HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`DITROPAN XL” safely and effectively. See full prescribing information
`for DITROPAN xL“°.
`
`DITROPAN XL” (oxybutynin chloride) Extended Release Tablets for
`oral use
`Initial U.S. Approval: 1975
`-------------------—-------INDICATIONS AND USAGE----------------------------
`
`I DITROPAN XI} (oxybutynin chloride) is a muscarinic antagonist
`indicated for the treatment of overactive bladder with symptoms of urge
`urinary incontinence, urgency, and frequency. (1)
`I DITROPAN XL“ is also indicated for the treatment of pediatric patients
`aged 6 years and older with symptoms of detrusor overactivity associated
`with a neurological condition (e.g.. spina bifida). (I)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`DITROPAN XL“ must be swallowed whole with the aid ofliquids, and must
`not be chewed, divided, or crushed. DITROPAN XL" may be administered
`with or without food. (2)
`- Adults: Start with 5 mg or ID mg, once daily at approximately the same
`time every day. Dose should not exceed 30 mg per day. (2.1)
`I Pediatric patients (6 years of age or older): Start with 5 mg, once daily at
`approximately the same time every day. Dose should not exceed 20 mg per
`day. (2.2)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Extended release tablets 5 mg. 10 mg and 15 mg (3)
`------------------------------CONTRAINDICATIONS-------------------------------
`I Urinary retention (4)
`I Gastric Retention (4)
`I Uncontrolled narrow angle glaucoma (4)
`I Known hypersensitivity to DITROPAN XL", oxybutynirt or any
`component of DITROPAN XL’? (4)
`-----------------------WARNINGS AND PRECAUTlONS-----------------------
`
`0 Angioedema: Angioedcma has been reported with oxybutynin. If
`symptoms of angioedema occur, discontinue DlTROPAN$' XL
`immediately and initiate appropriate therapy. (5.1)
`I Central Nervous System (CNS) effects: CNS effects have been reported
`with oxybutynin. If patient experiences anticholinergic CNS’ effects,
`consider dose adjustment or discontinuation of DlTROPAN”° XL. (5.2)
`I Worsening of Myasthenia Gravis: Use with caution in Myasthenia gravis
`patients due to risk of symptom aggravation (5.3)
`I Urinary Retention: Use with caution in patients with clinically significant
`bladder outflow obstruction because of the risk of urinary retention (5.4)
`I Gastrointestinal Adverse Reactions: Use with caution in patients with
`gastrointestinal obstructive disorders or decreased intestinal motility due to
`risk ofgastric retention. Use with caution in patients with gastroesophageal
`reflux or in patients concurrently taking drugs that can exacerbate
`esophagitis. (5.5)
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common (incidence 35%) adverse reactions were dry mouth,
`constipation, somnolence, headache, diarrhea, nausea, blurred vision,
`dyspepsia, dizziness, dry eyes, and urinary tract infection. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen at
`1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or
`www.fda.gav/medwalch.
`-------------------------------DRUG INTERACTIONS-------------------------------
`I Co-administration with other anticholinergic drugs may increase the
`frequency and/or severity of antieholinergic-like effects. (7)
`I Co-administration with strong cytochrome P450 (CYP) 3A4 inhibitors
`(e.g., ketoconazole) increases the systemic exposure ofoxybutynin. (7')
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`I Pediatric Use: DITROPANQ‘ XL is not recommended in pediatric patients
`who cannot swallow the tablet whole without chewing, dividing or
`cmshing, or in children under the age ot'6 years. (8.4)
`I Renal or Hepatic Itnpairment: There have been no studies conducted in
`patients with renal or hepatic impainnent. (8.6, 8.7)
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 07."2I]13
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`.3
`2
`
`U1-BOD
`
`6
`
`3'4
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1
`Adults
`2.2
`Pediatric Patients Aged 6 Years of Age and Older
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Angioederna
`5.2
`Central Nervous System Effects
`5.3 Worsening of Symptoms of Myasthenia Gravis
`5.4
`Urinary Retention
`5.5
`Gastrointestinal Adverse Reactions
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`Nursing Mothers
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Renal Impairment
`8.6
`Hepatic Impairment
`8.7
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharrnacodynam ics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIEDISTORAGE AND HANDLING
`16.1 Storage
`17 PATIENT COUNSELING INFORMATION
`
`["'Sections or subsections omitted from the full prescribing
`information are not listed]
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0001
`
`

