`tolterodine tartrate
`extended release capsules
`
`
`
`
`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-phenylpropanamine L-hydrogen tartrate.
`The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is
`475.6. The structural formula of tolterodine tartrate is represented below.
`
`
`C3H
`
`OH
`H
`
`C3H
`
`C 3H
`
`N
`
`C 3H
`
`C 3H
`
`
`HCOO
`OH
`CH
`CH
`COOH
`
`HO
`
`
`Tolterodine tartrate is a white, crystalline powder. The pKa 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 for oral administration contains 2 mg or 4 mg of tolterodine tartrate.
`Inactive ingredients are sucrose, starch, hypromellose, ethylcellulose, medium chain
`triglycerides, oleic acid, gelatin, and FD&C Blue #2. The 2-mg capsules also contain
`yellow iron oxide. Both capsule strengths are imprinted with a pharmaceutical grade
`printing ink that contains shellac glaze, titanium dioxide, propylene glycol, and
`simethicone.
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0001
`
`
`
`NDA 21-228
`Page 2
`
`CLINICAL PHARMACOLOGY
`Tolterodine is a competitive muscarinic receptor antagonist. 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 the 5-hydroxymethyl derivative, a major pharmacologically active
`metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity
`similar to that of tolterodine, contributes significantly to the therapeutic effect. Both
`tolterodine and the 5-hydroxymethyl metabolite 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.
`
`Tolterodine has a pronounced effect on bladder function. Effects on urodynamic
`parameters before and 1 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.
`
`Pharmacokinetics
`Absorption: In a study with 14C-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) 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 the 5-hydroxymethyl metabolite (“active
`moiety”), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine
`immediate release 4 mg (2 mg bid). Cmax and Cmin levels of tolterodine extended release
`are about 75% and 150% of tolterodine immediate release, respectively. Maximum
`serum concentrations of tolterodine extended release are observed 2 to 6 hours after dose
`administration.
`
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0002
`
`
`
`NDA 21-228
`Page 3
`
`Effect of Food: There is no effect of food on the pharmacokinetics of tolterodine
`extended release.
`
`Distribution: Tolterodine is highly bound to plasma proteins, primarily α1-acid
`glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the
`concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not
`extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%.
`The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6
`and 0.8, respectively, indicating that these compounds do not distribute extensively into
`erythrocytes. The volume of distribution of tolterodine following administration of a
`1.28-mg intravenous dose is 113 ± 26.7 L.
`
`Metabolism: Tolterodine is extensively metabolized by the liver following oral dosing.
`The primary metabolic route involves the oxidation of the 5-methyl group and is
`mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a
`pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to
`formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites,
`which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine,
`respectively.
`
`Variability in Metabolism: A subset (about 7%) of the Caucasian population is devoid of
`CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of
`tolterodine. The identified pathway of metabolism for these individuals (“poor
`metabolizers”) is dealkylation via cytochrome P450 3A4 (CYP3A4) to N-dealkylated
`tolterodine. The remainder of the population is referred to as “extensive metabolizers.”
`Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor
`metabolizers than in extensive metabolizers; this results in significantly higher serum
`concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl
`metabolite.
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0003
`
`
`
`NDA 21-228
`Page 4
`
`
`Excretion: Following administration of a 5-mg oral dose of 14C-tolterodine solution to
`healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered
`in feces in 7 days. Less than 1% (<2.5% in poor metabolizers) of the dose was recovered
`as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was recovered as the
`active 5-hydroxymethyl metabolite.
`
` summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine
`extended release and the 5-hydroxymethyl metabolite in extensive (EM) and poor (PM)
`metabolizers is provided in Table 1. These data were obtained following single and
`multiple doses of tolterodine extended release administered daily to 17 healthy male
`volunteers (13 EM, 4 PM).
`
`
` A
`
`
`
`
`Single dose
`4 mg*
`EM
`Multiple
`dose 4 mg
`4 (2 - 6)
`6.9 (3.5)
`1.7 (2.8)
`4 (2 - 6) 3.4 (4.9)
`EM
`--‡
`18 (16)
`13 (11)
`4 (3 - 6)
`19 (16)
`PM
`*Parameter dose-normalized from 8 to 4 mg for the single-dose data.
`Cmax = Maximum serum concentration; tmax = Time of occurrence of Cmax;
`Cavg = Average serum concentration; t½ = Terminal elimination half-life.
`†Data presented as median (range).
`‡ = not applicable.
