Detrol T”
`to/ierodine iarirate tablets
`
`
`§'.‘f;,',';‘;;*,?‘*
`
`Detrol
`
`Detroi
`
`
`
`tolterodinetartrate
`
`
`
`tolterodinetartrate
`
`tablets
`
`tablets
`
`Ill
`
`II
`
`III
`
`Iii
`
`0817413000
`
`0817413000
`
`
`
`1.‘..-
`
`DESCRIPTION
`DETROL Tablets contain tolterodine tartrate. The
`active moiety, tolterodine, is a muscarinic recep-
`tor antagonist. The chemical name of tolterodine
`tartrate is (R)-N,N-diisoprom/I-5-(2—hydroxv-5-
`methviphenvli-3-phenvlpropanamine L«hvdrogen
`tartrate. The empiricai formula of tolterodine tar«
`trate is C26H3,NO7, and its molecular weight is
`
`Petitioner Mylan Pharmaceuticals Inc. — E
`
`ibit 1009 - Page 1
`
`--sixi
`
`
`
`
`
`
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 1
`
`

`
`D€tl‘Ol
`brand of tolterodine tartrate tablets
`
`Detrol
`brand of tolterodine tartrate tablets
`
`475 6 The structural formula of tolterodine
`tartrate is represented below;
`
`H_.,c
`
`CH3
`
`OH Hgc
`G H Y
`NYCH3
`CH3
`
`cool-i
`(IJH—OH
`‘ HO_§H
`COOH
`
`Tolterodine tartrate is a white, crystalline pow-
`der.
`It
`is soluble at 12 mg/mL in water at room
`temperature and is soluble in methanol. Slightly
`soluble in ethanol, and practically insoluble in
`toluene.
`
`DETROL Tablets for oral administration contain
`1 or 2 mg of tolterodine tartrate. The inactive
`ingredients are colloidal anhydrous silica, calcium
`hydrogen phosphate dihydrate, cellulose micro-
`crystalline, hydroxypropyl methylcellulose, mag-
`nesium stearate. sodium starch glycolate (pH 3.0
`to 5.0), stearic acid. and titanium dioxide.
`CLINICAL PHARMACOLOGY
`Tolterodine is a competitive muscarinic recep-
`tor antagonist. Both urinary bladder contraction
`and salivation are mediated via cholinergic mus-
`carinic receptors. In the anesthetized cat, toltero-
`dine shows a selectivity for the urinary bladder
`over salivary glands; however, the clinical rele-
`vance of this finding has not ‘been established.
`After oral administration. tolterodine is metab-
`olized in the liver. resulting in the formation of
`the S-hydroxymethyl derivative, a major pharma-
`cologically active metabolite. The 5-hydroxy-
`methyl metabolite, which exhibits an antimus-
`carinic activity similar to that of tolterodine,
`contributes significantly to the therapeutic
`effect. Both tolterodine and the S-hydroxymethyl
`metabolite exhibit a high specificity for mus-
`carinic 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 in healthy volunteers. The main effects
`following a 6.4-mg single dose of tolterodine
`were an increase in residual urine, reflecting an
`incomplete emptying of the bladder, and a
`decrease in detrusor pressure. These findings are
`consistent with a potent antimuscarinic action on
`the lower urinary tract.
`Pharmacokinetics
`Absorption: in a study of “C-tolterodine in
`healthy volunteers who received a 5—mg oral
`dose, at least 77% of the radiolabeled dose was
`absorbed. Tolterodine is rapidly absorbed, and
`maximum serum concentrations (Cmax) typically
`occur within 1 to 2 hours after dose administra-
`
`concern and adjustment of dose is not needed.
`Distribution: Tolterodine is highly bound to
`plasma proteins, primarily (11-aCid glycoprotein.
`Unbound concentrations of tolterodine average
`3.7% 20.13% over the concentration range
`achieved in clinical studies. The 5-hydroxvmethyl
`metabolite is not extensively protein bound, with
`unbound fraction concentrations averaging
`36% :4.0%. The blood to serum ratio of toltero-
`dine and the S-hydroxymethyl metabolite aver-
`ages 06 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 1 26.7 L.