`
`FU LL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`DITROPAN XL® ox but nin chloride is a muscarinic anta ronist indicated for the treatment of
`3’
`Y
`E
`
`overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
`
`DITROPAN XL® is also indicated for the treatment of pediatric patients aged 6 years and older
`
`with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina
`
`bifida).
`
`2 DOSAGE AND ADMINISTRATION
`
`DITROPAN XL® must be swallowed whole with the aid of liquids, and must not be chewed,
`divided, or crushed.
`
`DITROPAN XL“ may be administered with or without food.
`
`2.1 Adults
`
`The recommended starting dose of DITROPAN XLI/“W is 5 or 10 mg once daily at approximately
`
`the same time each day. Dosage may be adjusted in 5—mg increments to achieve a balance of
`
`efficacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjustment may
`
`proceed at approximately weekly intervals.
`
`2.2 Pediatric Patients Aged 6 Years of Age and Older
`
`The recommended starting dose of DITROPAN XL® is 5 mg once daily at approximately the
`same time each day. Dosage may be adjusted in 5—mg increments to achieve a balance of
`
`efficacy and tolerability (up to a maximum of 20 mg/day).
`
`3 DOSAGE FORMS AND STRENGTHS
`
`DITROPAN XLWJ extended—release tablets are available as 5, 10 and 15 mg tablets for oral use:
`
`5 mg: Pale yellow, round, tablet with “5 XL” printed on one side with black ink.
`
`10 mg: Pink, round, tablet with “l 0 XL” printed on one side with black ink.
`
`15 mg: Gray, round, tablet with “l 5 XL” printed on one side with black ink.
`
`4 CONTRAINDICATIONS
`
`DITROPAN XLUQ is contraindicated in patients with urinary retention, gastric retention and other
`
`severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma.
`
`DITROPAN XL'('l‘ is also contraindicated in patients who have demonstrated hypersensitivity to
`
`the drug substance or other components of the product.
`
`There have been reports of
`
`hypersensitivity reactions, including anaphylaxis and angiodema.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0002
`
`

`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Angioedema
`
`Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some
`
`cases, angioedema occurred after the first dose. Angioedema associated with upper airway
`
`swelling may be life—threatening. lf involvement of the tongue, hypopharynx, or larynx occurs,
`
`oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary
`
`to ensure a patent airway should be promptly provided.
`
`5.2 Central Nervous System Effects
`
`Oxybutynin is associated with anticholinergic central nervous system (CNS) effects [see
`
`Adverse Reactions (6)]. A variety of CNS anticholinergic effects have been reported, including
`
`hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of
`
`anticholinergic CNS effects, particularly in the first few months after beginning treatment or
`
`increasing the dose. Advise patients not to drive or operate heavy machinery until they know
`
`how DITROPAN XL affects them. If a patient experiences anticholinergic CNS effects, dose
`
`reduction or drug discontinuation should be considered.
`
`DITROPAN XL® should be used with caution in patients with preexisting dementia treated with
`cholinesterase inhibitors due to the risk of aggravation of symptoms.
`
`5.3 Worsening of Symptoms of Myasthenia Gravis
`®
`
`DITROPAN XL
`
`should be used with caution in patients with myasthcnia gravis due to the risk
`
`of symptom aggravation.
`
`5.4 Urinary Retention
`
`DTTROPAN XL® should be administered with caution to patients with clinically significant
`bladder outflow obstruction because of the risk of urinary retention [see Com‘raindi'cazi'on.s* (4)] .
`
`5.5 Gastrointestinal Adverse Reactions
`
`DITROPAN XLW should be administered with caution to patients with gastrointestinal
`obstructive disorders because of the risk of gastric retention [see C0ntrai'na’i'cati0n.s' (4)].
`
`DITROPAN XL'R', like other anticholinergic drugs, may decrease gastrointestinal motility and
`
`should be used with caution in patients with conditions such as ulcerative colitis and intestinal
`
`atony.
`
`DITROPAN XL® should be used with caution in patients who have gastroesophageal reflux
`and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate
`
`esophagitis.
`
`As with any other nondeformable material, caution should be used when administering
`DITROPAN Xlfm to patients with preexisting severe gastrointestinal narrowing (pathologic or
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0003
`
`

