throbber
Approved by the AUA
`Board of Directors
`May 2014
`
`Authors’ disclosure of
`potential conflicts of
`interest and author/staff
`contributions appear at
`the end of the article.
`
`© 2014 by the American
`Urological Association
`
`
`
` 1
`
`AUA/SUFU Guideline
`
`DIAGNOSIS AND TREATMENT OF OVERACTIVE
`BLADDER (Non-Neurogenic) IN ADULTS:
`AUA/SUFU GUIDELINE
`
`E. Ann Gormley, Deborah J. Lightner, Kathryn L. Burgio, Toby C. Chai, J. Quentin
`Clemens, Daniel J. Culkin, Anurag Kumar Das, Harris Emilio Foster, Jr., Harriette
`Miles Scarpero, Christopher D. Tessier, Sandip Prasan Vasavada
`
`Purpose: The purpose of this guideline is to provide a clinical framework for the
`diagnosis and treatment of non-neurogenic overactive bladder (OAB).
`
`Methods: The primary source of evidence for the original version of this guideline
`was the systematic review and data extraction conducted as part of the Agency for
`Healthcare Research and Quality (AHRQ) Evidence Report/Technology Assessment
`Number 187 titled Treatment of Overactive Bladder in Women (2009).1 That
`report searched PubMed, MEDLINE, EMBASE, and CINAHL for English-language
`studies published from January 1966 to October 2008 relevant to OAB. AUA
`conducted additional literature searches to capture treatments not covered in
`detail by the AHRQ report (e.g., intravesical onabotulinumtoxinA) and relevant
`articles published between October 2008 and December 2011. Insufficient
`evidence was retrieved regarding diagnosis; this portion of the guideline,
`therefore, is based on Clinical Principles and Expert Opinion. The review yielded
`an evidence base of 151 treatment articles after application of inclusion/exclusion
`criteria. The AUA update literature review process, in which an additional
`systematic review is conducted periodically to maintain guideline currency with
`newly-published relevant literature, was conducted in February 2014. This review
`identified an additional 72 articles relevant to treatment. These publications were
`used to create the majority of the treatment portion of the guideline. When
`sufficient evidence existed, the body of evidence for a particular treatment was
`assigned a strength rating of A (high), B (moderate) or C (low). Additional
`treatment information is provided as Clinical Principles and Expert Opinion when
`insufficient evidence existed. See text and algorithm for definitions and detailed
`diagnostic, management and treatment frameworks.
`
`Guideline Statements
`
`Diagnosis:
`
`The Panel would like to
`
`acknowledge Martha M.
`
`Faraday, Ph.D., for her
`
`methodological expertise
`and invaluable
`
`contributions as well as
`
`the Vanderbilt Evidence-
`based Practice Center for
`
`the preparation of the
`
`evidence report
`commissioned by the
`
`Agency for Healthcare
`Research and Quality
`
`(AHRQ).
`
`1. The clinician should engage in a diagnostic process to document symptoms and
`signs that characterize OAB and exclude other disorders that could be the
`cause of the patient’s symptoms; the minimum requirements for this process
`are a careful history, physical exam, and urinalysis. Clinical Principle
`
`2. In some patients, additional procedures and measures may be necessary to
`validate an OAB diagnosis, exclude other disorders and fully inform the
`treatment plan. At the clinician’s discretion, a urine culture and/or post-void
`residual assessment may be performed and information from bladder diaries
`and/or symptom questionnaires may be obtained. Clinical Principle
`
`3. Urodynamics, cystoscopy and diagnostic renal and bladder ultrasound should
`not be used in the initial workup of the uncomplicated patient. Clinical Principle
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 1
`
`

`
`AUA/SUFU Guideline
`
` 2
`
`Overactive Bladder
`
`Guideline Statements
`
`4. OAB is not a disease; it is a symptom complex that generally is not a life-threatening condition. After assessment
`has been performed to exclude conditions requiring treatment and counseling, no treatment is an acceptable
`choice made by some patients and caregivers. Expert Opinion
`
`5. Clinicians should provide education to patients regarding normal lower urinary tract function, what is known about
`OAB, the benefits vs. risks/burdens of the available treatment alternatives and the fact that acceptable symptom
`control may require trials of multiple therapeutic options before it is achieved. Clinical Principle
`
` Treatment:
`
`First-Line Treatments:
`
`6. Clinicians should offer behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle
`training, fluid management) as first line therapy to all patients with OAB. Standard (Evidence Strength Grade B)