`Metabolism: Tolterodine is extensively metabo-
`lized by the liver following oral dosing. The pri-
`mary metabolic route involves the oxidation of
`the 5-methyl group and is mediated by the cyto-
`chrome P450 206 and leads to the formation of a
`pharmacologically active S-hydroxymethyl
`metabolite. Further metabolism leads to forma-
`tion of the 5-carboxylic acid and N-dealkylated S-
`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 population is devoid of cytochrome
`P450 206, the enzyme responsible for the forma-
`tion of the S-hydroxymethyl metabolite of
`tolterodine. The identified pathway of metabo-
`lism for these individuals, referred to as ‘poor
`metabolizers,'
`is de'aIkylation via cytochrome
`P450 3A4 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 S-hydroxy-
`methyl metabolite. Because of differences in the
`protein—binding characteristics of tolterodine and
`the S-hydroxymethyl metabolite, the sum of
`unbound serum concentrations of tolterodine
`and the S-hydroxymethyl metabolite is similar in
`extensive and poor metabolizers at steady state.
`Since tolterodine and the S-hydroxymethyl
`metabolite have similar antimuscarinic effects,
`the net activity of DETROL Tablets is expected to
`be similar in extensive and poor metabolizers.
`Excretion: Following administration of a 5-mg
`oral dose of 14C-tolterodine to healthy volun-
`teers, 77% of radioactivity was recovered in urine
`and 17% was recovered in feces. 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 S-hydroxymethyl metabolite. Most of the
`radioactivity was recovered within the first 24
`hours, which is consistent with the apparent half-
`life of tolterodine: 1.9 to 3.7 hours in pharmaco-
`kinetic studies.
`A summary of mean (2 standard deviation)
`pharmacokinetic parameters of tolterodine and
`the S-hydroxymethyl metabolite in extensive (EM)
`and poor (PM) metabolizers is provided in the fol-
`lowing table. These data were obtained following
`single- and multiple-doses of tolterodine 4 mg
`administered twice daily to 16 healthy male sub-
`Jects (8 EM, 8 PM).
`
`~I\l
`
`tion. The pharmacokinetics of tolterodine, :5~:_:d
`
`on CW, and area under the concentration-
`curve (AUC) determinations, are dose-pr
`tional over the range of 1 to 4 mg.
`Effect of Food: Food intake increases the
`bioavailabillty of tolterodine (average increase
`53%) and does not affect the levels of the 5-
`hydroxymethyl metabolite in extensive metabo-
`lizers. This change is not expected to be a safety
`
`__e
`or-
`
`D
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1009 — P ge 2
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 2
`
`

`
`Detrol
`brand of tolterodine tartrate tablets
`
`Detrol
`
`brand of tolterodine tartrate tablets
`
`Tolterodine
`
`tmax
`(hi
`
`Cmax'
`lug/L)
`
`Cam.
`(pg/U
`
`t1/2
`(h)
`
`CL/F
`(L/h)
`
`
`5-Hydroxymethyl Metabolite
`tmax
`Cmax.
`Cavg.
`t1/2
`(h)
`tug/U
`(pg/U
`(hi
`
`1.611 5
`1.4205
`
`’|.6:’|.2
`10:49
`
`0.501:0.35
`8524.3
`
`2010.7
`6 51:16
`
`5342697
`17:7 3
`
`1.8114
`-'
`
`18:0 7
`'
`
`0 62t0.26
`~
`
`3 1:0 7
`—
`
`4152377
`11:42
`
`
`
`12:05
`
`2 4:13
`
`
`
`
`
`0.922046
`
`2 920.4
`
`
`
`
`
`
`
`Phenotype
`(CYP2D6)
`Single-dose
`EM
`PM
`
`Multiple-dose
`EM
`PM
`
`
`
`
`
`
`22:01!
`05810.54
`26:28
`12:05
`1921.0
`1917.5
`1215.1
`9.6215
`
`
`‘ Parameter was dose-normalized from 4 mg to 2 mg.