`
`iatrogenic). There have been rare reports of obstructive symptoms in patients with known
`
`strictures in association with the ingestion of other drugs in nondeformable controlled-release
`formulations.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, the 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 clinical practice.
`
`The safety and effieaey of DITROPAN XL (5 to 30 mg/day) was evaluated in 774 adult subjects
`
`who participated in five double—blind, controlled clinical
`
`trials.
`
`In four of the five studies,
`
`Ditropan IR (5 to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions
`
`reported by 2 1% of subjects are shown in Table 1.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0004
`
`

`
`Table 1:
`
`Adverse Drug Reactions Reported by 2 1% 0|" DITROPAN XL-treated Adult Subjects in Five
`Double-blind, Controlled Clinical Trials of DITROPAN XL
`
`
`DITROPAN XL
`Ditropan IR‘
`System/Organ Class
`5 to 30 mg/day
`5 to 20 mg/day
`Preferred Term
`11 = 774
`n = 199
`%
`%
`
`3.0
`
`5.5
`
`IPsychiatric Disorders
`I
`Insomnia
`INervous System Disorders
`8.0
`7.5
`I Headache
`14.1
`5.6
`I Sorrmolence
`| TIT
`I Dysgeusia
`1.6
`1.5
`IEye Disorders
`9.6
`4.3
`I Vision blurred
` l3SlT
`IRespiratory, Thoracic and Mediastinal Disorders
`I Cough
`I Oropharyngeal pain
`I Dry throat
`
`1.9
`1.9
`1.7
`
`3.0
`1.5
`2.5
`
`IGastrointestinal Disorders
`I Dry mouth
`I Constipation
`I Diarrhea
`I Dyspepsia
`I Nausea
`I Abdominal pain
`I Vomiting
`I Flatulence
`I Gastro-esophageal reflux disease
`Skin and Subcutaneous Tissue Disorders
`I
`I Dry skin
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`34.9
`8.7
`7.9
`4.5
`4.5
`1.6
`1.3
`1.2
`1.0
`
`1.8
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`
`72.4
`15. 1
`6.5
`6.0
`11.6
`2.0
`1.5
`2. 5
`0.5
`
`2.5
`
`I
`I Dysuria
`1.9
`2.0
`I Urinary hesitation
`1.9
`8.5
`
`IGeneral Disorders and Administration Site Conditions
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0005
`
`

