FESOTERODINE FUMARATE

Transcription

1 FESOTERODINE FUMARATE TOVIAZ TABLET 1. 0 THERAPEUTIC CATEGORY Over-active Bladder Antimuscarinic Agent DESCRIPTION Fesoterodine fumarate (Toviaz) contains fesoterodine fumarate and is an extendedrelease tablet. Fesoterodine is rapidly de-esterified to its active metabolite, (R)-2-(3- diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist. Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3- diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C 30 H 41 NO 7 and its molecular weight is The structural formula is: The asterisk (*) indicates the chiral carbon. Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Page 1

2 3. 0 FORMULATION Fesoterodine fumarate (Toviaz) 4 mg tablet. Each extended-release tablet contains 4 mg of fesoterodine fumarate. Fesoterodine fumarate (Toviaz) 8 mg tablet. Each extended-release tablet contains 8 mg of fesoterodine fumarate. 4.0 CLINICAL PARTICULARS 4.1 Therapeutic indications Fesoterodine fumarate (Toviaz) is indicated for the treatment of overactive bladder with symptoms of urinary urgency, frequency and/or urge incontinence Dosage and Method of Administration General Fesoterodine fumarate (Toviaz) extended-release tablets can be taken with or without food and must be swallowed whole. 2 Adults (including the Elderly) The recommended starting dose of fesoterodine fumarate (Toviaz) is 4 mg once daily. The dose may be increased to 8 mg once daily based upon individual response and tolerability. Use in Children The safety and efficacy of fesoterodine fumarate (Toviaz) in pediatric populations have not been established. (see Section Pharmacokinetic Properties, Pharmacokinetics in Special Patient Groups) Use in Impaired Renal Function Doses of fesoterodine fumarate (Toviaz) greater than 4 mg are not recommended in patients with severe renal insufficiency. 3 (see Section Special Warnings and Precautions for Use, and Section 5.2 -Pharmacokinetic Properties, Pharmacokinetics in Special Patient Groups) Use in Impaired Hepatic Function Fesoterodine fumarate (Toviaz) is not recommended for use in patients with severe hepatic impairment. 4 (see Section 4.4 Special Warnings and Precautions for Use, and Section Pharmacokinetic Properties, Pharmacokinetics in Special Patient Groups) Use with Potent CYP3A4 Inhibitors Patients taking potent CYP3A4 inhibitors, such as ketoconazole, should not exceed a total daily dose of 4 mg. 5,6 (see Section Special Warnings and Page 2

3 Precautions for Use, and Section Interaction with Other Medicinal Products and Other Forms of Interaction) 4.3 Contraindications 7 Fesoterodine fumarate (Toviaz) is contraindicated in patients with: - Known hypersensitivity to fesoterodine - Urinary retention - Uncontrolled narrow angle glaucoma 4.4 Special warnings and precautions for use 7,8 Agioedema has been reported with fesoterodine (Toviaz) and has occurred after the first dose in some cases. If angioedema occurs, fesoterodine should be discontinued and appropriate therapy should be promptly provided. Fesoterodine fumarate (Toviaz) should be used with caution in the following patients: - At risk of urinary retention - At risk of decreased gastrointestinal motility - With Controlled narrow angle glaucoma - With Myasthenia gravis - With impaired renal function (see Section 4.2 Dosage and Method of Administration, Use in Impaired Renal Function, and Section 5.2 Pharmacokinetics in Special Patient Groups). - With impaired hepatic function (see Section 4.2 Dosage and Method of Administration, Use in Impaired Hepatic Function and Section 5.2 Pharmacokinetics in Special Patient Groups). - Patients on concomitant potent CYP3A4 inhibitors, such as ketoconazole (see Section 4.2 Dosage and Method of Administration, Use with Potent CYP3A4 Inhibitors, and Section 4.5 Interactions with Other Medicinal Products and Other Forms of Interaction). 4.5 Interaction with other medicinal products and other forms of interaction In vitro studies: Drugs Metabolized by Cytochrome P450 At therapeutic concentrations, the active metabolite of fesoterodine fumarate (Toviaz) does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, 9,10 or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 in vitro. 11 In vivo studies: CYP3A4 Inhibitors Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg twice a day for 5 days, C max and AUC of the Page 3

