of CYP3A4 by ketoconazole resulted in an
`approximately 2-fold increase in exposure to SPM7605. Induction of CYP3A4 by
`rifampin resulted in approximately 4 fold reduction in exposure to SPM 7605. No other
`notable drug—drug interactions have been reported.
`
`A total of 17 Phase 1 trials in healthy patients, and three Phase 2 trials and two Phase 3
`trials in patients with OAB syndrome have been conducted during the fesoterodine
`development program. Approximately 489 healthy subjects have received fesoterodine in
`Phase 1 trials and approximately 2288 patients with OAB have received fesoterodine in
`Phase 2 and 3 trials. In all these trials fesoterodine has been safe and well tolerated.
`
`

`

`During the EOP2 meeting in June 2003, the sponsor was advised to conduct two, 12—
`week, placebo-controlled trials with micturition frequency, urge incontinence episodes
`and the volume voided as the key endpoints. The sponsor was also advised to conduct a
`thorough QT trial preferably in the target population and to perform genotyping for CYP
`2D6 metabo‘lizer status in at least one Phase 3 trial.
`
`At the pre—NDA meeting in July 2005, the Division concurred that the sponsor had
`conducted the requested Phase 3 and thorough QT studies and also concurred with the
`sponsor’s request for partial waiver/deferral for pediatric patients.
`
`I.2.B. Efficacy
`The co-primaryendpoints and the key secondary endpoint for the pivotal studies are
`appropriate and clinically meaningful. The study results provide substantial evidence in
`support of effectiveness of fesoterodine 4mg and 8mg taken orally once daily for the
`treatment of patients 18 years and older with symptoms of overactive bladder (OAB).
`
`The conclusions from the clinical efficacy review were as folloWs:
`I
`Fesoterodine showed a statistically significant and clinically meaningful
`improvement in decreasing the number of micturitions during an average 24 hour
`period when compared to placebo over a treatment period of 12 weeks in both
`SP583 and SP584 trials. W“
`-~ ~ ~»-————»
`C;
`
`P
`
`I
`
`I
`
`I
`
`I
`
`For incontinence episode frequency, there was a clinically meaningful decrease
`shown in both pivotal studies and the improvements were statistically significant
`when compared to placebo. The improvement in incontinence episode frequency
`was statistically significant as early as2 weeks after the start of treatment in both
`studies for the 4mg dose (the starting dose).
`
`For volume voided, fesoterodine increased the average volume per void in both
`studies. The increase was statistically significant at the p <0.001 level for both
`fesoterodine 4mg and 8mg/day in study SP5 83, but only statistically significant
`in the 8mg dose group in study SP584.
`
`Fesoterodine also demonstrated a significant improvement in other clinical
`secondary endpoints in both Phase 3 studies.
`
`The magnitude of the fesoterodine treatment effect was consistent across
`different age groups, race and gender.
`
`I.2.C. Safety
`Safety data is primarily drawn from a total of 2288 patients with OAB who received
`fesoterodine SR in phase 2 and 3 trials during the drug development program. This
`includes 858 (3 8%) patients exposed to fesoterodine for >6months, 570 (25%) patients
`
`