`
`Table 1:
`
`Adverse Drug Reactions Reported by Z l% of DITROPAN XL-treated Adult Subjects in Five
`Double-blind, Controlled Clinical Trials of DITROPAN XL
`
`System/Organ Class
`Preferred Term
`
`DITROPAN XL
`5 to 30 mglday
`11 = 774
`(A1
`
`Ditropan IR‘
`5 to 20 mg/day
`n = 199
`IJAJ
`
`| Fatigue
`llnvestigations
`
`I Residual urine volume2 3.5 2.3
`1
`[R = immediate release
`
`3.0
`
`2.6
`
`
`
`The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine
`volume increased.
`
`The discontinuation rate due to adverse reactions was 4.4% with DITROPAN XL compared to
`
`0% with Ditropan IR. The most frequent adverse reaction causing discontinuation of study
`
`medication was dry mouth (0.7% ).
`
`The following adverse reactions were reported by <l% of DITROPAN XL®-treated patients and
`at a higher incidence than placebo in clinical
`trials: Metabolism and Nutrition Disorders.‘
`
`anorexia, fluid retention; Vascular disorders.‘ hot flush; Respiratory, thoracic and mediastinal
`
`disorders.‘ dysphonia; Gastrointestinal Disorders.‘ dysphagia,
`
`frequent bowel movements;
`
`General disorders and administration site conditions: chest discomfort, thirst.
`
`6.2 Postmarketing Experience
`
`The following additional adverse reactions have been reported from worldwide postmarketing
`experience with DITROPAN XL®. Because postmarketing reactions are reported voluntarily
`
`from a population of uncertain size, it is not always possible to reliably estimate their frequency
`
`or establish a causal relationship to drug exposure.
`
`Psychiatric Disorders.‘ psychotic disorder, agitation, hallucinations, memory impairment;
`
`Nervous System Disorders: convulsions; Eye Disorders.‘ glaucoma; Cardiac Disorders.‘
`
`arrhythmia,
`
`tachycardia, QT interval prolongation; Vascular Disorders.‘
`
`flushing; Skin and
`
`Subcutaneous Tissue Disorders.‘
`
`rash; Renal and Urinary Disorders.‘
`
`impotence; General
`
`Disorders and Administration Site Conditions.‘ hypersensitivity reactions, including angioedema
`
`with airway obstruction, urticaria,
`
`and face
`
`edema;
`
`anaphylactic
`
`reactions
`
`requiring
`
`hospitalization for emergency treatment; Injury, poisoning and procedural complications.‘ fall.
`
`Additional adverse events reported with some other oxybutynin chloride formulations include:
`
`cycloplegia, mydriasis, and suppression of lactation.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0006
`
`

`
`7 DRUG INTERACTIONS
`
`The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which
`
`produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic—like
`
`effects may increase the frequency and/or severity of such effects.
`
`Anticholinergic agents may potentially alter the absorption of some concomitantly administered
`
`drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs
`
`with a narrow therapeutic index.
`
`Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when
`DITROPAN XL® was administered with ketoconazole, a potent CYP3A4 inhibitor. Other
`
`inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g.,
`
`itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin),
`
`may alter oxybutynin mean pharmacokinetic parameters (i.e., Cm“ and AUC). The clinical
`
`relevance of such potential interactions is not known. Caution should be used when such drugs
`are co—administered.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category B. There are no adequate and well—controlled studies using DITROPAN
`XLW in pregnant women. DITROPAN XLW should be used during pregnancy only if the
`
`potential benefit to the patient outweighs the risk to the patient and fetus. Women who become
`pregnant during DITROPAN XL"° treatment are encouraged to contact their physician.
`
`Risk Summary
`
`Based on animal data, oxybutynin is predicted to have a low probability ofincreasing the risk of
`
`adverse developmental effects above background risk.
`
`Animal Data
`
`Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no
`
`evidence of impaired fertility or harm to the animal fetus.
`
`8.3 Nursing Mothers
`
`It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted
`in human milk, caution should be exercised when DITROPAN XLW is administered to a nursing
`woman.
`
`8.4 Pediatric Use
`
`The safety and efficacy of DITROPAN Xljh were studied in 60 children in a 24-week,
`open—label, non—randomized trial. Patients were aged 6-15 years, all had symptoms of detrusor
`
`overactivity in association with a neurological condition (eg, spina bifida), all used clean
`
`intermittent catheterization, and all were current users of oxybutynin chloride. Study results
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0007
`
`

