CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-030
`
`OFFICE DIRECTOR MEMO
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`October 31, 2008
`
`FROM:
`
`Julie Beitz, MD
`
`SUBJECT:
`
`Office Director Memo
`
`TO:
`
`NDA 22—030 Toviaz (fesoterodine fumarate) extended-release tablets;
`Pfizer, Inc.
`
`Summafl
`Fesoterodine fumarate is a muscarinic receptor antagonist that inhibits detrusor contractions and enhances
`bladder capacity. This memo documents my concurrence with the Division of Reproductive and Urologic
`Product’s (DRUP’s) decision that fesoterodine fumarate for the treatment of adults with overactive bladder
`with symptoms of urge urinary incontinence,-urgency, and urinary frequency be approved. The
`recommended starting dose is 4 mg once daily. Based upon individual response and tolerability, the dose
`may be increased to 8 mg once daily. The daily dose should not exceed 4 mg in patients with severe renal
`insufficiency or in patients taking potent CYP3A4 inhibitors. Fesoterodine fumarate is not recommended
`for use in patients with severe hepatic impairment.
`
`‘
`Regulatory Histog;
`NDA 22—030 was originally submitted by Schwarz Pharma Inc. on March 17, 2006, and received on March
`27, 2006. The sponsor’s API manufacturing facility in Shannon, Ireland, was not ready for FDA’s pre-
`approval inspection during the initial review cycle. On January 25, 2007, an approvable letter was issued
`stipulating that a satisfactory inspection of this site would be needed prior to approval and requesting that
`an updated summary of safety be submitted with the sponsor’s future response. On May 1, 2007, Schwarz
`Pharma Inc. submitted a complete response to the approvable letter. On August 1, 2007, ownership of this
`NDA was transferred from Schwarz Pharma, Inc. to Pfizer, Inc. During this review cycle, inspection of the
`Ireland manufacturing site was completed and it was found to be acceptable.
`
`This application was not referred to an FDA advisory committee because fesoterodine fumarate is a
`member of the anti-muscarinic class of products used to treat overactive bladder, including previously
`approved products. Fesoterodine fumarate did not pose unique concerns beyond those applicable to other
`members of this class.
`
`.
`Efficacy
`The efficacy of fesoterodine fumarate is supported by two 12-week randomized, placebo-controlled phase 3
`trials that enrolled adult patients with overactive bladder (with a combined total of 554 patients on
`fesoterodine fumarate 4 mg daily, 566 on fesoterodine fumarate 8 mg daily, and 554 on placebo). Patients
`were required to have overactive bladder symptoms for at least 6 months prior to study entry. The majority
`of patients were female (79%) with a mean age of 58 years. Both trials showed a statistically significant
`reduction from baseline to endpoint (Week 12) in the number of urge urinary incontinence episodes per 24
`hours for the 4 and 8 mg fesoterodine fumarate doses compared to placebo treatment. Both trials also
`showed a statistically significant reduction from baseline to endpoint (Week 12) in the number of
`micturitions per 24 hours for the 4 and 8 mg fesoterodine fumarate doses compared to placebo treatment.
`A reduction compared to placebo in the number of incontinence episodes was seen as early as 2 weeks
`following the start of fesoterodine fumarate treatment.
`
`For the secondary endpoint of voided volume per micturition, one of the phase 3 trials showed significant
`increases for both daily doses of fesoterodine fumarate compared to placebo treatment. In the second trial,
`
`