`

`exposed for >12 months and 162 (7%)ipatients exposed for >18m0nths. There were also '
`489 patients that received fesoterodine during Phase 1 trials.
`
`The overall size of the safety database and overall evaluation of safetywas adequate. The
`reported adverse clinical events are similar to the known side effects of other approved
`anti-muscarnic drugs, including dry mouth, constipation, dry eyes and urinary retention
`No significant cardiovascular, hepatic, hematologic or renal toxicities were
`identified.
`
`Important safety-related findings from the clinical review were:
`I Dry mouth, constipation, abdominal pain, headache, urinary retention, dry eyes
`and urinary tract infection were the most frequently reported adverse events that
`occurred in the tWO pivotal studies SP5 83 and SP5 84
`' Most reported clinical adverse events were mild to moderate1n severity and
`resolved without significant medical intervention.
`.
`' The anti-muscarinic adverse events seen in the pivotal trials (i.e., dry mouth,
`constipation and urinary retention) appeared to be dose-related.
`' A thorough clinical review of a small number of serious adverse events (SAEs) in.
`studies SP583 andSP584 revealed no probable association with the use of
`fesoterodine. This review took into consideration cases of chest pain, angina, MI,
`heart failure, QTc prolongation on ECG, pneumonia, bone fractures, spinal
`decompression, salpingitis, appendicitis, skin disorders and abnormalLFT’s. All
`these adverse events were mild to moderate in intensity and these patients had
`many co-morbid medical conditions that could have played a role1n these adverse
`events.
`
`I There was a modest dose-dependent increase in mean residual volume among
`fesoterodine-treated groups, yet this increase remained below a group average of
`SOmL.
`
`' Adverse events from the use of fesoterodine that led to discontinuation included
`dry mouth, constipation, dry eyes, urinary retention and urinary tract infection.
`I Of the 5 patients who were reported to have died during this drug program
`development, one patient (#10672) in study SP5 82 died from cerebrovascular
`accident, the second patient (#10527) in study SP5 83 died from MI, the third
`patient (#10943) in study SP738 died due to metastastases to the liver, the fourth
`patient (#11 184) in study SP738 died due to “sudden deat ” and fifth patient
`(#10618) died several months after completing study SP5 83 due to unknown
`causes. Four of the five deaths were considered by the investigators to be
`unrelated to study medication and the fifth (the “sudden deat ” case) was
`considered “unlikely related” to study medication.
`
`Narratives for these 5 patients, who died during fesoterodine development program, are
`as follows:
`
`Patient 10672, a 76--year old female who was randomized to treatment1n Phase 2 study
`SP5 82 with fesoterodine 12mg/day, suffereda fatal stroke (CVA) on Day 83. In the
`opinion of the investigator this fatal SAE was not related to trial medication and had a
`
`

`

`high probability of being related to her Concomitant co—morbid disease (cerebral artery
`sclerosis).
`
`Patient 10527, a 70—year-old female who had been randomized to fesoterodine 8mg/day,
`died as a result of a heart attack (myocardial infarction) that occurred 26 days after
`discontinuation of trial medication during study SP583. This patient'had completed the
`’ treatment period two weeks prior to hospitalization for bronchitis. Patient was discharged
`8 days later from the hospital and died on following day at home. This SAE was
`considered by the investigator to be unrelated to trial medication.
`
`Patient 10943, a 76-year401d female who had been taking fesoterodine 8mg/day during
`open-label treatment in SP738, died as a result of liver metastasis. Prior to open-label ‘
`treatment, this patient had taken fesoterodine 4mg/day during SP5 83 for a combined
`double-blind plus open-label fesoterodine exposure of 254 days. The patient was
`diagnosed with liver metastasis and peritoneal carcinomatosis with unknown primary
`tumor. The patient died from the existing metastasis to liver, approximately 3 weeks after
`the diagnosis. No autopsy was performed. This fatal SAE was considered by the
`investigator to be unrelated to trial medication but most likely from a co—morbid
`abdominal malignancy.
`
`Patient 11184, a 69—year-old female who had been taking fesoterodine 4mg/day for 333
`days experienced an SAE of “sudden death” during open-label treatment. Prior to open-
`label treatment, this patient had taken fesoterodine 8mg/day during SP583. Past medical
`history included diabetes mellitus and asthma. During the trial, mild aortic stenosis was
`diagnosed. The ECGs recorded prior to, and during administration of double-blind trial
`medication, showed sinus rhythm and left ventricular hypertrophy. This patient died after
`complaining of difficulty breathing. N0 autopsy was performed, but the death certificate
`attributed her death to natural causes. Both the investigator and the sponsor considered
`the sudden death unlikely to be related to trial medication.
`
`Patient 10618, an 82—year-old female who had been randomized to placebo group, died
`approximately 4 months after discontinuing from trial participation in study SP5 83.
`Reason for death was not provided. The investigator assessed the death as unrelated to '
`use of trial medication.
`
`After having reviewed the narratives above, this reviewer concurs with the
`investigators that none of the five deaths are related to the use of fesoterodine. ,
`
`'
`
`The 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 28mg once a day. There was no significant effect on ventricular
`repolarization or on cardiac conduction when compared to placebo and to the active
`control i.e. moxifloxacin. Fesoterodine exposure in both poor and extensive metabolizers
`did not increase the risk of QT prolongation.
`
`In view of the findings from this study, this reviewer does not find any realistic risk
`of QT prolongation with the use of fesoterodine in patients with OAB.
`
`