`
`demonstrated that administration of DITROPAN XLERJ 5 to 20 mg/day was associated with an
`
`increase from baseline in mean urine volume per catheterization from 108 mL to 136 mL, an
`
`increase from baseline in mean urine volume after morning awakening from 148 mL to 189 mL,
`
`and an increase from baseline in the mean percentage of catheterizations without a leaking
`
`episode from 34% to 51%.
`
`Urodynamic results were consistent with clinical results. Administration of DITROPAN XL®
`
`resulted in an increase from baseline in mean maximum cystometric capacity from 185 mL to
`
`254 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity
`
`from 44 cm H20 to 33 cm H20, and a reduction in the percentage of patients demonstrating
`
`uninhibited detrusor contractions (of at least 15 cm H20) from 60% to 28%.
`
`The pharmacokinetics of DITROPAN XLLR" in these patients were consistent with those reported
`for adults [See Clinical Plzarmacology (./2.3)].
`
`DITROPAN XL® is not recommended in pediatric patients who cannot swallow the tablet whole
`
`without chewing, dividing, or crushing, or in children under the age off).
`
`8.5 Geriatric Use
`
`The rate and severity of anticholincrgic effects reported by patients less than 65 years old and
`those 65 years and older were similar. The pharmacokinetics of DITROPAN XL® were similar
`
`in all patients studied (up to 78 years of age).
`
`8.6 Renal Impairment
`
`There were no studies conducted with DITROPAN XL® in patients with renal impairment.
`
`8.? Hepatic Impairment
`
`There were no studies conducted with DITROPAN XL® in patients with hepatic impairment.
`
`10 OVE RDOSAGE
`
`The continuous release of oxybutynin from DITROPAN XL“ should be considered in the
`treatment of overdosage. Patients should be monitored for at least 24 hours. Treatment should be
`
`symptomatic and supportive. Activated charcoal as well as a cathartic may be administered.
`
`Overdosage with oxybutynin chloride has been associated with anticholincrgic effects including
`
`central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting,
`
`and urinary retention.
`
`Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in a
`
`13-year-old boy who experienced memory loss, and a 34-year-old woman who developed stupor,
`
`followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac
`
`arrhythmia, and retention of urine. Both patients fully recovered with symptomatic treatment.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0008
`
`

`
`11 DESCRIPTION
`
`is an antispasmodic, muscarinie antagonist. Each
`DITROPAN XL® (oxybutynin chloride)
`DITROPAN XLW extended—release tablet contains 5 mg, 10 mg, or 15 mg of oxybutynin chloride
`USP, formulated as a once—a—day controlled-release tablet for oral administration. Oxybutynin
`chloride is administered as a racemate of R— and S—enantiomers.
`
`Chemically,
`
`oxybutynin
`
`chloride
`
`is
`
`d,l
`
`(raeemic)
`
`4—diethylamino—2—butynyl
`
`phcnylcyclohcxylglycolate hydrochloride. The empirical
`C22H3]NO3'HCl.
`
`formula of oxybutynin chloride is
`
`Its structural formula is:
`
`C: H5
`O
`4/
`__
`ll
`3
`--c—c-o-cH,—-c=c-cH,—N\
`(Ian
`
`cm
`
`-H0
`
`Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is readily
`
`soluble in water and acids, but relatively insoluble in alkalis.
`
`DITROPAN XL® also contains the following inert
`
`ingredients: butylated hydroxytoluene,
`
`cellulose acetate, hypromellose, lactose, magnesium stearatc, polyethylene glycol, polyethylene
`
`oxide, polysorbate 80, propylene glycol, sodium chloride, synthetic iron oxides and titanium
`dioxide.
`
`System Components and Performance
`DITROPAN XLQQ uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over
`approximately 24 hours. The system, which resembles a conventional tablet in appearance,
`
`comprises an osmotieally active bilayer core surrounded by a semipermeable membrane. The
`
`bilayer core is composed of a drug layer containing the drug and excipients, and a push layer
`
`containing osmotieally active components. There is a precision—laser drilled orifice in the
`
`semipermeable membrane on the drug—layer side of the tablet. In an aqueous environment, such
`
`as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing
`
`the drug to go into suspension and the push layer to expand. This expansion pushes the
`
`suspended drug out through the orifice. The semipermeable membrane controls the rate at which
`
`water permeates into the tablet core, which in turn controls the rate of drug delivery. The
`
`lumen is thus independent of pH or
`controlled rate of drug delivery into the gastrointestinal
`gastrointestinal motility. The function of DITROPAN XL® depends on the existence of an
`
`osmotic gradient between the contents of the bilayer core and the fluid in the gastrointestinal
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0009
`
`