`

`significant improvement in voided volume was observed for the 8 mg daily close but not for the 4 mg daily
`dose.
`
`Safety
`A total of 2288 patients with overactive bladder received fesoterodine fumarate in phase 2 and 3 clinical
`trials. Of these, 782, 785, and 222 patients received fesoterodine fumarate doses of 4 mg, 8 mg, or 12 mg
`respectively, in Phase 2 and 3 trials with treatment periods of 8 to 12 weeks. Approximately 80% of these
`patients had > 10 weeks of exposure in these trials. Longer exposures to fesoterodine fumarate were
`observed in 857 patients for Z 6 months, in 701 patients for Z 12 months, in 529 patients for 3 24 months,
`and in 105 patients for 3 36 months. The safety profile for fesoterodine fumarate is consistent with that of
`other anti-muscarinics marketed for the treatment of overactive bladder; in fact, fesoterodine fumarate
`produces the same active metabolite as does tolterodine, a drug already marketed for this use. The most
`common adverse events reported were dry mouth, constipation and urinary retention. These events were
`generally mild or moderate in intensity. The incidence of dry mouth was highest in those taking 8 mg‘daily
`(35%) as compared to 4 mg daily (19%) or placebo treatment (7%). As with other anti-muscarinics, use of
`fesoterodine fumarate is contraindicated in patients with urinary retention, gastric retention, or uncontrolled
`narrow-angle glaucoma.
`
`A randomized, double-blind, placebo- and moxifloxacin-controlled study involving 261 subjects and
`designed to evaluate the risk of QT prolongation at therapeutic and supratherapeutic doses of fesoterodine
`fumarate (4 and28 mg daily doses) did not demonstrate abnormalities in cardiac repolarization related to
`fesoterodine fumarate use.
`
`Fesoterodine fumarate is associated with an increase in heart rate. In the phase 3 trials, the mean increase
`in heart rate compared to placebo was 3-4 beats/minute in patients treated with 4 mg daily and 3-5
`beats/minute in patients treated with 8 mg daily.
`
`No evidence of drug—related carcinogenicity was found in 24-month studies of oral administration to mice
`and rats. Fesoterodine fumarate was not mutagenic or genotoxic in vitro or in viva.
`
`Fesoterodine fumarate produced no dose—related teratogenic effects in mice and rabbits. Following oral
`doses 6-27 times the maximum human recommended dose (MHRD), female mice demonstrated increased
`resorptions and decreased live fetuses; fetuses with cleft palate were also noted at an incidence within the
`background range. Following oral administration to female rabbits, incomplete ossification of the
`stemebrae (retardation of bone development) was noted in fetuses. There have been no adequate and well—
`controlled studies of fesoterodine fumarate conducted in pregnant women. DRUP has proposed, and I
`concur, with a Pregnancy Category C, i.e., that this product should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
`
`Pharmacokinetic Considerations
`
`Following oral administration, fesoterodine fumarate is rapidly and extensively hydrolyzed to its active
`metabolite, 5-hydroxymethyl tolterodine, which is responsible for the anti-muscarinic activity of
`fesoterodine fumarate. The active metabolite is further metabolized in the liver with involvement of
`CYP2D6 and CYP3A4. Exposure to the active metabolite is doubled in poor metabolizers of CYP2D6 as
`compared to extensive metabolizers. Poor metabolizers of CYP2D6 were also more likely than extensive
`metabolizers to experience anti-muscarinic adverse events (e.g., dry mouth), particularly at the 8 mg daily
`dose, however, no dosing adjustments are recommended based solely on intrinsic CYP2D6 metabolizer
`status. Co-administration of ketoconazole, a potent inhibitor of CYP3A4, with fesoterodine fumarate also
`increased exposure to the active metabolite two-fold; dry mouth occurred in up to 43% of patients c0-
`administered fesoterodine fumarate 8 mg daily and CYP3A4 inhibitors. Exposure was calculated as being
`nearly 6-fold higher in CYP2D6 poor metabolizers taking ketoconazole as compared to CYP2D6 extensive
`metabolizers not taking ketoconazole. Therefore, doses of fesoterodine fumarate greater than 4 mg are not
`recommended in patients taking potent CYP3A4 inhibitors.
`
`In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are
`1.4- and 2.1—fold higher respectively, as compared to healthy subjects. No dose adjustment is
`
`