4 active metabolite of fesoterodine fumarate (Toviaz) increased 2.0- and 2.3-fold, respectively, after oral administration of fesoterodine fumarate (Toviaz) 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, C max and AUC of the active metabolite of fesoterodine increased 2.1- and 2.5-fold, respectively, following co-administration of ketoconazole 200 mg twice a day for 5 days. 5 In a separate study coadministering fesoterodine fumarate (Toviaz) with ketoconazole 200 mg once a day for 5 days, the C max and AUC values of the active metabolite of fesoterodine fumarate (Toviaz) were increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers. 6 Therefore, doses of fesoterodine fumarate (Toviaz) greater than 4mg are not recommended in patients taking potent CYP3A4 inhibitors such as ketoconazole, itraconazole, miconazole and clarithromycin (see Section Dosage and Method of Administration and Section Special Warnings and Precautions for Use). There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. Following blockade of CYP3A4 by coadministration of the moderate CPY3A4 inhibitor fluconazole 200 mg twice a day for 2 days, C max and AUC of the active metabolite of fesoterodine increased approximately 19% and 27%, respectively. 42 No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). The effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined; it is not expected to be in excess of the effect of moderate inhibitors. CYP3A4 Inducers Following induction of CYP3A4 by rifampicin 600 mg once a day, C max and AUC of the active metabolite of fesoterodine fumarate (Toviaz) decreased by approximately 70% and 75%, respectively after oral administration of fesoterodine fumarate (Toviaz) 8 mg. The terminal half-life of the active metabolite was not changed. 12 Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments are recommended in the presence of CYP3A4 inducers. CYP2D6 Inhibitors The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C max and AUC of the active metabolite are increased 1.7- and 2-fold, respectively. 13 No dosing adjustments are recommended in the presence of CYP2D6 inhibitors. Oral Contraceptives Page 4

5 In the presence of fesoterodine fumarate (Toviaz), there are no changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel. 14 Warfarin A clinical study has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity of warfarin. 43 Drug-Laboratory Test Interactions Interactions between fesoterodine fumarate (Toviaz) and laboratory tests have not been studied. 4.6 Pregnancy and lactation Pregnancy There are no adequate data from the use of fesoterodine fumarate (Toviaz) in pregnant women. The potential risk for humans is unknown. Therefore, fesoterodine fumarate (Toviaz) should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Lactation It is not known whether fesoterodine fumarate (Toviaz) is excreted into human milk; therefore, breast-feeding is not recommended during treatment with fesoterodine fumarate (Toviaz). 4.7 Effects on ability to drive and use machines The ability to drive and use machinery may be negatively affected. Patients should be advised to exercise caution Undesirable effects Due to the pharmacological properties of fesoterodine fumarate (Toviaz), treatment may cause mild to moderate antimuscarinic effects like dry mouth, constipation, dry eyes, and dyspepsia. Table 1: Treatment emergent adverse reactions from pooled 4 mg and 8 mg, placebo-controlled clinical trials with an incidence exceeding the placebo rate and reported by 1% of patients 16 System organ class/preferred term Fesoterodine Fumarate Pooled N=1567 n (%) Placebo N=780 n (%) Eye disorders Dry eyes 32 (2.0) 1 (0.1) Page 5

