HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Detrol”
`LA safely and effectively. See full prescribing information for Detrol LA.
`
`Detroit“ LA (tolterodine ta11'rate extended release capsules)
`For oral administration
`Initial U.S. Approval: December 2000
`
`0
`
`-——-—-—---—--—-——-—-RECENT MAJOR CHANGES--—---—--—----—
`Contraindications: Hypersensitivity to fesoterodine fumarate (4)
`097201 1
`Warnings and Precautions: Angioedema (5.1)
`09/201 1
`Warnings and Precautions: Central Nervous System Effects (5.5)
`08/2012
`-———————————lNDICATIONS AND USAGE
`DETROL LA is an antimuscarinic indicated for the treatment of overactive
`bladder with symptoms of urge urinary incontinence, urgency, and frequency.
`(1)
`———————--DOSAGE AND ADMINISTRATION——————————
`4 mg capsules taken orally once daily with water and swallowed whole.
`(2.1)
`2 mg capsules taken orally once daily with water and swallowed whole
`in the presence of:
`0
`mild to moderate hepatic impairment (Child-Pugh class A or
`B) (2-2)
`severe renal impairment [Creatinine Clearance (CCr) 10-30
`mLfmin] (2.2)
`drugs that are potent CYP3A4 inhibitors. (2.2)
`0
`DETROL LA is not recommended for use in patients with CCr
`<10 mL/min. (2.2)
`DETROL LA is not recommended for use in patients with severe hepatic
`impairment (Child-Pugh Class C). (2.2)
`-------------DOSAGE FORMS AND STRENGTHS------------
`Capsules: 2 mg and 4 mg (3)
`------------------------ CONTRAINDICATIONS------------------------
`DETROL LA is contraindicated in patients with urinary retention, gastric
`retention, or uncontrolled narrow-angle glaucoma. DETROL LA is also
`contraindicated in patients with known hypersensitivity to the drug or its
`ingredients. or to fesoterodine fumarate extended-release tablets which. like
`DETROL LA. are metabolized to 5-hydroxymethyl toltcrodinc. (4)
`--------------VVARNINGS AND PRECAUTIONS--------------
`I
`Anaphylaxis and angioedema requiring hospitalization and emergency
`medical treatment have occurred with the first or subsequent doses of
`DETROL LA. (5.1)
`Urinary Retention: use caution in patients with clinically significant
`bladder outflow obstruction because of the risk of urinary retention.
`(5.2)
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`Gastrointestinal Disorders: use caution in patients with gastrointestinal
`obstructive disorders or decreased gastrointestinal motility because of
`the risk of gastric retention. (5.3)
`Controlled Narrow-Angle Glaucoma: use caution in patients being
`treated for narrow-angle glaucoma. (5.4)
`Central Nervous System Effects: Somnolcnce has been reported with
`Detrol LA. Advise patients not to drive or operate heavy machinery until
`they know how Detrol LA affects them (5.5).
`Myasthenia Gravis: use caution in patients with myasthenia gravis. (5.8)
`QT Prolongation: consider observations from the thorough QT study in
`clinical decisions to prescribe DETROL LA to patients with a known
`history of QT prolongation or to patients who are taking Class 1A (e.g..
`quinidine, procainamide) or Class III (e.g.. arniodarone. sotalol)
`antiarrhythmic medications. (5.9)
`————-—————:ADVERSE REACTIONS——-—--————--—
`The most common adverse reactions (incidence 34% and >placebo) were dry
`mouth, headache, constipation, and abdominal pain. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at
`1-800-433-1985 or FDA at I-800-FDA-I088 or www.[cla.gov/medwalcls.