`

`recommended for patients with mild to moderate hepatic insufficiency. Patients with severe hepatic
`impairment have not been studied; fesoterodine fumarate is not recommended for use in these patients.
`
`In patients with mild to moderate renal insufficiency (creatinine clearance of 30-80 mL/min), Cmax and
`AUC of the active metabolite are 1.5- and 1.8-fold higher respectively, as compared to healthy subjects. In
`patients with severe renal insufficiency (creatinine clearance of < 30 mL/min), Cmax and AUC are 2.0- and
`23-fold higher, respectively. No dose adjustment is recommended for patients with mild or moderate renal
`insufficiency. Doses of fesoterodine fumarate greater than 4 mg are not recommended in patients with
`severe renal insufficiency.
`
`Tradename Review
`
`The tradename "Toviaz" was submitted for review on April 1, 2008 and found to be acceptable. The
`previously submitted proposed tradename “Ii—vs. was also found acceptable.
`
`4
`h£ )
`
`Postmarket Studies
`
`The pediatric study requirement under PREA will be waived for ages 0 months to 5 years, 11 months,
`because necessary studies are impossible or highly impracticable. This is because study endpoints are
`difficult to evaluate in this age group.
`
`Submission of the pediatric study for ages 6 to 16 years, 11 months, is deferred because the product is
`ready for approval for use in adults and the pediatric study has not been completed. The deferred study will
`evaluate fesoterodine fumarate for the treatment of overactive bladder in the subgroup of pediatric patients
`with neurologic disease.
`
`No postmarket studies or clinical trials will be required under Title IX, Subtitle A, Section 901 of the Food
`and Drug Administration Amendments Act of 2007.
`
`Julie Beitz, MD
`Director,
`Office of Drug Evaluation 111
`CDER, FDA
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Julie Beitz
`
`10/31/2008 10:14:42 AM
`DIRECTOR
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`January 25, 2007
`
`FROM:
`
`Julie Beitz, MD
`
`SUBJECT:
`
`Office Director Memo
`
`b(4)
`
`m4;
`
`TO:
`
`NDA 22—030 K; (fesoterodine fumarate) extended release tablets;
`Shwarz Pharma, LLC
`
`b(4)
`
`m F
`
`esoterodine fumarate is a muscarinic receptor antagonist that inhibits detrusor contractions and enhances
`bladder capacity. The proposed starting dose is 4 mg administered orally once daily; based on individual
`response and tolerability, the daily dose may be increased to 8 mg. This memo documents my concurrence
`with the Division of Reproductive and Urologic Product’s (DRUP’s) decision that fesoterodine fumarate
`for the treatment of adults with overactive bladder with symptoms of urge urinary incontinence, urgency,
`and urinary frequency is approvable. The sponsor’s API manufacturing facility in Shannon, Ireland, was to
`be ready for FDA’s pre-approval inspection during the final 4 months of this review cycle. Due to
`decisions made by the sponsor toW
`Schwarz Pharma informed DRUP in writing on July 20, 2006 that it would not be ready for inspection
`during this review cycle. Before fesoterodine fumarate may be approved, a satisfactory inspection of this
`facility will be needed.
`
`‘
`Efficacy
`NDA 22-030 was submitted on March 17, 2006, and received on March 27, 2006. The sponsor's claim for
`efficacy is supported by two 12-week randomized, placebo-controlled phase 3 studies that enrolled adult
`patients with overactive bladder (with a combined total of 554 patients on fesoterodine fumarate 4 mg
`daily, 566 on fesoterodine fumarate 8 mg daily, and 554 on placebo). Patients were required to have
`overactive bladder symptoms for at least 6 months, including urinary urgency, and urinary frequency, and
`in most patients, urge urinary incontinence. Both studies showed a statistically significant reduction from
`baseline to endpoint (Week 12) in the number of urge urinary incontinence episodes per 24 hours for the 4
`and 8 mg fesoterodine fumarate doses compared to placebo treatment. Both studies also showed a
`statistically significant reduction from baseline to endpoint (Week 12) in the number of micturitions per 24
`hours for the 4 and 8 mg fesoterodine fumarate doses compared to placebo treatment. Improvement in the
`number of incontinence episodes ‘3 was seen as early as 2 weeks following the start of
`fesoterodine fumarate treatment, although the improvements at Week 2 for the 4 mg (starting) dose were
`statistically better than placebo for the urge incontinence endpoint only.
`
`For the key secondary endpoint of voided volume per micturition, one study showed significant increases
`for both daily doses of fesoterodine fumarate compared to placebo treatment. In the second study,
`significant improvement in voided volume was observed for the 8 mg daily dose but not for the 4 mg daily
`dose.
`
`Safety
`A total of 2288 patients with overactive bladder received fesoterodine fumarate in phase 2 and 3 clinical
`studies. Of these, 782, 785, and 222 patients received fesoterodine fumarate doses of 4 mg, 8 mg, or 12 mg
`respectively, in Phase 2 and 3 trials with treatment periods of 8 to 12 weeks. Most of these patients
`(approximately 80% in each group) received > 10 weeks of exposure. Longer expOsures to fesoterodine
`fumarate were observed in 858 patients for Z 6 months and in 570 patients for Z 12 months. The safety
`profile for fesoterodine fumarate derived from these 8- and 12-week, randomized, placebo-controlled
`studies and their 1-year open-label extension periods in patients with overactive bladder is consistent with
`
`