`Cm, = Maximum plasma concentration; tmx = Time of occurrence of Cum;
`Cm = Average plasma concentration; tm = Terminal elimination half-life; CL/F = Apparent oral clearance
`i — = not applicable.
`
`Pharmacokinetics in Special Populations
`Age: in Phase 1, multiple-dose studies in which
`tolterodine 2 mg was administered twice daily,
`serum concentrations of tolterodine and of the
`5-hydroxymethvl 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 1 or 2 mg twice daily. Mean serum
`concentrations of tolterodine and the 5—hydroxy-
`methyl metabolite in these elderly volunteers
`were approximately 20% and 50% higher, respec-
`tively, than reported in young healthy volunteers.
`However. no overall differences were observed in
`safety between older and younger patients in
`Phase 3, 12-week, controlled clinical studies;
`therefore, no dosage adjustment is recom-
`mended (see PRECAUTIONS, Geriatric Use).
`Pediatric: The pharmacokinetics of tolterodine
`have not been established in pediatric patients.
`Gender: The pharmacokinetics of tolterodine
`and the 5-hydroxymethyl metabolite are not
`influenced by gender. Mean cm“ of tolterodine
`(1.6 pg/L in males versus 2.2 pg/L in females) and
`the active 5—hydroxymethyl metabolite (2.2 pg/L
`in males versus 2.5 ug/L in females) are similar in
`males and females who were administered
`tolterodine 2 mg. Mean AUC values of tolterodine
`(6.7 pg/L in males versus 7.8 pg/L in females) and
`the 5-hydroxymethyl metabolite (10 pg/L in males
`versus 11 pg/L in females) are also similar. The
`elimination half-life of tolterodine 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: The pharmacokinetics of
`tolterodine in patients with renal insufficiency
`have not been evaluated. The renal excretion of
`tolterodine and the 5-hydroxymethyl metabolite
`are negligible, and a decrease in total body clear-
`ance is not expected in patients with renal insuffi-
`ciency. However, patients with renal impairment
`should be treated with caution.
`Hepatic Insufficiency: Liver impairment can
`significantly alter the disposition of tolterodine.
`in a study conducted in cirrhotic patients, [we
`elimination half-life of tolterodine was longe 'rr"
`cirrhotic patients (mean, 8.7 hours) than in
`healthy, young and elderly volunteers (mean, 2 to
`4 hours). The clearance of orally administered
`tolterodine was substantially lower in cirrhotic
`patients (1.1 :17 L/h/kg) than in the healthy vol-
`unteers (57:58 L/h/kg). Patients with signifi-
`cantly reduced hepatic function should not
`
`receive doses of DETROL greater than 1 mg twice
`daily (see PRECAUTIONS, General).
`Drug-Drug interactions
`Fluoxetine: Fluoxetine is a selective serotonin
`reuptake inhibitor and a potent inhibitor of cyto-
`chrome P45O 206 activity. in a study to assess the
`effect of fluoxetlne on the pharmacokinetics of
`tolterodine and its metabolites,
`it was observed
`that fluoxetlne significantly inhibited the metabo-
`lism of tolterodine in extensive metabolizers,
`resulting in a 4.8-fold increase in tolterodine AUC.
`There was a 52% decrease in CW, and a 20%
`decrease in AUC of the 5-hydroxymethyl metabo-
`lite. Fluoxetine thus alters the pharmacokinetics
`in patients who would otherwise be extensive
`metabolizers of tolterodine to resemble the
`pharmacokinetlc profile in poor metabolizers, The
`sums of unbound serum concentrations of
`tolterodine and the S-hydroxymethyl metabolite
`are only 25% higher during the interaction. No
`dose adjustment is required when DETROL and
`fluoxetlne are coadministered.
`Other Drugs Metabolized by Cytochrome
`P450 2D6: Tolterodine is not expected to influ-
`ence the pharmacokinetics of drugs that are
`metabolized by cytochrome P450 206, such as
`flecainide, vinblastine, carbamazepine, and tri-
`cyclic antidepressants; however, the potential
`effect of tolterodine on the pharmacokinetics of
`these drugs has not been formally evaluated.