`—--—::—DRUG INTERACTIONS————————
`Potent CYP3A4 Inhibitors: Coadministration may increase systemic
`exposure to DETROL LA. Reduce DETROL LA dose to 2 mg once
`daily. (7.2)
`Other Anticholinergics (antimuscarinics): Concomitant use with other
`anticholinergic agents may increase the frequency andfor severity of dry
`mouth. constipation, blurred vision, and other anticholinergic
`phannacologieal effects. (7.6)
`—-—-———--—-USE IN SPECIFIC POPULATIONS--——---—:-—-—-—-
`Pregnancy and Lar.'tcm'on.' DETROL LA should be used during
`pregnancy only ifthe potential benefit for the motherjustifies the
`potential risk to the fetus. DETROL LA should not be administered
`during nursing. (8.1. 8.3)
`Pediatric Use: Efficacy in the pediatric population has not been
`demonstrated. Safety information from a study ofa total of7 10 pediatric
`patients (486 on DETROL LA, 224 on placebo) is available. (8.4)
`Rena! 1mpm'rmeri.'.' DETROL LA is not recommended for use in patients
`with (‘Cr <10 mL/min. Dose adjustment in severe renal impairment
`(CCr: I0-30 mL!min). (8.6)
`Hepatic impcu'rrm=r1I.' Not recommended for use in severe hepatic
`impairment (Child Pugh Class C). Dose adjustment in mild to moderate
`hepatic impairment (Child Pugh Class A, B). (8.7)
`See I7 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 08/2012
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`I
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Dosage Adjustment in Specific Populations
`2.3 Dosage Adjustment in Presence of Concomitant Drugs
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Angioedema
`5.2 Urinary Retention
`5.3 Gastrointestinal Disorders
`5.4 Controlled Narrow—AngIc Glaucoma
`5.5 Central Nervous System Effects
`5.6 Hepatic Impairment
`5.7 Renal Impairment
`5.8 Myasthenia Gravis
`5.9 Use in Patients with Congenital or Acquired QT Prolongation
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Post-marketing Experience
`7 DRUG INTERACTIONS
`7.1
`Potent CYPZDG Inhibitors
`7.2 Potent CYP3A4 Inhibitors
`7.3 Other Interactions
`7.4 Other Drugs Metabolized by Cytochrome P450 Isoenzymes
`
`Reference ID: 3168106
`
`7.5 Drug-Laboratory-Test Interactions
`7.6 Other Anticholinergics
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Gender
`8.9 Race
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`I3 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis. Impainnent of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIEDISTORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Information for Patients
`17.2
`FDA-Approved Patient Labeling
`‘Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0001
`
`

`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`DETROL LA Capsules is indicated for the treatment of overactive bladder with symptoms of urge urinary
`incontinence, urgency, and frequency [see CLINICAL STUDIES (14)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Dosing Information
`
`The recommended dose of DETROL LA Capsules is 4 mg once daily with water and swallowed whole. The
`dose may be lowered to 2 mg daily based on individual response and tolerability; however, limited efficacy data
`are available for DETROL LA 2 mg [See CLINICAL STUDIES (}'4)].
`
`2.2
`
`Dosage Adjustment in Specific Populations
`
`For patients with mild to moderate hepatic impairment (Child—Pugh Class A or B) or severe renal impairment
`(CCr 10-30 mL/min), the recommended dose of DETROL LA is 2 mg once daily. DETROL LA is not
`recommended for use in patients with severe hepatic impairment (Child—Pugh Class C). Patients with
`CCr<l 0 mL/min have not been studied and use of DETROL LA in this population is not recommended [see
`WARNINGS AND PRECAUTIONS (5.6) and USE INSPECIFIC POPULA TIONS (8.6, 8. 7)].
`
`2.3
`
`Dosage Adjustment in Presence of Concomitant Drugs
`
`For patients who are taking drugs that are potent inhibitors of CYP3A4 [e.g., ketoconazole, clarithromycin,
`ritonavir], the recommended dose of DETROL LA is 2 mg once daily [see DRUG INTERACTIONS (7.2)].
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`The 2 mg capsules are blue—green with symbol and 2 printed in white ink.
`
`The 4 mg capsules are blue with symbol and 4 printed in white ink.
`
`4
`
`CONTRAINDICATIONS
`
`DETROL LA is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-
`angle glaucoma. DETROL LA is also contraindicated in patients with known hypersensitivity to the drug or its
`ingredients, or to fesoterodine fumarate extended-release tablets which, like DETROL LA, are metabolized to
`5-hydroxymethyl tolterodine [See WARNINGS AND PRECAUTIONS (5.2) (5.3), (5. 4)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Angioedema
`
`Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with
`
`the first or subsequent doses of DETROL LA. In the event of difficulty in breathing, upper airway obstruction,
`or fall in blood pressure, DETROL LA should be discontinued and appropriate therapy promptly provided.
`
`Reference ID: 3168106
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0002
`
`

`
`5.2
`
`Urinary Retention
`
`Administer DETROL LA Capsules with caution to patients with clinically significant bladder outflow
`obstruction because of the risk of urinary retention [see CONTRAINDICA TIONS (4)].