`

`.
`IL2.D. Dosing
`The 4mg and 8mg dose of fesoterodine was selected based on results from Phase 1 and
`Phase 2 studies. Fesoterodine given at a dose of 4mg once daily was determined by the
`sponsor to be the lowest effective dose in improving the symptoms of overactive bladder
`(OAB). However, to ensure efficacy in those patients who respond less than optimally to
`4mg/day, fesoterodine dose can be titrated up to 8mg once daily. Fixed dose efficacy
`data for 4mg/day and 8mg/day is available from controlled clinical studies SP583 and
`SP584, and open-label data is available for a titration regimen in the extensions studies.
`Fesoterodine is intended to be taken in the morning, and may be taken with or without
`food.
`'
`
`I.2.E. Special Populations
`Effect on age, gender and race: Fesoterodine did not demonstrate any difference
`in effectiveness based on age, gender or race. There is an expected difference in anti-
`muscurinic adverse events between younger and older patients for this class cf drugs. In
`general, reports of dry mouth, constipation and urinary retention are usually greater in
`incidence in the older population. However, in the fesoterodine trials, this was not seen.
`Therefore, no dosage adjustment is necessary in the older population, or based on gender '
`or race.
`'
`
`Renal insufficiency: In patients with mild or moderate renal insufficiency (CLCR ranging
`from 30—80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and
`1.8-fold respectively, as compared to healthy subjects. In patients with severe (CLCR < 30
`mL/min) renal insufficiency, Cmax and AUC are increased 2.0- and 23-fold,
`respectively. Therefore, based upon this information, in patients with mild or moderate
`renal insufficiency, no dose adjustment is recommended. Doses of fesoterodine greater
`than 4 mg are not recommended in patients with severe renal insufficiency.
`
`Hepatic impairment: In patients with moderate (Child-Pugh B) hepatic impairment,
`Cmax and AUC of the active metabolite are increased 1.4- and 2.1—fold, respectively, as
`compared to healthy subjects. Therefore, based upon this modest degree of increase in
`maximum exposure, no dose adjustment is recommended in patients with mild or
`moderate hepatic impairment. Subjects with severe hepatic impairment (Child-Pugh C)
`have not been studied; therefore fesoterodine is not recommended for use in these
`patients.
`
`Potential for dose dumping with ETOH consumption: The Clinical and Chemistry
`review of the sponsor’s in vitro data and the accompanying rationale demonstrates no
`need at this time for human clinical trials to assess the potential for dose dumping due to
`alcohol consumption.
`
`Pediatric issues: Sponsor has been granted a partial waiver for conducting pediatric
`studies in children 5 years of age and younger, and a deferral of studies for children aged
`6 to 15 years.
`
`

`

`Use in Pregnancy Information: There are no adequate and well-controlled studies in
`pregnant women. As a pregnancy Category C drug, fesoterodine should only be used
`during pregnancy ifthe potential benefitjustifies the potential risk to the fetus.
`
`II. Integrated Summary of Efficacy (ISEl
`
`II.A. Brief Statement of Conclusions
`Both the pivotal studies SP583 and SP584 were adequate and well-controlled studies
`conducted in Europe and the United States, respectively. Both provide substantial
`' evidence of efficaCy in the primary and key secondary efficacy variables. The primary
`efficacy variable were the average number of micturitions per 24 hours and the average
`number of urge urinary incontinence episodes per 24 hours.
`
`The improvement in the signs and symptoms of overactive bladder (OAB) is supported
`by data suggesting an associated improvement in quality of life. The proposed indication
`therefore is well supported by the efficacy data.
`
`II.B. Method of Efficacy Review
`The reviewer’s basic approach to the efficacy review involved:
`I
`Review of the proposed indication, study protocols, regulatory and scientific
`background
`I
`Identification and review of the controlled studies to support the indication
`I
`Conduct of a detailed review of each study for efficacy
`I
`I Detailed discussions and interactions with the Biometrics reviewer
`I Generate conclusion regarding efficacy from the two pivotal studies
`
`II.~C. List of Studies, Designs, Populations and Efficacy Variables
`The clinical reviewer focused on the two Phase 3 “pivotal” studies for efficacy
`determinations. These studies are referred to by number: SP583 and SP584. The three
`Phase 2 studies were reviewed as well, but are not presented herein.
`
`Study Designs
`II.C.1.
`Both trials (SP583 and SP584) were randomized, double-blind, placebo-controlled,
`parallel-group studies of efficacy and safety conducted at multiple centers in Europe (SP-
`583) and in the United States (SP-584) for a treatment duration of 12 weeks.
`
`Both the studies SP583 and SP584 collected diary—based data on micturition
`frequency per 24 hours, urge incontinence episodes per 24 hours, and volume voided
`with each micturition at baseline and again at Weeks 2, 8 and 12. Week 12 was the study
`endpoint. Diaries were recorded for 3 days and data for volume voidedwas collected for
`24 hours.
`
`