6 Gastrointestinal disorders Dry mouth 451 (28.8) 66 (8.5) Constipation 67 (4.3) 16 (2.1) Dyspepsia 26 (1.7) 2 (0.3) Abdominal pain 20 (1.3) 7 (0.9) Diarrhoea 16 (1.0) 5 (0.6) Renal and urinary disorders Dysuria 25 (1.6) 1 (0.1) Respiratory Dry throat 24 (1.5) 3 (0.4) In clinical trials of fesoterodine fumarate (Toviaz), cases of markedly elevated liver enzymes (ALT increased, GGT increased) were reported with the occurrence frequency no different from the placebo group. 15 The relation to fesoterodine fumarate (Toviaz) treatment is unclear. The following adverse events were reported during POST-MARKETING SURVEILLANCE: Eye disorders: Vision blurred 45 Cardiac disorders: Palpitations 45 Skin and subcutaneous tissue disorders: Angioedema 45, urticaria, pruritus Renal and urinary disorders: Urinary retention Overdose Overdosage with fesoterodine fumarate (Toviaz) can result in severe antimuscarinic effects and should be treated accordingly PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Fesoterodine is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolyzed by non-specific esterases to the 5- hydroxymethyl derivative, 17 its primary active metabolite, which is the active pharmacological principle of fesoterodine. 18 Page 6

7 The efficacy of fixed doses of fesoterodine 4 mg and 8 mg was evaluated in two Phase 3 randomized, double-blind, placebo-controlled, 12-week studies. Female (79%) and male (21%) patients with a mean age of 58 years (range years) were included. A total of 33% of patients were 65 years of age and 11% were 75 years of age. 1 Fesoterodine treated patients had statistically significant mean reductions in the number of micturitions per 24 hours and in the number of urge incontinence episodes per 24 hours at the end of treatment compared with placebo treated patients. Likewise, the response rate (% of patients reporting that their condition has been greatly improved or improved using a 4-point Treatment Benefit Scale) was significantly greater with fesoterodine compared with placebo. Furthermore, fesoterodine improved the mean change in the voided volume per micturition, and the mean change in the number of continent days per week (see Table 2). 1 Table 2: Mean Changes from Baseline to End of Treatment for Primary and Selected Secondary Endpoints 1 Parameter Study 1 Study 2 Placebo Feso 4 mg Feso 8 mg Tolterodine ER 4 mg Placebo Feso 4 mg Feso 8 mg Number of micturitions per 24 hours # N=279 N=265 N=276 N=283 N=266 N=267 N=267 Page 7

8 Study 1 Study 2 Baseline Parameter Change from Baseline p-value - <0.001 < <0.001 Responder rate (treatment response) # N=279 N=265 N=276 N=283 N=266 N=267 N=267 Responder 53.4% 74.7% 79.0% 72.4% 45.1% 63.7% 74.2% rate p-value - <0.001 < <0.001 <0.001 Number of urge incontinence episodes per 24 hours N=211 N=199 N=223 N=223 N=205 N=228 N=218 Baseline Change from Baseline p-value < <0.001 Number of continent days per week N=211 N=199 N=223 N=223 N=205 N=228 N=218 Baseline Change from Baseline p-value < <0.001 <0.001 Voided volume per micturition (ml) N=279 N=265 N=276 N=283 N=266 N=267 N=267 Baseline Change from Baseline p-value - <0.001 < <0.001 # primary end points; Feso=fesoterodine Cardiac electrophysiology: The effect of fesoterodine 4 mg and 28 mg on the QT interval was thoroughly evaluated in a double-blind, randomised, placeboand positive-controlled (moxifloxacin 400 mg) parallel group study with oncedaily treatment over a period of 3 days in 261 male and female subjects aged 45 to 65 years. Change from baseline in QTc based on the Fridericia correction method did not show any differences between fesoterodine 4 mg and 28 mg treatment and the placebo group Pharmacokinetic properties Absorption After oral administration, fesoterodine was well-absorbed and was not detected in plasma due to rapid and extensive hydrolysis by non-specific esterases. 20 Bioavailability of the active metabolite is 52%. 21 After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. 13,22 Maximum plasma levels are reached after approximately 5 hours. 13 Therapeutic plasma levels are achieved after the first administration of fesoterodine. No accumulation occurs after multiple-dose administration. 22 Page 8