`
`tract. Since the osmotic gradient remains constant, drug delivery remains essentially constant.
`
`The biologically inert components of the tablet remain intact during gastrointestinal transit and
`are eliminated in the feces as an insoluble shell.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Oxybutynin relaxes bladder smooth muscle. Oxybutynin chloride exerts a direct antispasmodic
`
`effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle.
`
`No blocking effects occur
`
`at
`
`skeletal neuromuscular
`
`junctions or autonomic ganglia
`
`(antinicotinic effects).
`
`Antimuscarinic
`
`activity
`
`resides
`
`predominantly
`
`in
`
`the
`
`R—isomer.
`
`A metabolite,
`
`desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro
`studies.
`
`12.2 Pharmacodynamics
`
`In patients with conditions characterized by involuntary bladder contractions, cystometric studies
`
`have demonstrated that oxybutynin increases bladder
`
`(vesical) capacity, diminishes
`
`the
`
`frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void.
`
`12.3 Pharmacokinetics
`
`Absorption
`
`Following the first dose of DITROPAN XLW, oxybutynin plasma concentrations rise for 4 to 6
`hours;
`thereafter
`steady concentrations are maintained for up to 24 hours, minimizing
`
`fluctuations between peak and trough concentrations associated with oxybutynin.
`
`The relative bioavailabilitics of R- and S-oxybutynin from DITROPAN XL‘/F“ are 156% and
`
`187%, respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R-
`
`and S—oxybutynin are summarized in Table 2. The plasma concentration—time profiles for R- and
`
`S—oxybutynin are similar in shape; Figure 1 shows the profile for R—oxybutynin.
`
`Table 2:
`
`Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of
`DITROPAN XL” 10 mg (n=43)
`
`Parameters (units)
`
`R-Oxybutynin
`
`S-Oxybutynin
`
`Cmax
`
`Tmax
`
`ti/2 (I1)
`
`AUCW43, (ng-h/mL)
`
`AUC1.,.‘(n_g-I1/|nL)
`
`ll)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0010
`
`

`
`Figure 1:
`
`Mean R-oxybutynin plasma concentrations following a single dose of DITROPAN XL® 10 mg
`and oxybutynin 5 mg administered every 8 hours (n=23 for each treatment).
`
`4
`
`-9- DITROPAN XL® 10 mg QD
`— -0- oxybutynin 5 mg TID
`
`
`
`
`
`MeanPlasmaR-OxybutyninConcentration(ng!mL)
`
`
`
`
`
`are achieved by Day 3 of repeated
`Steady state oxybutynin plasma concentrations
`DITROPAN XL® dosing, with no observed drug accumulation or change in oxybutynin and
`
`desethyloxybutynin pharmacokinetic parameters.
`
`DITROPAN XL® steady state pharmacokinetics were studied in 19 children aged 5-15 years
`with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The
`children were on DITROPAN XL® total daily dose ranging from 5 to 20 mg (0.10 to
`0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available
`data are normalized to an equivalent of 5 mg per day of DITROPAN XL®,
`the mean
`pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin
`
`are summarized in Table 3. The plasma-time concentration profiles for R- and S-oxybutynin are
`
`similar in shape; Figure 2 shows the profile for R-oxybutynin when all available data are
`
`normalized to an equivalent of 5 mg per day.
`
`1]
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0011
`
`