`

`that of other anti-muscarinics; in fact, fesoterodine fumarate produces the same active metabolite as does
`tolterodine, a drug already marketed for this use. The most common adverse events reported were dry
`mouth, constipation and urinary retention. These events were generally mild to moderate in intensity. The
`incidence of dry mouth was highest in those taking 8 mg daily (35%) as compared to 4 mg daily (19%) or
`placebo treatment (7%). As with other anti-muscarinics, use of fesoterodine fumarate is contraindicated in
`patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma.
`
`A randomized, double-blind, placebo- and positive-controlled study designed to evaluate the risk of QT
`prolongation at therapeutic and supratherapeutic doses of fesoterodine fumarate (4 and 24 mg daily doses)
`did not demonstrate abnormalities in cardiac repolarization related to fesoterodine fumarate use.
`
`No evidence of drug-related carcinogenicity was found in 24-month studies of oral administration to mice
`and rats. Fesoterodine fumarate was not mutagenic or genotoxic in vitro or in vivo.
`
`Fesoterodine fumarate produced no frank teratogenic effects in mice. At exposures similar to or higher
`than the expected clinical exposure, female mice demonstrated an increased incidence of pre- and post-
`implantation fetal loss, including resorptions; fetuses with cleft palate were also noted. These findings are
`sometimes observed with maternal stress and have been seen with other anti-muscarinics. In a
`
`multigenerational study in female mice exposed from implantation through weaning, there were no
`occurrences of cleft palate. Following oral administration to female rabbits, post-implantation loss, early
`resorptions, and incomplete ossification of the stemebrae (retardation of bone development) were also
`noted. There have been no adequate and well-controlled studies of fesoterodine fumarate conducted in
`pregnant women. A search of FDA’s postmarketing adverse event reporting system (AERS) database
`revealed no cases of human teratogenicity in association with use of a similar product, tolterodine. DRUP
`has proposed, and I concur, with a Pregnancy Category C, i.e., that this product should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Pharmacokinetic Considerations
`
`Following oral administration, fesoterodine fumarate is rapidly and extensively hydrolyzed to its active
`metabolite. The active metabolite is further metabolized in the liver with involvement of CYP2D6 and
`
`CYP3A4, with the CYP2D6 pathway being the major pathway. Exposure to the active metabolite is
`doubled in poor metabolizers of CYP2D6 as compared to extensive metabolizers. Poor metabolizers of
`CYP2D6 were also more likely than extensive metabolizers to experience anti-muscarinic adverse events
`(e.g., dry mouth), particularly at the 8 mg daily dose, however, no dosing adjustments are recommended
`based solely on intrinsic CYP2D6 metabolizer status. Co-administration of ketoconazole, a potent inhibitor
`of CYP3A4, with fesoterodine fumarate also increased exposure to the active metabolite two-fold; dry
`mouth occurred in up to 43% of patients co-administered fesoterodine fumarate 8 mg daily and CYP3A4
`inhibitors. Exposure was calculated as being approximately 4- to 5-fold higher in CYP2D6 poor
`metabolizers taking ketoconazole as compared to CYP2D6 extensive metabolizers not taking ketoconazole.
`Therefore, doses of fesoterodine fumarate greater than 4 mg are not recommended in patients taking potent
`CYP3A4 inhibitors.
`
`In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are
`1.4 and 2.1-fold higher compared to healthy subjects. No dose adjustment is recommended for patients
`with mild to moderate hepatic insufficiency. Patients with severe hepatic impairment have not been
`studied; fesoterodine fumarate is not recommended for use in these patients.
`
`In patients with mild to moderate renal insufficiency (creatinine clearance of 30-80 mL/min), Cmax and
`AUC of the active metabolite are 1.5 and 1.8-fold higher compared to healthy subjects. In patients with
`severe renal insufficiency (creatinine clearance of < 30 mL/min), Cmax and AUC are 2.0 and 23-fold higher
`compared to healthy subjects. No dose adjustment is recommended for patients with mild or moderate
`renal insufficiency. Doses of fesoterodine fumarate greater than 4 mg are not recommended in patients
`with severe renal insufficiency.
`
`Tradename Review
`The tradename 2-\ is acceptable.
`
`but}
`
`