9 Distribution Plasma protein binding of the active metabolite is low with approximately 50% bound to albumin and alpha-1-acid glycoprotein. 3,23 The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 l. 21 Metabolism After oral administration, fesoterodine is rapidly and extensively hydrolysed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-n-desisopropyl, and N-desisopropyl metabolite with involvement of CYP2D6 and CYP3A4. 24 None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine. 18 Mean Cmax and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolizers as compared with extensive metabolizers. 24 Elimination Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-n-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in feces. 21 The terminal half-life of the active metabolite following oral administration is approximately 7 hours. 24 Pharmacokinetics in Special Patient Groups: Age and gender The pharmacokinetics of fesoterodine is not significantly influenced by age and gender. No dose adjustment is recommended for the elderly. 25 Paediatric patients The pharmacokinetics of fesoterodine has not been evaluated in pediatric patients. Renal impairment In patients with mild or moderate renal impairment (CrCl ml/min), Cmax and AUC of the active metabolite increased up to 1.5 and 1.8-fold, respectively, as compared with healthy subjects. In patients with severe renal impairment (CrCL < 30 ml/min), Cmax and AUC are increased 2.0 and 2.3-fold, respectively, as compared with healthy subjects. 3 (see Section 4.2 Dosage and Method of Administration, and Section 4.4 Special Warnings and Precautions for Use) Hepatic impairment In patients with moderate hepatic impairment (Child Pugh B), Cmax and AUC of the active metabolite increased 1.4 and 2.1-fold, respectively, as compared Page 9

10 with healthy subjects. 4 Pharmacokinetics of fesoterodine in patients with severe hepatic impairment have not been studied. (see Section Dosageand method of administration, and Section 4.4 Special warnings and precautions for use) 5.3 Preclinical safety data In non-clinical safety pharmacology, general toxicity, genotoxicity and carcinogenicity studies no clinically relevant effects have been observed, except those related to the pharmacological effect of the active substance. Reproduction studies have shown minor embryotoxicity at doses close to maternally toxic doses (increased number of resorptions, pre-implantation and post-implantation losses). 6.0 PHARMACEUTICAL PARTICULARS 6.1 Shelf life Please see outer package for the expiry date of the product. 6.2 Storage Store at temperature not exceeding 25ºC. Protect from moisture. 6.3 Availability Fesoterodine fumarate (Toviaz) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated and engraved with FS on one side. Available as blister packs of 7 s in boxes of 28 s. Fesoterodine fumarate (Toviaz) extended-release tablets 8 mg are blue, oval, biconvex, film-coated and engraved with FT on one side. Available as blister packs of 7 s in boxes of 28 s. CAUTION: Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription. Keep out of reach of children. Manufactured by: Pfizer Manufacturing Deutschland GmbH Heinrich Mack Str. 35, D Illertisen, Germany Page 10

11 Imported by: Pfizer, Inc. 23/F Ayala Life-FGU Center 6811 Ayala Ave., Makati City Philippines Under authority of PFIZER, INC., New York, N.Y., U.S.A. Revision No.: 4 Revision Date: 23 May 2011 Reference Document: CDS ver 8 Reference Date: 19 May 2011 REFERENCES: 1 Data on File. Module 2.7.3, Summary of Clinical Efficacy. 03 Feb Data on File. CSR SP687. Randomized, non blind, two-fold crossover trial to investigate the influence of food on the pharmacokinetics of fesoterodine after single oral dose administration of 8 mg fesoterodine in 16 healthy, male subjects. 10 Jan Data on File. CSR SP568. Investigation of pharmacokinetics, safety and tolerability of 4 mg fesoterodine in male and female patients with renal impairment and in male and female healthy subjects following singledose administration. 30 Mar Data on File. CSR SP569. Open, group-comparison, single dose trial to evaluate the influence of liver impairment on the pharmacokinetics, safety and tolerability of 8 mg fesoterodine sustained-release oral administration in healthy and hepatic impaired male Caucasian subjects. 07 Apr Page 11