`
`Pharmacokinetics in Special Populations
`Age: In Phase 1, multiple-dose studies in which tolterodine immediate release 4 mg
`(2 mg bid) was administered, serum concentrations of tolterodine and of the 5-
`hydroxymethyl metabolite were similar in healthy elderly volunteers (aged 64 through
`80 years) and healthy young volunteers (aged less than 40 years). In another Phase 1
`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 the
`5-hydroxymethyl metabolite in these elderly volunteers were approximately 20% and
`
`Table 1. Summary of Mean (±SD) Pharmacokinetic Parameters of Tolterodine Extended Release
`and its Active Metabolite (5-hydroxymethyl metabolite) in Healthy Volunteers
`Tolterodine
`5-hydroxymethyl metabolite
`Cmax
`Cmax
`Cavg
`Cavg
`(µg/L)
`(µg/L)
`(µg/L)
`(µg/L)
`
`
`
`
`
`tmax†
`(h)
`
`
`t½
`(h)
`
`
`tmax†
`(h)
`
`
`t½
`(h)
`
`
`4 (2 - 6) 1.3 (0.8) 0.8 (0.57)
`
`
`
`
`8.4 (3.2)
`
`
`4 (3 - 6)
`
`
`1.6 (0.5)
`
`
`1.0 (0.32)
`
`
`8.8 (5.9)
`
`
`2.7 (0.90)
`--
`
`1.4 (0.6)
`--
`
`9.9 (4.0)
`--
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0004
`
`
`
`NDA 21-228
`Page 5
`
`50% higher, respectively, than 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 (see PRECAUTIONS, Geriatric
`Use).
`
`Pediatric:
`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 11-15 years. The dose-plasma concentration
`relationship was linear over the range of doses assessed. Parent/metabolite ratios differed
`according to CYP2D6 metabolizer status: EMs had low serum concentrations of
`tolterodine and high concentrations of the active 5-hydroxymethyl metabolite, while PMs
`had high concentrations of tolterodine and negligible active metabolite concentrations.
`
`Gender: The pharmacokinetics of tolterodine immediate release and the
`5-hydroxymethyl metabolite are not influenced by gender. Mean Cmax of tolterodine
`immediate release (1.6 µg/L in males versus 2.2 µg/L in females) and the active 5-
`hydroxymethyl metabolite (2.2 µg/L in males versus 2.5 µg/L in females) are similar in
`males and females who were administered tolterodine immediate release 2 mg. Mean
`AUC values of tolterodine (6.7 µg·h/L in males versus 7.8 µg·h/L in females) and the 5-
`hydroxymethyl metabolite (10 µg·h/L in males versus 11 µg·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 the 5-hydroxymethyl metabolite is 3.0 hours in
`females and 3.3 hours in males.
`
`Race: Pharmacokinetic differences due to race have not been established.
`
`Renal Insufficiency: Renal impairment can significantly alter the disposition of
`tolterodine immediate release and its metabolites. In a study conducted in patients with
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0005
`
`
`
`NDA 21-228
`Page 6
`
`creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5-
`hydroxymethyl metabolite levels were approximately 2-3 fold higher in patients with
`renal impairment than in healthy volunteers. Exposure levels of other metabolites of
`tolterodine (eg, 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 significantly reduced renal function is tolterodine 2 mg daily (see
`PRECAUTIONS, General).
`
`Hepatic Insufficiency: Liver impairment can significantly alter the disposition of
`tolterodine immediate release. In a study of tolterodine immediate release conducted in
`cirrhotic patients, 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 ± 1.7 L/h/kg) than in the healthy volunteers
`(5.7 ± 3.8 L/h/kg). The recommended dose for patients with significantly reduced hepatic
`function is tolterodine 2 mg daily (see PRECAUTIONS, General).
`
`Drug-Drug Interactions
`Fluoxetine: Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of
`CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of
`tolterodine immediate release and its metabolites, it was observed that fluoxetine
`significantly inhibited the metabolism of tolterodine immediate release in extensive
`metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52%
`decrease in Cmax and a 20% decrease in AUC of the 5-hydroxymethyl metabolite.
`Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be extensive
`metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in
`poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate
`release and the 5-hydroxymethyl metabolite are only 25% higher during the interaction.
`No dose adjustment is required when tolterodine and fluoxetine are coadministered.