`warfarin: in healthy volunteers, coadministra-
`tion of tolterodine 2 mg twice daily for 7 days
`and a single 25-mg dose of warfarin on day 4 had
`no effect on prothrombin time, Factor VII sup-
`pression, or on the pharmacokinetics of warfarin.
`Oral Contraceptives: Tolterodine 2 mg twice
`daily had no effect on the pharmacokinetics of an
`oral contraceptive (ethinyl estradiol 30 ug/|E‘V-
`onorgestrel 150 pg) as evidenced by the monitor-
`ing.-of ethinyl estradiol and levonorgestrel over a
`2-month cycle in healthy female volunteers.
`Diuretics: Coadministration of tolterodine up to
`4 mg twice daily for up to 12 weeks with diuretic
`agents, such as indapamide, hydrochlorothiazide,
`triamterene, bendroflumethiazide. chlorothiazide,
`methylchlorothiazide, or furosemide, did not cause
`any adverse electrocardiographic (ECG) effects.
`CLINICAL STUDIES
`
`DETROL Tablets were evaluated for the treat-
`ment of patients with an overactive bladder with
`symptoms of urinary frequency. urgency. or urge
`incontinence in three placebo-controlled, 12-week
`studies. A total of 339 patients received DETROL
`2 mg twice daily and 177 patients received placebo.
`The majority of patients were Caucasian (95%) and
`female (75%), with a mean age of 60 years (range,
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1009 — Pa
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 3
`
`

`
`Detrol
`
`brand Of tolterodine tartrate tablets
`
`Detrol
`brand Of tolterodine tartrate tablets
`
`19 to 91 years). At study entry, nearly all patients
`perceived they had urgency (98%) and most
`patients had increased frequency of micturitions
`(89%) and urge incontinence (83%). These charac-
`teristics were well balanced across treatment
`groups for the three studies.
`The efficacy endpoints included the change
`from baseline for:
`
`- number of micturitions per 24 hours (averaged
`over 7 days)
`
`- number of incontinence episodes per 24 hours
`(averaged over 7 days)
`- volume of urine voided per micturition (aver-
`aged over 2 days)
`Efficacy results for the three placebo-con-
`trolled, 12-week studies are presented in the fol-
`lowing figures:
`
`95% Confidence Intervals for the Difference between DETRoL'(2 mg bid) and Placebo
`for the Median change at Week 12 from Baseline
`Number of Micturitlons per 24 Hours
`
`Between Treatment Dillerence in Change from Baseline
`
`Placebo
`56
`10.6
`
`-1.1 (3.6)
`
`64
`10.4
`
`-1.2 (2.3)
`
`56
`10.9
`
`-1.1 (2.8)
`
`Favors DETROL
`
`Favors Placebo
`
`Placebo
`40
`2.5
`
`-0.8 (1.5)
`
`55
`3.2
`
`-1.1 (2.5)
`
`50
`2.2
`
`-0.9 (2.1)
`
`Between Treatment Diilerence in Change from Baseline
`
`Favors DETROL
`
`Study
`008 number of patients
`median baseline
`median (SD) change
`from baseline
`
`009 number of patients
`median baseline
`median (SD) change
`from baseline
`
`010 number of patients
`median baseline
`median (SD) change
`from baseline
`
`DETROL
`118
`10.5
`
`-22 (3.8)
`
`128
`10.4
`
`-2.2 (2.1)
`
`108
`11.0
`
`-1.5 (2.3)
`
`Number of Incontinence Episodes per 24 Hours
`Study
`;
`DETROL
`008 number of patients...