12 5 Data on File. CSR SP684. Randomized, non-blind, two-fold crossover study to investigate the influence of a pre- and co-administration of ketoconazole on the safety, tolerability and pharmacokinetics of a single oral dose administration of 8 mg fesoterodine in 18 healthy male subjects. 18 Feb Data on File. CSR SP564. Randomized, non-blind, two-fold crossover trial to investigate the influence of a pre- and co-administration of ketoconazole on the safety, tolerability and pharmacokinetics of a single oral dose administration of 8 mg fesoterodine in 18 healthy male subjects. 11 Nov Data on File. Investigator s Brochure, Fesoterodine, 19 Nov United States Package Insert, TOVIAZ (fesoterodine fumarate), 26 Nov Data on File. Report BA Interaction of the compounds SPM 8272, SPM 7605, SPM 5509, SPM 6923 and SPM 9078 with the cytochrome P450 isoenzymes 3A4 and 2D6, Schwarz, 23 Nov Data on File. Report BA Interaction of the compounds SPM 8272, SPM 7605, SPM 5509, SPM 6923 and SPM 9078 with the cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4, Schwarz, 30 Jul 2002 (Report Amendment No. 1). 11 Data on File. Report 692. Determinatin of the cytochrome P450 induction potential of fesoterodine in human hepatocytes, Schwarz, 13 Dec Data on File. CSR SP683. Non-blind, two period sequential trial to investigate the influence of a pre- and co-administration of rifampicin on the safety, tolerability and pharmacokinetics of a single oral dose administration of 8 mg fesoterodine in 12 healthy male subjects. 23 Mar Data on File. CSR SP565. Pharmacokinetics, dose proportionality and food effect of SPM 8272 after single oral dosing of sustained-release SPM 8272 in healthy volunteers with different status of CYP2D6. 28 Aug Data on File. CSR SP677. Randomized, double-blind, placebo-controlled, crossover, multiple dose trial to investigate the influence of 8 mg fesoterodine sustained-release for 14 days on the suppression of ovulation by oral hormonal contraception in healthy female subjects. 20 Nov Data on File. Module 2.7.4, Summary of Clinical Safety. 10 Feb Page 12

13 16 Day 120 LoQ. Table 3: TEAEs Proposed for EU Labeling, Population Pool S1. 12 Sep Data on File. Report 02/SP/04. Interaction of SPM 5509, SPM 7605, SPM 8272, and SPM 9078 with cloned human muscarinic acetylcholine receptors: Determination of agonistic and antagonistic activities, Biofrontera, 16 Dec Data on File. Report In-vitro pharmacology study of SPM 8272, SPM 7605, SPM 9078, SPM 5509, SPM 6923 and SPM 7833, CEREP, 18 Mar Data on File. CSR SP686. A double-blind, single-site, randomized, placebo- and positive-controlled, parallel-design trial of the electrocardiographic effects of 4 mg and 28 mg per day of fesoterodine administered orally to steady-state to healthy male and female subjects: a thorough QT trial. 06 May Data on File. CSR SP560. Single dose tolerance study with ascending doses of SPM 8272 (Project SPM 907) in healthy male Caucasian volunteers. 28 Mar Data on File. CSR SP567. Sequential, randomized, non-blinded trial to investigate the absolute bioavailability of fesoterodine after oral administration of fesoterodine and i.v. administration of fesoterodine and SPM 7605 to healthy male subjects. 05 Apr Data on File. CSR SP566. A phase I, randomized, double-blind, placebocontrolled maximum tolerated dose trial to determine the tolerability, pharmacokinetics and pharmacodynamics of sustained-release SMP 8272 in healthy male subjects. 30 Oct Data on File. Report BA Plasma protein-binding of SPM 8272 and SPM 7605 in human, dog, monkey, mouse, rabbit and rat plasma samples, Schwarz Biosciences, 19 Mar Data on File. Module 2.7.2, Summary of Clinical Pharmacology. 06 Jan Data on File. CSR SP570. Randomized, double-blind, placebo-controlled, parallel group trial to evaluate the safety, tolerability and pharmacokinetics of single dose oral treatment of 8 mg SPM 8272 in healthy young male, elderly male and elderly female subjects. 19 Nov Page 13