`

`Study Populations
`II.C.2.
`In study SP583, a total of 1135 patients were randomized and 1132 were treated: 279
`with placebo, 265 with fesoterodine 4mg/day, 276 with fesoterodine 8mg/day and 283
`with tolterodine 4mg/day. Mostpatients (>80% in any treatment group) completed the
`' fiill 12 weeks of treatment. Most of patients (81%) were female. The mean patient age
`was 57 years with a range of 19 to 86 years. In study SP5'84, a total of 836 patients were
`randomized and 832 patients were treated: 266 with placebo, 267 with fesoterodine
`4mg/day and 267 patients with fesoterodine 8mg/day. Most patients (>80% in any
`treatment group) completed full 12 weeks of treatment. Most of the patients (76%) were
`female. The mean age was 59 years with a range of 21 to 91 years. A total of 9% of
`patients were poor metabolizers for CYP2D6 by genotyping.
`
`Efficacy Variables
`II.C.3.
`The primary efficacy endpoints for both trials were: a) change-from—baseline in the
`average number of micturitions per 24 hours, and b) change-from—baseline in the average
`number of urge urinary incontinence episodes per 24 hours.
`
`A key secondary endpoint was the average volume voided per micturition.
`
`Statistical Analysis Plans (SAP)
`II.D.
`The statistical analysis plans were consistent for both Phase 3 protocols. The critical
`elements of these SAPS were:
`
`I All statistical analysis plans were finalized prior to treatment assignment
`I All randomized patients with a baseline measurement were included in the
`efficacy analysis
`,
`p
`
`I
`
`Last-observation-carried—forward (LOCF) approach was used for any missing
`data
`,
`-
`‘
`
`I Analysis of variance (ANOVA) was planned as the test of treatment differences.
`The reader is referred to the Biometrics review for more details regarding the
`SAP and actual analyses conducted.
`
`Efficacy Results
`ILE.
`The following three tables (Tables 1—3) were generated by the reviewer from the data in
`Sponsor’s study reports for Studies SP5 83 and SP5 84. Tables 1 and 2 describe the
`Sponsor’s reported results for the primary efficacy endpoints: average number of
`micturitions per 24 hours and average number of urge incontinence episodes per 24
`hours, respectively. Table 3 describes the Sponsor’s reported results for the key
`secondary endpoint: average volume voided per micturition. The accompanying two
`figures (Figures 1 and 2) show the primary efficacy data graphically and over time.
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`—l 74(2.7)
`
`-1.94(3.1)
`
`1126-4
`-1.02(3.4)
`
`.-1.86(3.6)
`
`-194(3 0)
`
`P<0.001
`
`P<0.001
`
`P=0.032
`
`P<0.001'
`
`Change from -1.02(3.0)
`baseline
`
`
`
`P-value for
`change from
`baseline vs.
`
`
`
`
`Table 1. Micturitions per 24 hours*
`
`. Stud SP-583
`
`
`
`n=279
`
`n=265
`
`(n=276
`
`
`
`'
`
`Stud SP-584
`
`
`
`n=266)
`12-267
`
`n=26
`
`(n=267)
`
`placebo
`*Data presented as Mean (SD). Sample size reflects number of patients at baseline. P-
`value derived from analysis of the variance test using baseline to endpoint difference and
`LOCF.
`
`
`
`Fi re 1. Chan 6 from baseline in fre uenc of micturitions er 24 hours
`
`CPI!inMisha:inion»:Wu.—nBaum:
`
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`
`10
`
`