`93
`median baseline
`24
`median (SD) change
`from baseline
`
`-1.2 (3.2)
`
`009 number of patients
`median baseline
`median (50) change
`from baseline
`
`010 number of patients
`median baseline
`median (SD) change
`from baseline
`
`volume voided per Mlcturition (mL)
`Study
`008 number of patients
`median baseline
`median (SD) change
`from baseline
`
`009 number of patients
`median baseline
`median (50) change
`from baseline
`
`010 number of patients
`median baseline
`median (SD) change
`from baseline
`
`116
`25
`
`»1.4 (2.5)
`
`90
`2.7
`
`-1.5 (2.4)
`
`DETROL
`118
`156
`
`34 (54)
`
`128
`149
`
`34 (S0)
`
`108
`148
`
`27 (45)
`
`
`Favors Placebo
`
`
`-50
`
`Favors DE TROL
`
`.‘ The difference between DETROL and placebo was statistically significant
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1009 — Page 4
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 4
`
`

`
`Detrol
`brand of tolterodine tartrate tablets
`
`Detrol
`brand of tolterodine tartrate tablets
`
`INDICATIONS AND USAGE
`DETROL Tablets are indicated for the treatment
`of patients with an overactive bladder with symp-
`toms of urinary frequency, urgency, or urge
`incontinence.
`
`CONTRAINDICATIONS
`DETROL Tablets are contraindicated in patients
`with urinary retention, gastric retention, or
`uncontrolled narrow-angle glaucoma. DETROL 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 should be administered with
`caution to patients with clinically significant blad-
`der outflow obstruction because of the risk of
`urinary retention and to patients with gastroin-
`testinal obstructive disorders, such as pyloric
`stenosis, because of the risk of gastric retention
`(see CONTRAINDICATIONS).
`'
`’
`Controlled Narrow-Angle Glaucoma: DETROL
`should be used with caution in patients being
`treated for narrow-angle glaucoma.
`Reduced Hepatic and Renal Function:
`Patients with significantly reduced hepatic
`function should not receive doses of
`DETROL greater than 1 mg twice daily.
`Patients with renal impairment should be
`treated with caution (see CLINICAL PHARMA-
`COLOGY, Pharmacokinetics in Special
`Populations).
`
`Information for Patients
`Patients should be informed that antimus-
`carinic agents such as tolterodine may pro-
`duce blurred vision.
`Drug Interactions
`Cytochrome P450 3A4 Inhibitors: Pharma-
`cokinetic studies with patients concomitantly
`receiving cytochrome P450 3A4 inhibitors, such
`as macrolide antibiotics (erythromycin and clar-
`ithromycin) or antifungal agents lketoconazole,
`itraconazole. and miconazole), have not been
`performed. Patients receiving cytochrome
`P450 5A4 inhibitors should not receive doses of
`DETROL greater than 1 mg twice daily.
`Drug-Laboratory-Test Interactions
`Interactions between tolterodine and labora-
`tory tests have not been studied.
`carcinogenesis, Mutagenesis, Impairment of
`Fertility
`Carcinogenicity studies with tolterodine were
`conducted in mice and rats. At the maximum tol-
`erated dose in mice (30 mg/kg/day), female rats
`(20‘ mg/kg/day), and male rats (50 mg/kg/day),
`AUC values obtained for tolterodine were 355,
`291, and 462 pg-h/L, respectively. In comparison,
`the human AUC value for a 2-mg dose adminis-
`tered twice daily is estimated at 54 pg-h/L. Thudsfi,
`tolterodine exposure in the carcinogenicity stu
`ies 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 four
`strains of Salmonella typhimurium and in two
`strains of Escherichia coli, a gene mutation
`
`assay in L5178Y mouse lymphoma cells, and chro-
`mosomal 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 mat-
`ing and during gestation with 20 mg/kg/day (cor-
`responding to AUC value of about 500 pg-h/L),
`neither effects on reproductive performance or
`fertility were seen. Based on AUC values, the sys-
`temic exposure was about 15-fold higher in ani-
`mals 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
`50 to 40 mg/kg/day, tolterodine has been shown
`to cause embryolethality, reduce fetal weight,
`and increase the incidence of fetal abnormalities
`(cleft palate, digital abnormalities, intra-abdomi-
`nal hemorrhage, and various skeletal abnormali-
`ties, primarily reduced ossification) in mice. At
`these closes, 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 u9'h/L, which is about
`three-fold higher than that resulting from the
`human dose. This dose_"tlid not result in any
`embryotoxicity or teratogenicity. There are no
`studies of tolterodine in pregnant women.