`
`5.3
`
`Gastrointestinal Disorders
`
`Administer DETROL LA with caution in patients with gastrointestinal obstructive disorders because of the risk
`of gastric retention.
`
`DETROL LA, like other antimuscarinic drugs, may decrease gastrointestinal motility and should be used with
`caution in patients with conditions associated with decreased gastrointestinal motility (e.g., intestinal atony) [see
`CONTRAINDICA TIONS (4)].
`
`5.4
`
`Controlled N arrow-Angle Glaucoma
`
`Administer DETROL LA with caution in patients being treated for narrow—angle glaucoma [See
`CONTRAINDICA TIONS (4)].
`
`5.5
`
`Central Nervous System Effects
`
`Detrol LA is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions
`(6.2)] including dizziness and somnolence [see Adverse Reactions (6.1)]. Patients should be monitored for
`signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise
`patients not to drive or operate heavy machinery until the drug’s effects have been determined. If a patient
`experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
`
`5.6
`
`Hepatic Impairment
`
`The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients
`than in the healthy volunteers. For patients with mild to moderate hepatic impairment (Child—Pugh Class A or
`B), the recommended dose for DETROL LA is 2 mg once daily. DETROL LA is not recommended for use in
`patients with severe hepatic impairment (Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION (2.2)
`and USE IN SPECIFIC POPULA TIONS (8. 6)].
`
`5.7
`
`Renal Impairment
`
`Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of
`DETROL LA should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10-
`30 mL/min). Patients with CCr<l0 mL/min have not been studied and use of DETROL LA in this population is
`not recommended [see DOSAGE AND ADMINISTRATION (2.2) and USE IN SPECIFIC POPULA TIONS
`(8. 7)].
`
`5.8 Myasthenia Gravis
`
`Administer DETROL LA with caution in patients with myasthenia gravis, a disease characterized by decreased
`cholinergic activity at the neuromuscular junction.
`
`5.9
`
`Use in Patients with Congenital or Acquired QT Prolongation
`
`3
`
`Reference ID: 3168106
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0003
`
`

`
`In a study of the effect of tolterodine immediate release tablets on the QT interval [see CLINICAL
`PHARIIJACOLOGY (12. 2)], the effect on the QT interval appeared greater for 8 mg/day (two times the
`therapeutic dose) compared to 4 mg/day and was more pronounced in CYPZD6 poor metabolizers (PM) than
`extensive metabolizers (EMS). The effect of tolterodine 8 mg/day was not as large as that observed after four
`days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped.
`
`These observations should be considered in clinical decisions to prescribe DETROL LA to patients with a
`known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or
`Class 111 (eg, amiodarone, sotalol) antiarrhythmic medications. There has been no association of Torsade de
`Pointes in the international post—marketing experience with DETROL or DETROL LA.
`
`6
`
`ADVERSE REACTIONS
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`
`6.]
`
`Clinical Trials Experience
`
`The efficacy and safety of DETROL LA Capsules was evaluated in 1073 patients (537 assigned to DETROL
`LA; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months. These included a
`total of 1012 patients (505 randomized to DETROL LA 4 mg once daily and 507 randomized to placebo)
`enrolled in a randomized, placebo-controlled, double—blind, 12-week clinical efficacy and safety study.
`
`Adverse events were reported in 52% (n=263) of patients receiving DETROL LA and in 49% (n:247) of
`patients receiving placebo. The most common adverse events reported by patients receiving DETROL LA were
`dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse
`event for patients treated with DETROL LA, occurring in 23.4% of patients treated with DETROL LA and
`7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision (accommodation abnormalities),
`
`urinary retention, and dry eyes are expected side effects of antimuscarinic agents. A serious adverse event was
`reported by 1.4% (n=7) of patients receiving DETROL LA and by 3.6% (n=l 8) of patients receiving placebo.
`
`Table 1 lists the adverse events, regardless of causality, that were reported in the randomized, double—blind,
`placebo-controlled 12-week study at an incidence greater than placebo and in greater than or equal to 1% of
`patients treated with DETROL LA 4 mg once daily.