`

`Table 2. Incontinence episodes per 24 hours*.
`
`
`
`
`
`
`
`Placebo
`n=211
`3.7(3 1)
`
`Stud SP—583
`Feso 4mg
`n=199
`3.8(3 4)
`
`' Stud SP-584
`‘
`Feso 8mg.
`Feso 4mg
`Placebo
`Feso 8mg
`
`n=222‘3L
`(n=205)
`(n=228)
`n=218
`3.7(2 9)
`3.7(3.3)
`3.9(3 5)
`3.9(3.3)
`
`1.4035)
`2.1012)
`
`
`
`-2.06(2.7) —2.27(2.4)
`-1.77(3.1)
`Change from -1.20(3.3)
`
`
`
`
`baseline
`'
`
`
`P-value for
`P<0.001
`
`change from
`
`
`baseline vs.
`
`
`la‘cebo
`
`* Data presented as Mean (SD). Sample size reflects number of patients at baseline. P—
`value derived from analysis of the variance test using baseline to endpoint difference and
`LOCF.
`
`
`
`
`
`-1.0(2.7)
`
`
`
`
`
`
`
`
`
`-2.42(2.8)
`
`P<0.001
`
`_
`
`Figure 2.
`Change fmm Baseline in average number ofurge incriminate episodes per 24 hours for
`anti: fisit by randomized twat-meat populafim: (has in 31684)
`
`magnateper2“3mm}
`
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`

`

`Table 3. Volume voided per micturition"
`
`Placebo
`n=279
`
`150.2(52.0)
`159.9(62.0)
`9.8(43.5)
`
`Stud SP-583
`Feso 4mg
`Feso 8mg
`n=265
`n=276
`
`160.0(59.5)
`187.0(92.6)
`27.0(70.3)
`,
`
`153.9(56.9)
`187 503.7)
`33.5(54 2)
`
`
`
`
`Change
`-
`from
`baseline '
`
`
`
`
`
`
`P-value (A
`
`
`baseline
`
`vs.
`
`
`placebo)
`*Data presented as Mean (SD). Sample size reflects number of patients at baseline. P-
`value derived from analysis of the variance test using baseline to endpoint difference and
`LOCF.
`’
`-
`'
`
`159.4(69.0
`167.5(95.7)
`7.9(69.4)
`
`P=<0.001
`
`P<0.001
`
`P<0.001
`
`
`
`Placebo
`n=266
`
`
`
`
`
`
`Study SP—584
`Feso 4mg
`
`n—26
`‘
`n=267
`
`
`152.0(60.2)
`155.9(57.7)
`169.5(78.0)
`189.3(77.3)
`17.0(61.1)
`33.4(62.5)
`
`
`
`
`
`
`.
`II.E.1. Summary of efficacy results
`In the primary efficacy trials, fesotero-dine 4 and 8mg administered once daily fer 12
`weeks improved both the two primary and key secondary efficacy variables. All three key
`variables as shown above in tabular format (change in the average number of
`micturitions per 24 hours, change in the average number of urge incontinence
`episodes per 24 hours, and volume voided) improved in a dose-responsive, statistically
`
`
`.- -;—¢..._.-—»-—-«-’—-“"“‘_“significant manner compared to placebo treatment. 3%)
`
`The diary endpoints were explored further by other analyses. One method of exploring
`the data was to calculate the number of “continent days” achieved. Treatment with
`fesoterodine increased the mean number of continent days per week in a dose-dependent
`manner during both studies and this benefit appeared to continue in the long-term
`extension trials. Increases in mean number of Continent days per week were observed at
`the first post-dose visit, 2 weeks after the initiation of trial medication. Overall, patients
`who were receiving fesoterodine in these trials gained a mean of about 2 to 3 continent
`days per week and this effect appeared to be maintained in long-term, opne-label
`treatment.
`'
`
`Fesoterodine use decreased (improved) the mean number of total voids per 24 hours
`during both Phase trials and also in the Phase 2 dose-ranging trials. Decreases in mean
`number oftotal voids per 24 hours were observed at the first post—dose Visit, 53-,“
`NW
`
`‘
`A
`bk 3
`
`Data from long-term, open-label extension trials provide additional support for these
`results from these Phase 3 pivotal studies of fesoterodine.
`
`12
`
`