`
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0006
`
`
`
`NDA 21-228
`Page 7
`
`Other Drugs Metabolized by Cytochrome P450 Isoenzymes: Tolterodine immediate
`release does not cause clinically significant interactions with other drugs metabolized by
`the major drug metabolizing CYP enzymes. In vivo drug-interaction data show that
`tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2,
`2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine,
`debrisoquine, S-warfarin, and omeprazole. In vitro data show that tolterodine immediate
`release is a competitive inhibitor of CYP2D6 at high concentrations (Ki 1.05 µM), while
`tolterodine immediate release as well as the 5-hydroxymethyl metabolite are devoid of
`any significant inhibitory potential regarding the other isoenzymes.
`
`CYP3A4 Inhibitors: The effect of a 200-mg daily dose of ketoconazole on the
`pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers,
`all of whom were poor metabolizers (see Pharmacokinetics, Variability in Metabolism
`for discussion of poor metabolizers). In the presence of ketoconazole, the mean Cmax and
`AUC of tolterodine increased by 2 and 2.5 fold, respectively. Based on these findings,
`other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole,
`miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine
`or vinblastine may also lead to increases of tolterodine plasma concentrations (see
`PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`Warfarin: In healthy volunteers, coadministration of tolterodine immediate release 4 mg
`(2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on
`prothrombin time, Factor VII suppression, or on the pharmacokinetics of warfarin.
`
`Oral Contraceptives: Tolterodine immediate release 4 mg (2 mg bid) had no effect on the
`pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150 µg)
`as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month
`period in healthy female volunteers.
`
`Diuretics: Coadministration of tolterodine immediate release up to 8 mg (4 mg bid) for
`up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide,
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0007
`
`
`
`NDA 21-228
`Page 8
`
`triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide,
`did not cause any adverse electrocardiographic (ECG) effects.
`
`CLINICAL STUDIES
`DETROL LA Capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study.
`DETROL LA 4 mg was evaluated for the treatment of overactive bladder with symptoms
`of urge urinary incontinence and frequency in a randomized, placebo-controlled,
`multicenter, double-blind, Phase 3, 12-week study. A total of 507 patients received
`DETROL LA 4 mg once daily in the morning and 508 received placebo. The majority of
`patients were Caucasian (95%) and female (81%), with a mean age of 61 years (range, 20
`to 93 years). In the study, 642 patients (42%) were 65 to 93 years of age. The study
`included patients known to be responsive to tolterodine immediate release and other
`anticholinergic medications, however, 47% of patients never received prior
`pharmacotherapy for overactive bladder. At study entry, 97% of patients had at least 5
`urge incontinence episodes per week and 91% of patients had 8 or more micturitions per
`day. The primary efficacy endpoint was change in mean number of incontinence
`episodes per week at week 12 from baseline. Secondary efficacy endpoints included
`change in mean number of micturitions per day and mean volume voided per micturition
`at week 12 from baseline.
`
`
`
`
`
`
`Treatment
`Difference, vs
`Placebo (95% CI)
`
`-4.8‡
`(-6.9, -2.8)
`
`-0.6‡ (-1.0, -0.2)
`
`
`
`
`
`Number of incontinence episodes/week
`
`Mean Baseline
`
`Mean Change from Baseline
`Number of micturitions/day
`
`Mean Baseline
`
`Mean Change from Baseline
`Volume Voided per micturition (mL)
`
`Mean Baseline
`
`Mean Change from Baseline
`SD = Standard Deviation.
`* Intent-to-treat analysis.
`† 1 to 2 patients missing in placebo group for each efficacy parameter.
`‡ The difference between DETROL LA and placebo was statistically significant.
`
`
`
`Table 2. 95% Confidence Intervals (CI) for the Difference between DETROL LA (4 mg daily) and
`Placebo for Mean Change at Week 12 from Baseline*
`
`
`DETROL LA
`Placebo
` (n=507)
`(n=508)†
`
`
`22.1
`23.3
`-11.8 (SD 17.8)
`-6.9 (SD 15.4)
`
`
`10.9
`11.3
`-1.8 (SD 3.4)
`-1.2 (SD 2.9)
`
`
`141
`136
`34 (SD 51)
`14 (SD 41)
`
`
`
`
`
`20‡ (14, 26)
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0008
`
`
`
`NDA 21-228
`Page 9
`
`
`INDICATIONS AND USAGE
`DETROL LA Capsules are once daily extended release capsules indicated for the
`treatment of overactive bladder with symptoms of urge urinary incontinence, urgency,
`and frequency.
`
`CONTRAINDICATIONS
`DETROL LA Capsules are contraindicated in patients with urinary retention, gastric
`retention, or uncontrolled narrow-angle glaucoma. DETROL LA is also contraindicated
`in patients who have demonstrated hypersensitivity to the drug or its ingredients.