`

`Phase 4 Studies
`No Phase 4 study commitments are requested at this time. Studies in pediatric patients will be waived for
`patients aged <‘years and deferred for patients aged—‘16 years.
`
`b“)
`
`Julie Beitz, MD
`Director,
`Office of Drug Evaluation III
`CDER, FDA
`
`“Us“
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electrOnic signature.
`
`Julie Beitz
`
`1/25/2007 11:07:10 AM
`DIRECTOR
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`.
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`January 22, 2007
`
`FROM:
`
`Julie Beitz, MD
`
`SUBJECT:
`
`Office Director Memo
`
`TO:
`
`i“(fesoterodine fumarate) extended release tablets;
`NDA 22-030
`Shwarz Pharma, LLC
`
`film:
`Fesoterodine fumarate is a muscarinic receptor antagonist that inhibits detrusor contractions and enhances
`bladder capacity. The proposed starting dose is 4 mg administered orally once daily; based on individual
`response and tolerability, the daily dose may be increased to 8 mg. This memo documents my concurrence
`with the Division of Reproductive and Urologic Product’s (DRUP’s) decision that fesoterodine fumarate
`for the treatment of adults with overactive bladder with symptoms of urge urinary incontinence, urgency,
`and urinary frequency is approvable. The sponsor’s API manufacturing facility in Shannon, Ireland, was to
`be ready for FDA’s pre-approval inspection during the final 4 months of this review cycle. Due to
`decisions made by the sponsor to \ww—m—M
`Schwarz Pharma informed DRUP on May 16, 2006 that it would not be ready for inspection during this
`review cycle. Before fesoterodine fumarate may be approved, a Satisfactory inspection of this facility will
`be needed.
`
`l1(4)
`
`Efficacy
`NDA 22—030 was received on March- 27, 2006. The sponsor's claim for efficacy is supported by two 12-
`week randomized, placebo-controlled phase 3 studies that enrolled adult patients with overactive bladder
`(with a combined total of 5 54 patients on fesoterodine fumarate 4 mg daily, 566 on fesoterodine fumarate 8
`mg daily, and 554 on placebo). Patients were required to have overactive bladder symptoms for at least 6
`months, including urinary urgency, and urinary frequency, and in most patients, urge urinary incontinence.
`Both studies showed a statistically significant reduction from baseline to endpoint (Week 12) in the number
`of urge urinary incontinence episodes per 24 hours for the 4 and 8 mg fesoterodine fumarate doses
`compared to placebo treatment. Both studies also showed a statistically significant reduction fiom baseline
`to endpoint (Week 12) in the number of micturitions per 24 hours for the 4 and 8 mg fesoterodine fumarate
`doses compared to placebo treatment. Improvement in the number of incontinence episodes (-
`was seen as early as 2 weeks following the start of fesoterodine fumarate treatment, although
`the improvements at Week 2 for the 4 mg (starting) dose were statistically better than placebo for the urge
`incontinence endpoint only.
`
`For the key secondary endpoint of voided volume per micturition, one study showed significant increases
`for both daily doses of fesoterodine fumarate compared to placebo treatment. In the second study,
`significant improvement in voided volume was observed for the 8 mg daily dose but not for the 4 mg daily
`dose.
`
`Safefl
`A total of 2288 patients with overactive bladder received fesoterodine fumarate in phase 2 and 3 clinical
`studies. Of these, 782, 785, and 222 patients received fesoterodine fumarate doses of 4 mg, 8 mg, or 12 mg
`respectively, in Phase 2 and 3 trials with treatment periods of 8 to 12 weeks. Most of these patients
`(approximately 80% in each group) received > 10 weeks of exposure. Longer exposures to fesoterodine
`fiimarate were observed in 858 patients for Z 6 months and in 570 patients for Z 12 months. The safety
`profile for fesoterodine fumarate derived from these 8- and 12-week, randomized, placebo-controlled
`studies and their 1-year open-label extension periods in patients with overactive bladder is consistent with
`
`