`

`II.E.2. Efficacy results by age
`Subgroup analyses ofthe 3 key variables’by age showed no substantial differences
`compared to the primary comparisons. Consistent with the primary analysis, all
`subgroups, regardless of age responded in a more pronounced manner to fesoterodine
`than to placebo. A dose-responsive effect was observed for fesoterodine 4 and 8mg/day.
`Overall, the response to fesoterodine was similar in all age groups analyzed.
`
`.
`II.E.3. Efficacy results by gender
`Subgroup analyses of the key variables by gender showed no substantial differences
`compared to the primary comparisons. Overall, the response to fesoterodine was similar
`among males and females. In addition, gender did not influence the pharmacokinetics of
`fesoterodine, as supported by results of population pharmacokinetic analyses. Based on
`efficacy and pharmacokinetic results, no dosage adjustment based on gender is
`necessary.
`
`II.E.4. Efficacy results by race
`Subgroup analyses of the key variables by race showed no substantial differences
`compared to the primary comparisons. Consistent with the primary analysis, all
`subgroups studied, regardless of race, responded in a more pronounced manner to
`fesoterodine than to placebo. The only exception to this was in change from baseline in
`number of micturitions per 24 hours at the fesoterodine 8mg/day dose in the non-White
`subgroup, where the improvement was less than that observed with placebo. The effects ‘
`of fesoterodine 4mg/day and tolterodine were more pronounced than for placebo,
`however, there was a relatively high placebo response for this parameter, and a relatively
`limited population for each treatment arm. Therefore, this was no considered to be a
`clinically meaningfulfinding.
`
`Based on efficacy and pharmacokinetic results, no dosage adjustment is necessary in
`this population group.
`’
`
`ILF. Efficacy Conclusions
`The pivotal studies (SP-583 and SP-584) showed statistically significant changes
`from baseline in both primary endpoints (number of micturitions per 24 hours and
`number of urge incontinence episodes per 24 hours) and in the key secondary endpoint '
`(volume voided per micturition) when compared to placebo for a period of 12 weeks.
`The improvement was evident as early as M‘— from the commencement ofthe
`treatment. The results were similar in magnitude and consistent for the two primary
`endpoints and the key secondary endpoint inboth trials. The results were similar
`regardless of patients’ age, gender or race. Exploratory secondary endpoints also
`supported the benefit of fesoterodine for the treatment of this condition.
`
`gkm
`
`Therefore, in the opinion of this reviewer, the effectiveness of fesoterodine is well
`supported by results from the controlled studies.
`
`13
`
`