14 26 Data on File. LPT 12359/99. Mutagenicity study of SPM 8272 in the Salmonella typhimurium and Eschericia coli reverse mutation assay (in vitro), LPT. 28 Jan Data on File. LPT 12360/99. In vitro assessment of the clastogenic activity of SPM 8272 in V79 cells, LPT. 07 Aug Data on File. LPT 12361/99. In vitro assessment of the clastogenic activity of SPM 8272 in cultured human peripheral lymphocytes, LPT. 07 Aug Data on File. LPT 12362/99. Micronucleus test of SPM 8272 in bone marrow cells of the NMRI Mouse by oral administration, LPT. 20 Apr Data on File. LPT 12981/00. Examination of the influence of SPM 8272 on the fertility and early embryonic development to implantation of CD-1 mice by oral administration to the animals of the F 0 -generation, 15 Jan Data on File. LPT 12982/00. Dose-range finding study for a study of embryo-fetal development in CD-1 mice with SPM 8272 by oral administration, LPT. 12 Dec Data on File. LPT 13178/00. Study of embryo-fetal development in rabbits with SPM 8272 by oral administration, LPT. 15 Jan Data on File. LPT 13249/00. Examination of SPM 8272 for effects on the pre- and postnatal development (including maternal function) following oral administration to the dams of CD-1 mice of the F0-generation, LPT, 09 Jul Data on File. LPT 13347/00. Study of embryo-fetal development in CD-1 mice with SPM 8272 by oral administration, LPT, 15 Aug Data on File. LPT 13347/00. Study of embryo-fetal development in CD-1 mice with SPM 8272 by oral administration, LPT (Report Amendment No. 1), 15 Aug Data on File. LPT 13399/ week carcinogenicity study of SPM 8272 by oral administration to CD-1 mice, LPT, 11 Jan Data on File. LPT 13400/ week carcinogenicity study of SPM 8272 by oral administration to CD rats, LPT, 07 Jun Data on File. LPT 13683/ week supplementary toxicity study of SPM 8272 by oral administration to CD-1 mice, 21 Dec Page 14

15 39 Data on File. LPT 15408/02. Study of embryo-fetal development in rabbits with SPM 8272 by subcutaneous administration, LPT, 25 Nov Data on File. LPT 15411/02. Mutagenicity study of SPM 8272 in the Salmonella typhimurium reverse mutation assay (in vitro) employing mouse S9 mix, LPT, 12 Dec Data on File. LPT 15412/02. In vitro assessment of the clastogenic activity of SPM 8272 in cultured human peripheral lymphocytes employing mouse S9 mix, LPT, 23 Apr Data on File. CSR A An open-label, randomized, 2-way crossover study to evaluate the effect of fluconazole, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetics of fesoterodine in healthy subjects. 09 Oct Data on File. CSR A An open-label, randomized, 2-way crossover study to evaluate the steady-state effect of fesoterodine on the pharmacokinetics and pharmacodynamics of a single supratherapeutic dose of warfarin in healthy subjects. 11 Dec Data on File. Fesoterodine Periodic Safety Update Report (20 October 2008 through 19 April 2009). 45 Data on File. PSUR 5 Type II Variation EMEA/H/C/723/II/29. Effect of Fluconazole on Fesoterodine Study Results, Urinary Tract Infection Frequency in Clinical Studies and Review of Confusional State, Palpitations, Blurred Vision, Angioedema. Effective date 21 July 2010 Page 15