`Therefore, DETROL should be used during preg-
`nancy only if the potential benefit for the mother
`justifies the potential risk for the fetus.
`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, administra-
`tion of DETROL should be discontinued during
`nursing.
`Pediatric use
`The safety and effectiveness of DETROL in pedi-
`atric patients have not been established.
`Geriatric Use
`Of the 1120 patients who were treated in the
`four, Phase 3, 12-week clinical studies of DETROL,
`474 (42%) were 65 to 91 years of age. No overall
`differences in safety were observed between the
`older and younger patients (see CLINICAL PHAR-
`MACOLOGY, Pharmacokinetics
`in Special
`Populations).
`
`ADVERSE REACTIONS
`The Phase 2 and 3 clinical trial program for
`DETROL included 2049 patients who were treated
`with DETROL (N=1619) or placebo (N=430). No dif-
`ferences in the safety profile of tolterodine were
`identified based on age, gender, race, or metabo-
`lism. Four Phase 3. 12-week, controlled clinical
`studies form the basis for the main evaluation of
`safety, and the results are summarized below.
`Adverse events considered to be treatment-
`related were dry mouth, dyspepsia, headache,
`constipation, and xerophthalmia. Dry mouth,
`constipation, abnormal vision (accommodation
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1009 — Page 5
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 5
`
`

`
`.=."'{
`D€tl'Ol
`brand of tolterodine tartrate tablets‘
`
`Detrol
`brand Of tolterodlne tartrate tablets
`
`abnormalities), urinary retention, and xeroph-
`thalmia are expected side effects of antimus—
`carinic agents.
`-
`Dry mouth was the most frequently reported
`adverse event for patients treated with DETROL
`2 mg twice daily in the Phase 3 clinical studies,
`occurring in 39.5% of patients treated with
`DETROL and 15.9% of placebo-treated patients;
`0.8% of patients treated with DETROL discontin-
`ued treatment due to dry mouth.
`The frequency of discontinuation due to
`
`adverse events was highest during the first 4
`weeks of treatment. Eight percent of patients
`treated with DETROL 2 mg twice daily discontin-
`ued treatment due to adverse events; the most
`common adverse events leading to discontinua-
`tion were dizziness and headache.
`The following table lists the adverse events
`reported in 1% or more of the patients treated
`with DETROL 2 mg twice daily in the 12-week
`studies. The adverse events are reported regard»
`less of causality.
`
`Incidence l%) of Adverse Events Reported In 21% of Patients Treated with
`DETROL (2 mg bid) In 12-week. Phase 5 Clinical studies
`Body System
`
`Adverse Event‘
`
`
`
`% Patients Reporting Adverse Events
`% Patients Reporting Serious Adverse Events
`9’. Patients Discontinuing due to Adverse Events
`Autonomic Nervous
`'
`
`drvmoutn
`
`
`
`back pain
`chest pain
`
`fatigue
`
`
`headache
`influenza-like symptoms
`
`
`fall
`paresthesia
`vertigo/dizziness
`abdominal pain
`constipation
`diarrhea
`dyspepsia
`flatulence
`nausea
`vomiting/nausea
`bronchitis ‘
`coughing _
`pharyngitis
`
`
`rhinitis
`
`
`sinusitis
`URI
`
`dysuria
`micturition frequency
`urinary retention/mict dis
`UTl
`pruritus
`rash/erythema
`.
`
`.