`
`7. Behavioral therapies may be combined with pharmacologic management. Recommendation (Evidence Strength
`Grade C)
`
`Second-Line Treatments:
`
`8. Clinicians should offer oral anti-muscarinics or oral β3-adrenoceptor agonists as second-line therapy. Standard
`(Evidence Strength Grade B)
`
`9. If an immediate release (IR) and an extended release (ER) formulation are available, then ER formulations should
`preferentially be prescribed over IR formulations because of lower rates of dry mouth. Standard (Evidence
`Strength Grade B)
`
`10. Transdermal (TDS) oxybutynin (patch [now available to women ages 18 years and older without a prescription]*
`or gel) may be offered. Recommendation (Evidence Strength Grade C)*Revised June 11, 2013
`
`11. If a patient experiences inadequate symptom control and/or unacceptable adverse drug events with one anti-
`muscarinic medication, then a dose modification or a different anti-muscarinic medication or a β3-adrenoceptor
`agonist may be tried. Clinical Principle
`
`12. Clinicians should not use anti-muscarinics in patients with narrow-angle glaucoma unless approved by the
`treating ophthalmologist and should use anti-muscarinics with extreme caution in patients with impaired gastric
`emptying or a history of urinary retention. Clinical Principle
`
`13. Clinicians should manage constipation and dry mouth before abandoning effective anti-muscarinic therapy.
`Management may include bowel management, fluid management, dose modification or alternative anti-
`muscarinics. Clinical Principle
`
`14. Clinicians must use caution in prescribing anti-muscarinics in patients who are using other medications with anti-
`cholinergic properties. Expert Opinion
`
`15. Clinicians should use caution in prescribing anti-muscarinics or β3-adrenoceptor agonists in the frail OAB patient.
`Clinical Principle
`
`16. Patients who are refractory to behavioral and pharmacologic therapy should be evaluated by an appropriate
`specialist if they desire additional therapy. Expert Opinion
`
`Third-line Treatments:
`
` 17. Clinicians may offer intradetrusor onabotulinumtoxinA (100U) as third-line treatment in the carefully-selected
`and thoroughly-counseled patient who has been refractory to first- and second-line OAB treatments. The patient
`must be able and willing to return for frequent post-void residual evaluation and able and willing to perform self-
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 2
`
`

`
`AUA/SUFU Guideline
`
` 3
`
`Overactive Bladder
`
`Guideline Statements
`
`catheterization if necessary. Standard Option (Evidence Strength Grade B C)
`
` 18. Clinicians may offer peripheral tibial nerve stimulation (PTNS) as third line treatment in a carefully selected
`patient population. Recommendation (Evidence Strength Grade C)
`
`19. Clinicians may offer sacral neuromodulation (SNS) as third line treatment in a carefully selected patient
`population characterized by severe refractory OAB symptoms or patients who are not candidates for second-line
`therapy and are willing to undergo a surgical procedure. Recommendation (Evidence Strength – Grade C)
`
` 20. Practitioners and patients should persist with new treatments for an adequate trial in order to determine
`whether the therapy is efficacious and tolerable. Combination therapeutic approaches should be assembled
`methodically, with the addition of new therapies occurring only when the relative efficacy of the preceding
`therapy is known. Therapies that do not demonstrate efficacy after an adequate trial should be ceased. Expert
`Opinion
`
`Additional Treatments:
`
`21. Indwelling catheters (including transurethral, suprapubic, etc.) are not recommended as a management strategy
`for OAB because of the adverse risk/benefit balance except as a last resort in selected patients. Expert Opinion
`
`22. In rare cases, augmentation cystoplasty or urinary diversion for severe, refractory, complicated OAB patients
`may be considered. Expert Opinion
`
`Follow-Up:
`
`23. The clinician should offer follow up with the patient to assess compliance, efficacy, side effects and possible
`alternative treatments. Expert Opinion
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 3
`
`

`
`AUA/SUFU Guideline
`
`
`
`Overactive Bladder
`
` 4
`
`Introduction
`
`Section 1: Purpose
`
`This guideline’s purpose is to provide direction to
`clinicians and patients regarding how to recognize non-
`neurogenic overactive bladder (OAB), conduct a valid
`diagnostic process and approach treatment with the
`goals of maximizing symptom control and patient
`quality of life while minimizing adverse events and
`patient burden.