`
`PRECAUTIONS
`General
`Risk of Urinary Retention and Gastric Retention: DETROL LA Capsules should be
`administered with caution to patients with clinically significant bladder outflow
`obstruction because of the risk of urinary retention and to patients with gastrointestinal
`obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see
`CONTRAINDICATIONS).
`
`Controlled Narrow-Angle Glaucoma: DETROL LA should be used with caution in
`patients being treated for narrow-angle glaucoma.
`
`Reduced Hepatic and Renal Function: For patients with significantly reduced hepatic
`function or renal function, the recommended dose for DETROL LA is 2 mg daily (see
`CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).
`
`Information for Patients
`Patients should be informed that antimuscarinic agents such as DETROL LA may
`produce the following effects: blurred vision, dizziness, or drowsiness.
`
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0009
`
`
`
`NDA 21-228
`Page 10
`
`Drug Interactions
`CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme
`CYP3A4, significantly increased plasma concentrations of tolterodine when
`coadministered to subjects who were poor metabolizers (see CLINICAL
`PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For
`patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole
`antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin,
`clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is
`2 mg daily.
`
`Drug-Laboratory-Test Interactions
`Interactions between tolterodine and laboratory tests have not been studied.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenicity studies with tolterodine immediate release were conducted in mice and
`rats. At the maximum tolerated dose in mice (30 mg/kg/day), female rats (20
`mg/kg/day), and male rats (30 mg/kg/day), AUC values obtained for tolterodine were
`355, 291, and 462 µg·h/L, respectively. In comparison, the human AUC value for a 2-mg
`dose administered twice daily is estimated at 34 µg·h/L. Thus, tolterodine exposure in
`the carcinogenicity studies was 9- to 14-fold higher than expected in humans. No
`increase in tumors was found in either mice or rats.
`
`No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including
`bacterial mutation assays (Ames test) in 4 strains of Salmonella typhimurium and in 2
`strains of Escherichia coli, a gene mutation assay in L5178Y mouse lymphoma cells, and
`chromosomal aberration tests in human lymphocytes. Tolterodine was also negative in
`vivo in the bone marrow micronucleus test in the mouse.
`
`In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day
`(corresponding to AUC value of about 500 µg·h/L), neither effects on reproductive
`performance or fertility were seen. Based on AUC values, the systemic exposure was
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0010
`
`
`
`NDA 21-228
`Page 11
`
`about 15-fold higher in animals than in humans. In male mice, a dose of 30 mg/kg/day
`did not induce any adverse effects on fertility.
`
`Pregnancy
`Pregnancy Category C. At oral doses of 20 mg/kg/day (approximately 14 times the
`human exposure), no anomalies or malformations were observed in mice. When given at
`doses of 30 to 40 mg/kg/day, 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) in mice. At these doses, the AUC values were about 20- to 25-fold
`higher than in humans. Rabbits treated subcutaneously at a dose of 0.8 mg/kg/day
`achieved an AUC of 100 µg·h/L, which is about 3-fold higher than that resulting from the
`human dose. This dose did not result in 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.
`
`Nursing Mothers
`Tolterodine immediate release 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.
`
`Pediatric Use
`Efficacy in the pediatric population has not been demonstrated.
`
` A
`
` total of 710 pediatric patients (486 on DETROL LA, 224 on placebo) aged 5-10 with
`urinary frequency and urge incontinence were studied in two phase 3 randomized,
`placebo-controlled, double blind, 12 week studies. The percentage of patients with
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0011
`
`
`
`NDA 21-228
`Page 12
`
`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.
`
`Geriatric Use
`No overall differences in safety were observed between the older and younger patients
`treated with tolterodine (see CLINICAL PHARMACOLOGY, Pharmacokinetics in
`Special Populations).
`
`ADVERSE REACTIONS
`The Phase 2 and 3 clinical trial program for DETROL LA Capsules included 1073
`patients who were treated with DETROL LA (n=537) or placebo (n=536). The patients
`were treated with 2, 4, 6, or 8 mg/day for up to 15 months. 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. The adverse reaction
`information from clinical trials does, however, provide a basis for identifying the adverse
`events that appear to be related to drug use and for approximating rates. The data
`described below reflect exposure to DETROL LA 4 mg once daily every morning in 505
`patients and to placebo in 507 patients exposed for 12 weeks in the Phase 3, controlled
`clinical 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
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0012
`
`
`
`NDA 21-228
`Page 13
`
`of antimuscarinic agents. A serious adverse event was reported by 1.4% (n=7) of patients
`receiving DETROL LA and by 3.6% (n=18) of patients receiving placebo.