`

`that of other anti-muscarinics; in fact, fesoterodine fumarate produces the same active metabolite as does
`tolterodine, a drug already marketed for this use. The most common adverse events reported were dry
`mouth, constipation and urinary retention. These events were generally mild to moderate in intensity. The
`incidence of dry mouth was highest in those taking 8 mg daily (3 5%) as compared to 4 mg daily (19%) or
`placebo treatment (7%). As with other anti-muscarinics, use of fesoterodine fumarate is contraindicated in
`patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma.
`
`A randomized, double-blind, placebo- and positive-controlled study designed to evaluate the risk of QT
`prolongation at therapeutic and supratherapeutic doses of fesoterodine fumarate (4 and 24 mg daily doses)
`did not demonstrate abnormalities in cardiac repolarization related to fesoterodine fumarate use.
`
`No evidence of drug-related carcinogenicity was found in 24-month studies of oral administration to mice
`and rats. Fesoterodine fumarate was not mutagenic or genotoxic in vitro or in viva.
`
`Fesoterodine fumarate had no effects on fertility and produced no frank teratogenic effects in mice given
`15 mg/kg/day, a dose which produced exposures about equal to the expected clinical exposure. At a dose
`of 75 mg/kg/day (producing exposures 6-30 times the expected clinical exposure of an 8 mg daily dose),
`female mice exposed during the period of organogenesis demonstrated an increased incidence of pre- and
`post-implantation fetal loss, including resorptions; fetuses with clefi palate were also noted. These findings
`are sometimes observed with maternal stress and have been seen with other anti-muscarinics. In a
`
`multigenerational study in femalemice exposed from implantation through weaning, there were no
`occurrences of cleft palate. Following oral administration to female rabbits, post-implantation loss, early
`resorptions, and incomplete ossification of the stemebrae (retardation of bone development) were also
`noted. There have been no adequate and well-controlled studies of fesoterodine fumarate conducted in
`pregnant women. A search of FDA’s postmarketing adverse event reporting system (AERS) database
`revealed no cases of human teratogenicity in association with use of a similar product, tolterodine. DRUP
`has proposed, and I concur, with a Pregnancy Category C, i.e., that this product should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Pharmacokinetic Considerations
`
`Following oral, administration, fesoterodine fumarate is rapidly and extensively hydrolyzed to its active
`metabolite. The active metabolite is further metabolized in the liver with involvement of CYP2D6 and
`
`CYP3A4, with the CYP2D6 pathway being the major pathway. Exposure to the active metabolite is
`doubled in poor metabolizers of CYP2D6 as compared to extensive metabolizers. Poor metabolizers of
`CYP2D6 were also more likely than extensive metabolizers to experience anti-muscarinic adverse events
`(e.g., dry mouth), particularly at the 8 mg daily dose, however, no dosing adjustments are recommended
`based solely on intrinsic CYP2D6 metabolizer status. Co-administration of ketoconazole, a potent inhibitor
`of CYP3A4, with fesoterodine fumarate also increased exposure to the active metabolite two-fold; dry
`mouth occurred in up to 43% of patients co-administered fesoterodine fumarate 8 mg daily and CYP3A4
`inhibitors. Exposure was calculated as being approximately 4- to 5-fold higher in CYP2D6 poor
`metabolizers taking ketoconazole as compared to CYP2D6 extensive metabolizers not taking ketoconazole.
`Therefore, doses of fesoterodine fumarate greater than 4 mg are not recommended in patients taking potent
`CYP3A4 inhibitors.
`
`In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are
`1.4 and 2.1-fold higher compared to healthy subjects. No dose adjustment is recommended for patients
`with mild to moderate hepatic insufficiency. Patients with severe hepatic impairment have not been
`studied; fesoterodine fumarate is not recommended for use in these patients. ‘
`
`In patients with mild to moderate renal insufficiency (creatinine clearance of 30—80 mL/min), Cmax and
`AUC of the active metabolite are 1.5 and 1.8-fold higher compared to healthy subjects. In patients with
`severe renal insufficiency (creatinine clearance of < 30 mL/min), Cmax and AUC are 2.0 and 23-fold higher
`compared to healthy subjects. No dose adjustment is recommended for patients with mild or moderate
`renal insufficiency. Doses of fesoterodine fumarate greater than 4 mg are not recommended in patients
`with severe renal insufficiency.
`
`

`

`Tradename Review
`
`The tradename a”... is acceptable.
`
`M4)
`
`Phase 4 Studies
`
`.
`
`No Phase 4 study commitments are requested at this time. Studies in pediatric patients will be waived for
`patients aged ‘Nyears and deferred for patients aged\\-16 years.
`
`Julie Beitz, MD
`Director,
`Office of Drug Evaluation 111
`CDER, FDA
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Julie Beitz
`
`1/22/2007 03:47:54 PM
`DIRECTOR
`'
`
`