` The strategies and approaches
`recommended in this document were derived from
`evidence-based and consensus-based processes. There
`is a continually expanding literature on OAB; the Panel
`notes that this document constitutes a clinical strategy
`and is not intended to be interpreted rigidly. The most
`effective approach for a particular patient is best
`determined by the individual clinician and patient. As
`the science relevant to OAB evolves and improves, the
`strategies presented here will require amendment to
`remain consistent with the highest standards of clinical
`care. This document was created to serve as a guide
`for all types of providers who evaluate and treat OAB
`patients, including those in general practice as well as
`those who specialize in various branches of medicine.
`
`Section 2: Methodology
`
`The primary source of evidence for the first version of
`this guideline was the systematic review and data
`extraction conducted as part of the Agency for
`Healthcare Research and Quality (AHRQ) Evidence
`Report/Technology Assessment Number 187 titled
`Treatment of Overactive Bladder in Women (2009).1
`That report, prepared by the Vanderbilt University
`Evidence-Based Practice Center
`(EPC), searched
`PubMed, MEDLINE, EMBASE and CINAHL for English-
`language studies published from January 1966 to
`October 2008 relevant to OAB and excluded non-
`relevant studies, studies with
`fewer
`than 50
`participants and studies with fewer than 75% women.
`AUA conducted an additional literature search to
`capture articles published between October 2008 and
`December 2011. In addition, because the Panel wished
`to consider data for male as well as female patients,
`studies excluded by the AHRQ report because there
`were
`fewer than 75% women participants were
`extracted and added to the database. Studies that
`focused primarily on nocturia were also added to the
`database. Given that the AHRQ report included limited
`information
`regarding use of neuromodulation
`
`Introduction
`
`therapies, including sacral neuromodulation (SNS) and
`peripheral tibial nerve stimulation (PTNS) (also known
`as posterior tibial nerve stimulation) and limited
`information
`regarding
`the use of
`intravesical
`onabotulinumtoxinA
`to
`treat non-neurogenic OAB
`patients, additional searches were performed
`to
`capture this literature and relevant data were added to
`the database. The AUA update
`literature review
`process, in which an additional systematic review is
`conducted periodically to maintain guideline currency
`with newly-published relevant literature, was conducted
`in February 2014. This review identified an additional
`72 articles relevant to treatment. These articles were
`added to the database, and AUA’s qualitative and
`quantitative analyses were updated as appropriate.
`
`Data from studies published after the literature search
`cut-off will be incorporated into the next version of this
`guideline. Preclinical studies (e.g., animal models),
`pediatric studies, commentary and editorials were
`eliminated. Review article references were checked to
`ensure inclusion of all possibly relevant studies.
`Multiple reports on the same patient group were
`carefully examined
`to ensure
`inclusion of only
`nonredundant information.
`
`OAB Diagnosis. The review revealed insufficient
`publications to address OAB diagnosis from an evidence
`basis; the diagnosis portions of the algorithm (see
`Figure 1), therefore, are provided as Clinical Principles
`or as Expert Opinion with consensus achieved using a
`modified Delphi technique if differences of opinion
`emerged.2 A Clinical Principle is a statement about a
`component of clinical care that is widely agreed upon
`by urologists or other expert clinicians for which there
`may or may not be evidence in the medical literature.
`Expert Opinion refers to a statement, achieved by
`consensus of the Panel, that is based on members'
`clinical training, experience, knowledge and judgment
`for which there is no evidence.
`
`OAB Treatment. With regard to treatment, a total of
`151 articles from the original search processes met the
`inclusion criteria; an additional 72 relevant articles
`were retrieved as part of the update literature review
`process and also have been incorporated. The Panel
`judged that these were a sufficient evidence base from
`which to construct the majority of the treatment
`portion of the algorithm. Data on study type (e.g.,
`randomized controlled trial, controlled clinical trial,
`observational study), treatment parameters (e.g.,
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 4
`
`

`
`AUA/SUFU Guideline
`
`
`
`Overactive Bladder
`
` 5
`
`dose, administration protocols, follow-up durations),
`patient characteristics (i.e., age, presence of specific
`symptoms such as urgency, urgency incontinence and/
`or frequency, detrusor overactivity documented by
`urodynamics), adverse events, and primary outcomes
`(as defined by study authors) were extracted. The
`primary outcomes for most studies were reductions in
`frequency, urgency incontinence, incontinence and
`urgency.