`
`The frequency of discontinuation due to adverse events was highest during the first 4
`weeks of treatment. Similar percentages of patients treated with DETROL LA or placebo
`discontinued treatment due to adverse events. Treatment was discontinued due to adverse
`events and dry mouth was reported as an adverse event in 2.4% (n=12) of patients treated
`with DETROL LA and in 1.2% (n=6) of patients treated with placebo.
`
`Table 3 lists the adverse events reported in 1% or more of patients treated with DETROL
`LA 4 mg once daily in the 12-week study. The adverse events were reported regardless
`of causality.
`
`
`Table 3. Incidence* (%) of Adverse Events Exceeding Placebo Rate and
`Reported in ≥1% of Patients Treated with DETROL LA (4 mg daily)
`in a 12-week, Phase 3 Clinical Trial
`Adverse Event
`% DETROL LA
`n=505
`
`dry mouth
`23
`headache
`6
`fatigue
`2
`dizziness
`2
`constipation
`6
`abdominal pain
`4
`dyspepsia
`3
`xerophthalmia
`3
`vision abnormal
`1
`somnolence
`3
`anxiety
`1
`sinusitis
`2
`dysuria
`1
`
`Body System
`
`Autonomic Nervous
`General
`
`Central/Peripheral Nervous
`Gastrointestinal
`
`
`Vision
`
`Psychiatric
`
`Respiratory
`Urinary
`* in nearest integer.
`
`% Placebo
`n=507
`8
`4
`1
`1
`4
`2
`1
`2
`0
`2
`0
`1
`0
`
`
`
`Postmarketing Surveillance
`
`The following events have been reported in association with tolterodine use in clinical
`practice: anaphylactoid reactions, including angioedema; tachycardia; palpitations;
`peripheral edema; and hallucinations. Because these spontaneously reported events are
`from the worldwide postmarketing experience, the frequency of events and the role of
`tolterodine in their causation cannot be reliably determined.
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0013
`
`
`
`NDA 21-228
`Page 14
`
`
`
`OVERDOSAGE
`A 27-month-old child who ingested 5 to 7 tolterodine immediate release tablets 2 mg was
`treated with a suspension of activated charcoal and was hospitalized overnight with
`symptoms of dry mouth. The child fully recovered.
`
`Management of 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 not
`observed with tolterodine immediate release at doses up to 8 mg (4 mg bid) and higher
`doses were not evaluated.
`
`DOSAGE AND ADMINISTRATION
`The recommended dose of DETROL LA Capsules are 4 mg daily. DETROL LA should
`be taken once daily with liquids and swallowed whole. The dose may be lowered to 2 mg
`daily based on individual response and tolerability, however, limited efficacy data is
`available for DETROL LA 2 mg (see CLINICAL STUDIES).
`
`For patients with significantly reduced hepatic or renal function or who are currently
`taking drugs that are potent inhibitors of CYP3A4, the recommended dose of DETROL
`LA is 2 mg daily (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug
`Interactions).
`
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0014
`
`
`
`HOW SUPPLIED
`DETROL LA Capsules 2 mg are blue-green with symbol and 2 printed in white ink.
`DETROL LA Capsules 4 mg are blue with symbol and 4 printed in white ink. DETROL
`LA Capsules are supplied as follows:
`
`
`Bottles of 500
`
`Bottles of 30
`2 mg Capsules NDC 0009-5190-01 2 mg Capsules NDC 0009-5190-03
`4 mg Capsules NDC 0009-5191-01 4 mg Capsules NDC 0009-5191-03
`
`Unit Dose
`
`
`Bottles of 90
`Blisters
`2 mg Capsules NDC 0009-5190-02 2 mg Capsules NDC 0009-5190-04
`4 mg Capsules NDC 0009-5191-02 4 mg Capsules NDC 0009-5191-04
`
`Store at 25°C (77°F ); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
`Room Temperature]. Protect from light.
`
`Rx only
`
`US Patent No. 5,382,600
`Manufactured for
`Pharmacia & Upjohn Company
`A subsidiary of Pharmacia Corporation
`Kalamazoo, MI 49001, USA
`By
`International Processing Corporation
`Winchester, Kentucky 40391
`
`Revised April 2004
`
`
`
`
`
`
`
` 818 229 007
`692167
` 4688-76
`
`NDA 21-228
`Page 15
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2009 - 0015