`
`Table 3:
`
`Mean 1: SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
`Parameters in Children Aged 5-15 Following Administration of 5 to 20 mg DITROPAN XL®
`Once Daily (n=19), All Available Data Normalized to an Equivalent of DITROPAN XL® 5 mg
`Once Daily
`
`R-Oxybutynin
`
`S-Oxybutynin
`1.3;l:0.8
`
`R-Desethyloxybutynin
`7.8i3.7
`
`S-Desethyloxybutynin
`4.2;I:2.3
`
`73.6:b47.7
`
`5.0
`
`5.0
`
`5.0
`
`23.75: 14.4
`
`125.1 :l:66.7
`
`Figure 2:
`
`2.0
`
`Mean steady state (:1: SD) R-oxybutynin plasma concentrations following administration of5 to
`20 mg DITROPAN XL® once daily in children aged 5-15. Plot represents all available data
`normalized to an equivalent of DITROPAN XL® 5 mg once daily.
`
`
`
`
`
`MeanR—OxybutyninPlasma
`
`_. ‘Ln
`
`
`
`Concentration(ng/mL) 9-1U10
`
`0.0
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Time (hours)
`
`Food Effects
`
`The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted
`conditions.
`
`Distribution
`
`Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of
`
`distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride. Both
`
`enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of
`
`N-desethyloxybutynin are also highly bound (>97%) to plasma proteins. The major binding
`
`protein is alpha-l acid glycoprotein.
`
`Metabolism
`
`Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly
`
`CYP3A4 found mostly in the
`
`liver
`
`and gut wall.
`
`Its metabolic products
`
`include
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0012
`
`

`
`phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin,
`which is pharmacologically active. Following DITROPAN XLW administration, plasma
`concentrations of R— and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations
`
`observed with oxybutynin.
`
`Excretion
`
`Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose
`
`excreted unchanged in the urine. Also, less than 0.1% ofthe administered dose is excreted as the
`
`metabolite desethyloxybutynin.
`
`Dose Proportionality
`
`Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Chm, and AUC) following
`administration of5—2O mg of DITROPAN XL® are dose proportional.
`
`Use in Specific Populations
`Pediatric
`
`The pharmacokinetics of DITROPAN XL“ were evaluated in 19 children aged 5-15 years with
`detrusor overactivity associated with a neurological condition (e.g.,
`spina bifida). The
`pharmacokinetics of DITROPAN Xlfm in these pediatric patients were consistent with those
`
`reported for adults (see Tables 2 and 3, and Figures 1 and 2 above).
`
`Gender
`
`There are no significant differences in the pharmacokinctics of oxybutynin in healthy male and
`female volunteers following administration of DITROPAN XL®.
`
`Race
`
`there are no significant differences in the pharmacokinetics of
`that
`Available data suggest
`oxybutynin based on race in healthy volunteers following administration of DITROPAN XL”.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day
`
`showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50 times the
`
`maximum human exposure, based on a human equivalent dose taking into account normalization
`
`of body surface area.
`
`Oxybutynin
`
`chloride
`
`showed
`
`no
`
`increase of mutagenic
`
`activity when
`
`tested
`
`in
`
`Schizosaccharomyces
`
`p()mpl1olicq'fiJi*mis',
`
`Saccharomyces
`
`cerev:'.s'i'ae,
`
`and
`
`Salmonella
`
`zfyphimufium test systems.
`
`Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no
`
`evidence of impaired fertility.
`
`l3
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0013
`
`

`
`14 CLINICAL STUDIES
`
`DITROPAN XL® was evaluated for the treatment of patients with overactive bladder with
`symptoms of urge urinary incontinence, urgency, and frequency in three controlled efficacy
`
`studies. The majority of patients were Caucasian (89.0%) and female (91.9%) with a mean age of
`
`59 years (range, 18 to 98 years). Entry criteria required that patients have urge or mixed
`
`incontinence (with a predominance of urge) as evidenced by 2 6 urge incontinence episodes per
`
`week and 2 10 micturitions per day. Study 1 was a fixed-dose escalation design, whereas the
`
`other two studies used a dose-adjustment design in which each patient’s final dose was adjusted
`
`to a balance between improvement of incontinence symptoms and tolerability of side effects. All
`
`three studies included patients known to be responsive to oxybutynin or other anticholinergie
`
`medications, and these patients were maintained on a final dose for up to 2 weeks.
`
`The efficacy results for the three controlled trials are presented in the following tables and
`
`figures.
`
`Number of Urge Urinary Incontinence Episodes Per Week
`
`Mean Baseline
`
`Mean (SD) Change from
`Baseline,
`
`n
`
`34
`
`34
`
`DITROPAN xL®
`
`n
`
`Placebo
`
`15.9
`
`-15.8 (3.9)
`
`16
`
`15
`
`20.9
`
`-7.5 (8.6)
`
`
`DI FIOPAN XL®*
`
`95% Confidence Interval for
`Difference
`
`.,
`
`H33’ '28)
`
`(DITROPAN XL® - Placebo)
`
`* The difference between DITROPAN XL® and placebo was statistically significant.
`
`T Covariate adjusted mean with missing observations set to baseline values
`
`-40
`
`-20
`
`0
`
`20
`
`40
`
`Mean Change (iSD) in Episodes Per Week from Baseline
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0014
`
`