`
`The quality of individual studies was assessed by the
`EPC using accepted criteria to determine the quality of
`internal and external validity. The criteria and rating
`scheme are described in detail in the published report
`The same system was used to assess the quality of
`additional included studies.
`
`Table 1: AUA Nomenclature
`Linking Statement Type to Level of Certainty and
`Evidence Strength [Updated Version]
`Standard: Directive statement that an action should
`(benefits outweigh risks/burdens) or should not (risks/
`burdens outweigh benefits) be taken based on Grade A
`(high quality; high certainty) or B (moderate quality;
`moderate certainty) evidence
`Recommendation: Directive statement that an action
`should (benefits outweigh risks/burdens) or should not
`(risks/burdens outweigh benefits) be taken based on
`Grade C (low quality; low certainty) evidence
`Option: Non-directive statement that leaves the deci-
`sion regarding an action up to the individual clinician
`and patient because the balance between benefits and
`risks/burdens appears equal or appears uncertain based
`on Grade A (high quality; high certainty), B (moderate
`quality; moderate certainty), or C (low quality; low
`certainty) evidence
`Clinical Principle: a statement about a component of
`clinical care that is widely agreed upon by urologists
`or other clinicians for which there may or may not be
`evidence in the medical literature
`Expert Opinion: a statement, achieved by consensus
`of the Panel, that is based on members' clinical train-
`ing, experience, knowledge, and judgment for which
`there is no evidence
`
`Introduction
`
`is
`The categorization of evidence strength (ES)
`conceptually distinct from the quality of individual
`studies. Evidence strength refers to the body of
`evidence available for a particular question and includes
`consideration of study design, individual study quality,
`consistency of findings across studies, adequacy of
`sample sizes and generalizability of samples, settings
`and treatments for the purposes of the guideline. AUA
`categorizes evidence strength as Grade A (well-
`conducted RCTs or exceptionally strong observational
`studies), Grade B (RCTs with some weaknesses of
`procedure or generalizability or generally strong
`observational studies) or Grade C (observational
`studies that are inconsistent, have small sample sizes
`or have other problems that potentially confound
`interpretation of data).
`
`AUA Nomenclature: Linking Statement Type to
`Evidence Strength. The AUA nomenclature system
`explicitly links statement type to body of evidence
`strength and the Panel’s judgment regarding the
`risks/burdens.3
`balance between benefits and
`Standards are directive statements that an action
`should (benefits outweigh risks/burdens) or should not
`(risks/burdens outweigh benefits) be undertaken based
`on Grade A (high level of certainty) or Grade B
`( m o d e r at e
`l e v e l
`o f
`c e r t a i n t y )
`e v i de n c e .
`Recommendations are directive statements that an
`action should (benefits outweigh risks/burdens) or
`should not (risks/burdens outweigh benefits) be
`undertaken based on Grade C (low level of certainty)
`evidence. Options are non-directive statements that
`leave the decision to take an action up to the individual
`clinician and patient because the balance between
`benefits and risks/burdens appears relatively equal or
`unclear; Options may be supported by Grade A (high
`certainty), B (moderate certainty) or C (low certainty)
`evidence.
` Options generally reflect the Panel’s
`judgment that a particular decision is best made by the
`clinician who knows the patient with full consideration
`of the patient’s prior treatment history, current quality
`of life, preferences and values.
`
`Limitations of the Literature. The Panel proceeded
`with full awareness of the limitations of the OAB
`literature. For example, despite the relatively large
`number of randomized controlled trials (RCTs) with
`placebo control groups and randomized designs with
`active controls that assessed pharmacologic OAB
`treatments,
`the overwhelming majority of
`trials
`followed patients for only 12 weeks. Additional
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 5
`
`

`
`AUA/SUFU Guideline
`
`
`
`Overactive Bladder
`
` 6
`
`limitations included the use of different inclusion criteria
`across studies assessing the same treatment, poorly-
`defined patient groups or use of patient groups with
`limited generalizability to the typical clinical setting in
`which OAB patients are seen, lack of consistency in
`outcome measures and limited outcome measure and
`adverse event reporting. With regard to measures,
`although most studies reported urinary frequency and
`urinary incontinence, many studies did not report other
`key measures such as urgency, and only a handful
`reported nocturia data. With regard to adverse events,
`most pharmacologic studies reported rates of dry
`mouth and constipation, but few reported on other
`clinically-relevant issues such as cardiac or cognitive
`adverse events. The original completed evidence
`report and the updated literature review evidence
`report may be requested from AUA.