`1.3
`4.2
`1.7
`2.1
`2.1
`1.5
`1.1
`1.1
`5.9
`2.5
`1.1
`1.7
`5.5
`1.3
`1.9
`1.7
`
`
`
`
`
`General
`
`Central/
`Peripheral Nervous
`Gastrointestinal
`
`Respiratory
`
`Urinary
`
`Skin/
`Appendages
`
`Musculoskeletal
`Vision
`
`f-Placebo
`' N=176
`
`15.9
`3.4
`1.7
`7.4
`7.4
`6.3
`0.6
`0.6
`9.1
`6.3
`4.5
`6.3
`1.7
`0.6
`5.7
`0.6
`0.6
`1.7
`2.3
`1.1
`5.7
`9.1
`4.0
`1.7
`2.8
`7.4
`1.1
`2 .8
`0.6
`2.8
`
`4.0
`1.7
`
`0. 6
`1.7
`1.1
`0.6
`1.1
`0.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`arthralgia
`vision abnormal (including
`accommodation)
`xerophth '
`
`Psychiatric
`
`Metabolic/Nutritional
`Cardiovascular
`Resistance Mechanism
`
`nervousness
`somnolence
`weight gain
`hypertension
`infection
`infection fungal
`
`' Abbreviations; URI = upper respiratory infection, UTI = urinary tract infection, mict dis = micturition disorders.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1009 — Page 6
`
`47
`3.8
`
`1.1
`3.0
`
`21
`1.1
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 6
`
`

`
`:1.
`
`817 413 000
`692167
`'
`
`"
`
`‘
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1009 — Page 7
`
`
`
`FOI’:
`Pharmacia & Upjohn company
`Kalamazoo, MI 49001, USA
`.-
`‘: March 1993
`~
`
`
`
`tablets of DETROL 2 mg was treated with a sus-
`
`OVERDOSAGE
`A 27—month—old child who ingested S to 7
`pension of activated charcoal and was hospital‘
`ized overnight with symptoms of dry mouth. The
`child fully recovered.
`Management Of overdosage
`Overdosage with DETROL 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 at doses up to
`4 mg twice daily of tolterodine (higher doses
`were not evaluated).
`DOSAGE AND ADMINISTRATION
`The initial recommended dose is 2 mg twice
`daily. The dose may be lowered to 1 mg twice
`daily based on individual response and tolerability
`For patients with significantly reduced hepatic
`function or who are currently taking drugs that
`are inhibitors of cytochrome P450 3A4, the rec-
`ommended dose is 1 mg twice daily (see PRECAU~
`TIONS, General).
`‘
`HOW suppuep
`DETROL Tablets 1 mg (white, round. biconvex.
`film-coated tablets engraved with arcs above and
`below the letters '70-) and DETROL Tablets 2 mg
`(white, round, biconvex. fllm~coated tablets
`engraved with aacs above and below the letters
`'DT') are supplied as follows:
`Bottles of 60
`1 mg
`NDC 0009-4541-02
`2 mg
`NDC 0009-4544-02
`Bottles of S00
`1 mg
`NDC 0009-4541-O3
`2 mg
`NDC 0009-4544-03
`Unit Dose Pack of 140
`1 mg
`NDC 0009-4s41~o1
`2 mg
`NDC 0009-4544-01
`
`'
`
`’
`
`'
`
`store at controlled room temperature 20° to
`25° C (68° to 77° F) lsee USP].
`Ii only
`I
`US Patent No. 5,382,600
`Manufactured by:
`_ Pharmacia 8. Upjohn S.p.A.
`
`Ascoli Plceno, ltaly
`
`_-
`’
`
`_
`
`:5»
`me
`at‘
`Or_
`,,_,,
`or
`ys—
`mi-
`of
`-cts
`
`of
`he
`Ems
`; of
`M"
`mt
`ties’
`mi-
`iaIi-
`. At
`- to
`lted
`day
`iout
`the
`any
`-' ”°
`‘en’
`reg"
`‘"9’
`
`iice.
`dine
`had
`iring
`tion
`le is
`stra-
`iring
`
`’ed'
`‘ the
`rROL,
`Vera"
`.1H,t\r,'f
`eciai
`
`’‘ for
`3at_ed
`O dif-
`were
`tabo-
`linical
`on of
`Iv.
`nent-
`ache,
`outh.
`lation
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1009 - Page 7