`
`Reference ID: 3168106
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0004
`
`

`
`Table 1. Incidence* (‘’/o) of Adverse Events Exceeding Placebo Rate and Reported in 21% of Patients
`Treated with DETROL LA (4 mg daily) in a 12-week, Phase 3 Clinical Trial
`Body System
`Adverse Event
`% DETROL LA
`% Placebo
`n=505
`n=507
`
`Autonomic Nervous
`General
`
`Central/Peripheral
`Nervous
`
`Gastrointestinal
`
`Vision
`
`Psychiatric
`
`Respiratory
`Urinary
`* in nearest integer.
`
`dry mouth
`headache
`
`fatigue
`dizziness
`
`constipation
`abdominal pain
`dyspepsia
`xerophthalmia
`vision abnormal
`
`somnolence
`anxiety
`sinusitis
`dysuria
`
`23
`6
`
`2
`2
`
`6
`4
`3
`3
`1
`
`3
`1
`2
`1
`
`8
`5
`
`l
`1
`
`4
`2
`1
`2
`0
`
`2
`0
`1
`O
`
`The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment.
`Similar percentages ofpatients treated with DETROL LA or placebo discontinued treatment due to adverse
`events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients
`receiving DETROL LA [n=12 (2.4%) vs. placebo n=6 (1.2%)].
`
`6.2
`
`Post-marketing Experience
`
`The following events have been reported in association with tolterodine use in worldwide post-marketing
`experience:
`
`General: anaphylaxis and angioedema; CardiovaSc'ular.' tachycardia, palpitations, peripheral edema;
`Ga.str01'nte.s‘tinal.' diarrhea; Central/Perzplreral Nervous.’ confusion, disorientation, memory impairment,
`hallucinations.
`
`Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported
`after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.
`
`Because these spontaneously reported events are from the worldwide post—marketing experience, the frequency
`of events and the role of tolterodine in their causation cannot be reliably determined.
`
`7
`
`DRUG INTERACTIONS
`
`7.1
`
`Potent CYPZD6 Inhibitors
`
`Fluoxetine, a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine
`immediate release in CYP2D6 extensive metabolizers, resulting in a 4.8—fold increase in tolterodine AUC.
`There was a 52% decrease in Cnm and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the
`pharmacologically active metabolite of tolterodine [see CLINICAL PHARMACOLOGY (12.1)]. The sums of
`unbound serum concentrations of tolterodine and 5-1-IMT are only 25% higher during the interaction. No dose
`
`Reference ID: 3168106
`
`5
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0005
`
`

`
`adjustment is required when tolterodine and fluoxetine are co—administered [see CLINICAL
`PHARMACOLOGY (12. 3)].
`
`7.2
`
`Potent CYP3A4 Inhibitors
`
`Ketoconazole (200 mg daily), a potent CYP3A4 inhibitor, increased the mean Cm,‘ and AUC of tolterodine by
`2- and 2.5-fold, respectively, in CYP2D6 poor metabolizers.
`
`For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, clarithromycin, or
`ritonavir, the recommended dose of DETROL LA is 2 mg once daily [See DOSAGE AND
`ADMINISTRA TION(2. 2) and CLINICAL PHARMA COLOGY (12. 3)].
`
`7.3
`
`Other Interactions
`
`No clinically relevant interactions have been observed when tolterodine was co—administered with warfarin,
`with a combined oral contraceptive drug containing ethinyl estradiol and levonorgestrel, or with diuretics [see
`CLINICAL PHARMA COLOG Y (1 2. 3)]
`
`7.4
`
`Other Drugs Metabolized by Cytochrome P450 Isoenzymes
`
`In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant
`inhibition of CYP 1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine,
`debrisoquine, S-warfarin, and omeprazole [see CLINICAL PHARMACOLOGY (12. 3)].
`
`7.5
`
`Drug-Laboratory-Test Interactions
`
`Interactions between tolterodine and laboratory tests have not been studied.
`
`7.6
`
`Other Anticholinergics
`
`The concomitant use of DETROL LA with other anticholinergic (antimuscarinic) agents may increase the
`frequency and/or severity of dry mouth, constipation, blurred vision, somnoience, and other anticholinergic
`pharmacological effects.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.]
`
`Pregnancy
`
`Pregnancy Category C.