`
`The Overactive Bladder Panel was created in 2009 by
`the American Urological Association Education and
`Research, Inc. (AUA).
` The Practice Guidelines
`Committee (PGC) of the AUA selected the Panel Chair
`and Vice Chair who in turn appointed the additional
`panel members with specific expertise in this area. The
`AUA conducted a thorough peer review process of the
`original document. The draft guidelines document was
`distributed to 78 peer reviewers, of whom 31 provided
`comments. The panel reviewed and discussed all
`submitted comments and revised the draft as needed.
`Once finalized, the guideline was submitted for approval
`to the PGC. Then it was submitted to the AUA Board of
`Directors (BOD) for final approval. Funding of the
`panel was provided by the AUA and the Society of
`Urodynamics, Female Pelvic Medicine & Urogenital
`Reconstruction
`(SUFU), although panel members
`received no remuneration for their work. AUA’s
`amendment process provides for the amendment of
`existing evidence-based guideline statements and/or
`the
`creation of new evidence-based guideline
`statements in response to the publication of a sufficient
`volume of new evidence. The process also provides for
`the amendment or addition of Clinical Principle and
`Expert Opinion statements based on consensus among
`panel members that elements of current practice have
`shifted such that a new or revised Clinical Principle or
`Expert Opinion statement is needed. Evidence-based
`guideline amendments require the agreement of a
`methodologist and panel members that new evidence is
`sufficient to change or add evidence-based statements.
`All guideline amendments require approval of the AUA
`Practice Guidelines Committee (PGC) and BOD.
`
`Introduction
`
`Section 3: Background
`
`Definition. Overactive bladder (OAB) is a clinical
`diagnosis characterized by the presence of bothersome
`urinary symptoms. Most studies of OAB, including this
`guideline, exclude individuals with symptoms related to
`neurologic conditions. The International Continence
`Society (ICS) defines OAB as the presence of “urinary
`urgency, usually accompanied by
`frequency and
`nocturia, with or without urgency urinary incontinence,
`in the absence of UTI or other obvious pathology.”4
`Therefore, OAB symptoms consist of four components:
`urgency, frequency, nocturia and urgency incontinence.
`OAB studies have used varying combinations of these
`symptoms to identify patients for study inclusion and to
`define treatment response.
` These methodologic
`differences across studies make it a challenge to
`interpret the OAB literature related to epidemiology and
`treatment.
`
`Urgency is defined by the ICS as the “complaint of a
`sudden, compelling desire to pass urine which is
`difficult to defer.”4 Urgency is considered the hallmark
`symptom of OAB, but it has proven difficult to precisely
`define or to characterize for research or clinical
`purposes. Therefore, many studies of OAB treatments
`have relied upon other measures (e.g., number of
`voids, number of incontinence episodes) to measure
`treatment response.
`
`Urinary frequency can be reliably measured with a
`voiding diary. Traditionally, up to seven micturition
`episodes during waking hours has been considered
`normal,5 but this number is highly variable based upon
`hours of sleep,
`fluid
`intake, comorbid medical
`conditions and other factors.
`
`Nocturia is the complaint of interruption of sleep one or
`more times because of the need to void.4 In one study,
`three or more episodes of nocturia constitutes
`moderate or major bother.6 Like daytime frequency,
`nocturia is a multifactorial symptom which is often due
`to factors unrelated to OAB (e.g., excessive nighttime
`urine production, sleep apnea).
`
`the
`is defined as
`incontinence
`Urgency urinary
`involuntary leakage of urine, associated with a sudden
`compelling desire to void. Incontinence episodes can
`be measured reliably with a diary, and the quantity of
`urine leakage can be measured with pad tests.
`However, in patients with mixed urinary incontinence
`(both stress and urgency incontinence), it can be
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 6
`
`

`
`AUA/SUFU Guideline
`
`
`
`Overactive Bladder
`
` 7
`
`difficult to distinguish between incontinence subtypes.
`Therefore, it is common for OAB treatment trials to
`utilize total incontinence episodes as an outcome
`measure.
`
` In population-based studies, OAB
`Epidemiology.
`prevalence rates range from 7% to 27% in men, and
`9% to 43% in women.7-14 No clear differences exist
`between studies conducted in North America vs. other
`populations. Some studies report higher prevalence
`rates in women than men,7-10 while others found similar
`rates across genders.11-14 However, urgency urinary
`incontinence is consistently more common in women
`than in men. OAB symptom prevalence and severity
`tend to increase with age.11-12, 15 A proportion of OAB
`cases (37-39%) remit during a given year, but the
`majority of patients have symptoms for years.15, 16 To
`date, no population-based studies have directly
`examined epidemiologic differences across racial/ethnic
`groups.