`

`III. Integrated Summary of Safety {ISSI
`
`III. A. Brief Statement of Conclusions
`
`The adverse event profile of fesoterodine appears to be similar to that of other
`antimuscrinic drugs. Dry mouth, constipation and urinary retention were the most
`, frequently reported events in the pivotal studies (SP583 and SP584). These adverse
`events were mild to moderate in intensity. The other less frequently reported but
`clinically significant adverse events associated with fesoterodine were urinary tract
`infection, karato-conjunctivitis sicca (dry eyes), headache, nasopharyngitis and
`hypertension.
`
`No hepatotoxicity was reported in any trials of fesoterodine, although there were a few
`patients with mild increase in serum transaminase levels, but <3X ULN. There was no
`determination of a direct association between these increases in transaminase levels and
`fesoterodine. These events will be labeled. There is no evidence of renal toxicity in
`association with fesoterodine.
`
`No apparent QT safety signal was identified among patients in the pivotal studies SP—583
`and SP584. Study SP686 was specifically designed and conducted to study the effect
`of fesoterodine on cardiac repolarization. The study was adequately powered and
`included a positive control, as recommended in the FDA draft guidance document.
`This trial,,in evaluating the effects of feSoterodine at both therapeutic and supra-
`therapeutic doses (4mg and 28mg once daily), showed that fesoterodine resulted in no
`significant cardiac repolarization or cardiac conduction when compared to placebo and
`the active control moxifloxacin. However, there was a mild-moderate increase in heart
`rate following treatment in the high dose group. This increase in heart rate was
`asymptomatic, appeared to pose no specific cardiac risk, and will be labeled.
`
`In View of all the facts summarized above, fesoterodine is considered to be safe at
`doses of 4mg and 8mg twice daily given orally to patients with OAB.
`
`III.B. Description of Patient Exposure and Demographics
`The pivotal study SP583 was conducted at 16 European sites and 1135 patients with _
`OAB were enrolled. A total of 541 patients received the study treatment: fesoterodine
`4mg (n=265) once daily and fesoterodine 8mg (n=276) once daily. 279 patients received
`placebo and 283 patients got tolterodine 4mg once daily as an “active control” for 12
`weeks.
`
`The second pivotal study SP584 was conducted at multiple US sites and 1587 patients
`with OAB were enrolled. 836 patients were randomized and a total of 832 patients
`received the study treatment: fesoterodine 4mg (n=282) once daily and fesoterodine 8mg
`(n=279) once daily. 271 patients received placebo for the duration of 12 weeks.
`
`14
`
`

`

`In both studies, the patient population was predominantly female (76%) and mean age
`group was approximately 59 years (21—91 years). In the second pivotal, where genotyping
`was done routinely, 10% of the patient population were poor metabolizers for CYP2D6.
`
`III.C. Method of Integrated Safety Review
`The reviewer conducted detailed analyses of safety from each of the two listed pivotal
`trials that included each of the following items.
`0 Deaths
`
`Serious adverse events
`
`Medically significant adverse events
`Overall treatment emergent adverse events
`
`Discontinuation of study medication due to adverse events
`Laboratory findings
`Vital signs and ECG findings
`Special safety concerns
`Antimuscarinic side effects
`
`In addition, the reviewer analyzed the sponsor’s integrated summary of safety from both
`the original NDA and the 120-Day Safety Update for the same parameters as those listed
`above.
`
`III.D. Safety Results
`
`III.I). 1. Deaths
`
`As of the submission of this NDA and all safety updates thereafter, a total of 5 deaths
`was reportedin all placebo and active controlled studies. None of these deaths were
`judged by the investigator to be related to the study medication.
`
`Of the 5 patients who have died during this drug program development, one patient
`(#10672) in study SP5 82 died from cerebrovascular accident, the second patient (#10527)
`in study SP583 died from MI, the third patient (#10943) in study SP738 died due to
`metastastases to liver, the fourth patient (#11184) in study SP738 died due to
`“sudden dea ”, and fifth patient (#10618) died several months after completing study
`SP5 83 due to unknown causes. Four cf the five deaths were considered by the
`investigators to be unrelated to festerodine. The “sudden death” case was considered
`unlikely related to the trial medication.
`
`.
`
`15
`
`

`

`
`Trial number!
`
`Dose and duration of
`Preferred term!
`
`
`
`trial medication at onset
`subject number
`
`
`
`of AE
`
`
`
`
`Fesoterodine lngfday
`Cerebrovascular disorder} Not related.
`for 83 days
`stroke
`
`
`
`
`
`
`
`
`
`
`
`513738! 10943
`
`SP738g’11184
`
`Table 4.
`
`Subjects who had adverse events with fatal outcomes
`
`reported term
`
`Causality (per
`investigator)
`
`$133821 10672
`
`‘
`
`SP5 834’ 10527
`
`NAa
`
`Myocardial infarction’
`heart- attack
`
`Not related
`
`Eesoterodine Singfday for Metastases to liver? liver Not related
`254 days
`»
`' metastasis
`
`
`
`
`
`fesoterodine 4mgiday for
`333 days
`
`Sudden death? sudden
`death
`
`Unlikely
`
`AE=adverse event, NA=aot applicab‘fe
`
`,
`
`Case narratives for these 5 patients, who died during the fesoterodine development
`program, are as follows:
`
`Patient 10672, a 76-year old female who was randomized to treatment in study SP582
`