`
`n
`
`53
`
`53
`
`DITROPAN XL®
`
`27.6
`
`-17.e(11.9)
`
`n
`
`52
`
`52
`
`oxybutynin
`
`23.0
`
`-19.4(11.9)
`
`Mean Baseline
`
`Mean (SD) Change from
`Basemm
`
`95% Confidence Interval for
`
`Difference
`
`(DITROPAN XL® — oxybutynin)
`
`‘I’ Covariate adjusted mean Wi1h missing observations SET 10 baseline values
`
`(-2.8, 6.5)
`DIT OPAN XL®
`(-3.0, 1.6)**
`
`-40
`
`-20
`
`0
`
`20
`
`40
`
`Mean Change (iSD) in Episodes Per Week from Baseline
`
`n
`
`111
`
`111
`
`DITROPAN XL®
`
`n
`
`oxybutynin
`
`18.9
`
`115
`
`19.5
`
`-14.5 (3.7)
`
`115
`
`-13.8 (8.6)
`
`Mean Baseline
`
`Mean (SD) Change from
`Basemm
`
`95% Confidence Interval for
`
`Difference
`
`(DITROPAN XL® - oxybutynin)
`
`** The difference between DITHOPAN XL® and oxybutynin fulfilled the criteria for comparable efficacy.
`
`1 Covariate adjusted mean with missing observations set to baseline values
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2036 - 0015
`
`

`
`oxybutynin"
`
`-4D
`
`-20
`
`D
`
`DITFIOPAN XL®**
`
`20
`
`40
`
`Mean Change (:SD) in Episodes Per Week from Baseline
`
`16 HOW SUPPLIEDISTORAGE AND HANDLING
`
`DITROPAN XL® extended-release tablets are available in three dosage strengths, 5 mg (pale
`yellow), 10 mg (pink), and 15 mg (gray) and are imprinted on one side with "5 XL", "10 XL", or
`"15 XL" with black ink. DITROPAN XLGD extended-release tablets are supplied in bottles of
`100 tablets.
`
`5 mg
`
`10 mg
`
`15 mg
`
`100 count bottle
`
`100 count bottle
`
`100 count bottle
`
`NDC 50458-805-01
`
`NDC 50458-S10-01
`
`NDC 50458-815-01
`
`16.1 Storage
`
`Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
`
`Temperature]. Protect from moisture and humidity.
`
`17 PATIENT COUNSELING INFORMATION
`
`0
`
`Patients should be informed that oxybutynin may produce angioedema that could result in
`life threatening airway obstruction. Patients should be advised to promptly discontinue
`oxybutynin therapy and seek immediate medical attention if they experience swelling of the
`tongue, edema of the laryngopharynx, or difficulty breathing.
`
`0 Patients should be informed that anticholinergic (antimuscarinic) agents such as DITROPAN
`XL®, may produce clinically significant adverse reactions related to anticholinergic activity
`including:
`
`0 Urinary retention and constipation
`
`0 Heat prostration due to decreased sweating. Heat prostration can occur when
`anticholinergic medicines are administered in the presence of high environmental
`temperature.
`
`0
`
`Patients should be informed that anticholinergic medicines such as DITROPAN XL® may
`produce drowsiness (somnolence), dizziness or blurred vision. Patients should be advised to
`exercise