`
`At approximately 9-12 times the clinical exposure to the pharmacologically active components of DETROL®
`LA, no anomalies or malformations were observed in mice (based on the AUC of tolterodine and its 5—HMT
`metabolite at a dose of 20 mg/kg/day). At 14-18 times the exposure (doses of 30 to 40 mg/kg/day) in mice,
`tolterodine has been shown to be embryolethal and reduce fetal weight, and increase the incidence of fetal
`abnormalities (cleft palate, digital abnormalities, intra—abdominal hemorrhage, and various skeletal
`abnormalities, primarily reduced ossification). Pregnant rabbits treated subcutaneously at about 0.3 - 2.5 times
`the clinical exposure (dose of 0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity. There are no
`studies of tolterodine in pregnant women. Therefore, DETROL LA should be used during pregnancy only if the
`potential benefit for the mother justifies the potential risk to the fetus.
`
`Reference ID: 3168106
`
`6
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0006
`
`

`
`8.3
`
`Nursing Mothers
`
`Tolterodine is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20 mg/kg/day
`during the lactation period had slightly reduced body weight gain. The offspring regained the weight during the
`maturation phase.
`
`It is not known whether tolterodine is excreted in human milk; therefore, DETROL LA should not be
`
`administered during nursing. A decision should be made whether to discontinue nursing or to discontinue
`DETROL LA in nursing mothers.
`
`8.4
`
`Pediatric Use
`
`Efficacy in the pediatric population has not been demonstrated.
`
`The pharmacokinetics of tolterodine extended release capsules have been evaluated in pediatric patients ranging
`in age from 1 1-15 years. The dose—plasma concentration relationship was linear over the range of doses
`assessed. Parent/metabolite ratios differed according to CYPZD6 metabolizer status [see CLINICAL
`PHARMA COLOGY(l2.3)]. CYP2D6 extensive metabolizers had low serum concentrations of tolterodine
`and high concentrations of the active metabolite 5-HMT, while poor metabolizers had high concentrations of
`tolterodine and negligible active metabolite concentrations.
`
`A total of 7'10 pediatric patients (486 on DETROL LA, 224 on placebo) aged 5-10 with urinary frequency and
`urge incontinence were studied in two randomized, placebo—controlled, double-blind, 12-week studies. The
`percentage of patients with urinary tract infections was higher in patients treated with DETROL LA (6.6%)
`compared to patients who received placebo (4.5%). Aggressive, abnormal, and hyperactive behavior and
`attention disorders occurred in 2.9% of children treated with DETROL LA compared to 0.9% of children
`treated with placebo.
`
`8.5
`
`Geriatric Use
`
`No overall differences in safety were observed between the older and younger patients treated with tolterodine.
`
`In multiple—dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum
`Concentrations of tolterodine and of 5-HMT were Similar in healthy elderly volunteers (aged 64 through 80
`years) and healthy young volunteers (aged less than 40 years). In another clinical study, elderly volunteers (aged
`71 through 81 years) were given tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum
`concentrations of tolterodine and 5—HMT in these elderly volunteers were approximately 20% and 50% higher,
`respectively, than concentrations reported in young healthy volunteers. However, no overall differences were
`observed in safety between older and younger patients on tolterodine in the Phase 3, 12-week, controlled
`clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended.
`
`8.6
`
`Renal Impairment
`
`Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In
`a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine and 5—HMT
`levels were approximately 2-3 fold higher in patients with renal impairment than in healthy volunteers.
`Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, N-
`dealkylated tolterodine, and N-dealkylated hydroxy tolterodine) were significantly higher (10-30 fold) in
`renally impaired patients as compared to the healthy volunteers. The recommended dose for patients with severe
`renal impairment (CCr: 10-30 mL/min) is DETROL LA 2 mg daily. Patients with CCr<10 mL/min have not
`7
`
`Reference ID: 3168106
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0007
`
`

`
`been studied and use of DETROL LA in this population is not recommended [see DOSAGE AND
`ADMINISTRATION (2.2) and WARNINGS AND PRECAUTIONS (5. 6)]. DETROL LA has not been studied
`in patients with mild to moderate renal impairment [CCr 30-80 mL/min].
`
`8.7
`
`Hepatic Impairment
`
`Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study of
`tolterodine immediate release conducted in cirrhotic patients (Child—Pugh Class A and B), the elimination half-
`life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young,
`and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine immediate release
`was substantially lower in cirrhotic patients (1.0 :1: 1.7 L/h/kg) than in the healthy volunteers (5.7 d: 3.8 Lfh/kg).
`The recommended dose for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) is
`DETROL LA 2 mg once daily. DETROL LA is not recommended for use in patients with severe hepatic
`impairment (Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION (2.2) and WARNINGS AND
`PRECAUTIONS (5.4)].
`
`8.8
`
`Gender
`
`The pharmacokinetics of tolterodine immediate release and 5-HMT are not influenced by gender. Mean Cm,‘ of
`tolterodine immediate release (1.6 pg/L in males versus 2.2 ug/L in females) and the active 5—HMT (2.2 ug/L in
`males versus 2.5 ug/L in females) are similar in males and females who were administered tolterodine
`immediate release 2 mg. Mean AUC values of tolterodine (6.7 pg-h/L in males versus 7.8 ug-h/L in females)
`and 5—HMT (10 ug-h./L in males versus 1 1 pg-h/L in females) are also similar. The elimination half—life of
`tolterodine immediate release for both males and females is 2.4 hours, and the half—life of 5-HMT is 3.0 hours in
`females and 3.3 hours in males.
`
`8.9
`
`Race
`
`Pharmacokinetic differences due to race have not been established.
`
`10
`
`OVERDOSAGE
`
`Overdosage with DETROL LA Capsules can potentially result in severe central anticholinergic effects and
`should be treated accordingly.
`
`ECG monitoring is recommended in the event of overdosage. In dogs, changes in the QT interval (slight
`prolongation of 10% to 20%) were observed at a suprapharmacologic dose of 4.5 mg/kg, which is about 68
`times higher than the recommended human dose. In clinical trials of normal volunteers and patients, QT interval
`prolongation was observed with tolterodine immediate release at doses up to 8 mg (4 mg bid) and higher doses
`were not evaluated [see WARNINGS AND PRECAUTIONS (5. 9) and CLINICAL PHARMACOLOGY
`(12. 2)].
`
`A 27-month-old child who ingested 5 to 7 tolterodine immediate release 2 mg tablets was treated with a
`suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully
`recovered.
`
`1 1
`
`DESCRIPTION
`
`DETROL LA Capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor
`antagonist. The chemical name of tolterodine tartrate is (R)—N,N—diisopropyl—3—(2—hydroxy—5—methylphenyl)—3—
`8
`
`Reference ID: 3168106
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0008
`
`

`
`phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is C26H37NO-;,. Its
`structure is:
`
`H c
`3
`
`H
`
` on H3c\r,cH.,
`
`N
`
`“H3
`‘T
`CH3
`
`<|;ooH
`"H—DH
`' Ho—¥H
`coon
`
`Tolterodine tartrate is a white, crystalline powder with a molecular weight of 475.6. The pK,, value is 9.87 and
`the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically
`insoluble in toluene. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3.
`
`DETROL LA 4 mg capsule for oral administration contains 4 mg of tolterodine tartrate. Inactive ingredients are
`sucrose, starch, hypromellose, ethylcellulose, medium chain triglycerides, oleic acid, gelatin, and FD&C Blue
`#2.
`
`DETROL LA 2 mg capsule for oral administration contains 2 mg of tolterodine tartrate, and the following
`inactive ingredients: sucrose, starch, hypromellose, ethylcellulose, medium chain triglycerides, oleic acid,
`gelatin, yellow iron oxide, and FD&C Blue #2.
`
`Both the 2 mg and 4 mg capsule strengths are imprinted with a pharmaceutical grade printing ink that contains
`shellac glaze, titanium dioxide, propylene glycol, and simethicone.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Tolterodine acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors. Both
`urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.
`
`After oral administration, tolterodine is metabolized in the liver, resulting in the formation of 5-hydroxymethyl
`tolterodine (5-HMT), the major pharmacologically active metabolite. 5-HMT, which exhibits an antimuscarinic
`activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and 5-
`HMT exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other
`neurotransmitter receptors and other potential cellular targets, such as calcium channels.
`
`12.2
`
`Pharmacodynamics
`
`Tolterodine has a pronounced effect on bladder function. Effects on urodynamic parameters before and l and 5
`hours after a single 6.4 mg dose of tolterodine immediate release were determined in healthy volunteers. The
`main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete
`emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an
`antimuscarinic action on the lower urinary tract.
`
`Cardiac Electrophysiolagy
`The effect of 2 mg BID and 4 mg BID of DETROL immediate release (tolterodine IR) tablets on the QT
`interval was evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg
`QD) study in healthy male (N=25) and female (N=23) volunteers aged 18-55 years. Study subjects
`[approximately equal representation of CYP2D6 extensive metabolizers (EMS) and poor metabolizers (PMs)]
`9
`
`Reference ID: 3168106
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0009
`
`

`
`completed sequential 4-day periods of dosing with moxifloxacin 400 mg QD, tolterodine 2 mg BID, tolterodine
`4 mg BID, and placebo. The 4 mg BID dose of tolterodine IR (two times the highest recommended dose) was
`chosen because this dose results in tolterodine exposure similar to that observed upon coadministration of
`tolterodine 2 mg BID with potent CYP3A4 inhibitors in patients who are CYP2D6 poor metabolizers [see
`DRUG INTERACTIONS (7. 2)]. QT interval was measured over a 12-hour period following dosing, including
`the time of peak plasma concentration (Tmax) of tolterodine and at steady state (Day 4 of dosing).
`
`Table 2 summarizes the mean change from baseline to steady state in corrected QT interval (QTC) relative to
`placebo at the time of peak tolterodine (1 hour) and moxifloxacin (2 hour) concentrations. Both F ridericia’s
`(QTCF) and a population-specific (QTCP) method were used to correct QT interval for heart rate. No single QT
`correction method is known to be more valid than others. QT interval was measured manually and by machine,
`and data from both are presented. The mean increase of heart rate associated with a 4 mg/day dose of
`tolterodine in this study was 2.0 beats/minute and 6.3 beats/minute with 8 mg/day tolterodine. The change in
`heart rate with moxifloxacin was 0.5 beats/minute.
`
`Table 2. Mean (CI) change in QTL. from baseline to steady state (Day 4 of closing)
`at T,.,,,_,,
`relative to Iacebo
`
`Drug.’Dose
`
`Tolterodine
`
`2 In BlD*
`
`N
`
`48
`
`(msee) (manual)
`
`5.01
`
`(msee)
`(machine)
`1.16
`
`0.28, 9.74
`
`(-2.99, 5.30
`
`(msee)
`(manual)
`4.45
`
`-0.37, 9.26
`
`(msee)
`(machine)
`2.00
`
`(4.53,12.15)
`
`-1.81, 5.81 4m |31D*
`
`Moxifloxacill
`
`45
`
`(7.11,16.58)
`19.26"
`
`(1.48, 9.77)
`8.90
`
`(5.49,15.12)
`19.10 '
`
`9.29-
`
`*At Tum of 1 hr; 95% Confidence Interval.
`1At Tum of 2 hr; 90% Confidence Interval.
`*The effect on QT interval with 4 days of moxifloxacin dosing in this QT trial may be greater than typically observed in
`QT trials ofothcr drugs.
`
`The reason for the difference between machine and manual read of QT interval is unclear.
`
`The QT effect of tolterodine immediate release tablets appeared greater for 8 mg/day (two times the therapeutic
`dose) compared to 4 mg/day. The effect of tolterodine 8 mg/day was not as large as that observed after four
`days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped.
`
`To1terodine’s effect on QT interval was found to correlate with plasma concentration of tolterodine. There
`appeared to be a greater QTC interval increase in CYP2D6 poor metabolizers than in CYP2D6 extensive
`metabolizers after tolterodine treatment in this study.
`
`This study was not designed to make direct statistical comparisons between drugs or dose levels. There has been
`no association of Torsade de Pointes in the international post—marl<eting experience with DETROL or DETROL
`LA [see WARNINGS AND PRECAUTIONS (5. 7)].
`
`12.3
`
`Pharmacokinetics
`
`Absorption: In a study with MC-tolterodine solution in healthy volunteers who received a 5 mg oral dose, at
`least 77% of the radiolabeled dose was absorbed. Cmax and area under the concentration—time curve (AUC)
`
`Reference ID: 3168106
`
`10
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2070 - 0010
`
`

`
`determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg.
`Based on the sum of unbound serum concentrations of tolterodine and 5—HMT (“active moiety”), the AUC of
`tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). CW, and
`Cm. levels of tolterodine extended release are about 75% and l50% of tolterodine immediate release,
`
`respectively. Maximum serum concentrations of tolterodine extended release are observed 2 to 6 hours after
`close administration.
`
`Effect ofFo0a': There is no effect of food on the pharrnacokinetics of tolterodine extended release.
`
`Distribution: Tolterodine is highly bound to plasma proteins, primarily or 1—acid glycoprotein. Unbound
`concentrations of tolterodine average 3.7