`
`Patient-Reported Outcomes (PROs) and OAB.
`Since OAB is a symptom-based diagnosis, the quality of
`life (QOL) impact of the symptoms is a critical aspect of
`the condition. The degree of bother caused by OAB
`symptoms directly affects OAB care-seeking, treatment
`intensity and satisfaction with treatment. Therefore,
`assessment of patient-reported outcomes (PROs) can
`be a critical component of OAB management.
`Numerous questionnaire
`instruments have been
`developed to assess symptoms, degree of bother and
`health-related QOL in patients with OAB and urinary
`incontinence.17 This lack of standardization has often
`limited the comparability and generalizability of PROs
`across research studies.
` To address this,
`the
`International Consultation on
`Incontinence has
`developed a
`series of
`standardized modular
`questionnaires for pelvic conditions, including OAB.18
`The Panel encourages the development of such
`standardized PRO tools which can be used in OAB
`research and clinical practice.
`
`Impact on Psychosocial Functioning and Quality
`of Life (QoL). The Panel fully recognizes that OAB
`constitutes a significant burden for patients. These
`burdens include the time and effort required to manage
`symptoms during the course of daily life as well as the
`resources required to obtain treatments that may be
`costly and may present logistical challenges (e.g.,
`therapies that require frequent visits to a physician’s
`office). The negative impact of OAB symptoms on
`
`Introduction
`
`psychosocial functioning and quality of life also has
`been well-documented.19-22 Carrying out the activities
`of daily life and engaging in social and occupational
`activities can be profoundly affected by lack of bladder
`control and incontinence. Urinary incontinence in
`particular may have severe psychological and social
`consequences, resulting in restricted activities and
`unwillingness to be exposed to environments where
`access to a bathroom may be difficult. Patients also
`report negative impact on sexual function and marital
`satisfaction23 and OAB symptoms have been linked to
`depressive illness.24, 25 This negative impact also is
`evident among older adults (e.g., ≥ 65 years), resulting
`in significant impairments in QoL, including high rates
`of anxiety and depression, with the majority of patients
`reporting they have not sought treatment.26
`
`Successful treatment of OAB symptoms with behavioral
`approaches, medications, neuromodulation therapies,
`and onabotulinumtoxinA, balanced against adverse
`events, costs and ultimately patient compliance, all
`have been reported to improve patient quality of life
`(see Discussion sections under each treatment type).
`
`Section 4: Patient Presentation
`
`Symptoms. When symptoms of urinary frequency
`(both daytime and night) and urgency, with or without
`urgency incontinence, are self-reported as bothersome
`the patient may be diagnosed with overactive bladder
`(OAB).27 Additionally, a caregiver or partner may
`perceive these symptoms as bothersome and lead the
`patient to seek care. It is common for patients to have
`suffered with their symptoms for an extended time
`before seeking medical advice.
`
`Differentiation. OAB symptoms (frequency, urgency
`and urgency incontinence) may occur only at night,
`causing a single symptom of nocturia. The differential
`of nocturia includes nocturnal polyuria (the production
`of greater than 20 to 33% of total 24 hour urine output
`during the period of sleep, which is age-dependent with
`20% for younger individuals and 33% for elderly
`individuals),28 low nocturnal bladder capacity or both.
`In nocturnal polyuria, nocturnal voids are frequently
`normal or large volume as opposed to the small volume
`voids commonly observed in nocturia associated with
`OAB. Sleep disturbances, vascular and/or cardiac
`disease and other medical conditions are often
`associated with nocturnal polyuria. As such, it is often
`age-dependent, increasing in prevalence with aging and
`
`Copyright © 2014 American Urological Association Education and Research, Inc.®
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1021 - Page 7
`
`

`
`AUA/SUFU Guideline
`
`
`
`Overactive Bladder
`
` 8
`
`with poorer general health.
`
`OAB also must be distinguished from other conditions
`such as polydipsia. In OAB, urinary frequency is
`associated with many small volume voids. Frequency
`that is the result of polydipsia and resulting polyuria
`may mimic OAB; the two can only be distinguished with
`the use of frequency-volume charts. In polydipsia,
`urinary frequency occurs with normal or large volume
`voids and the intake is volume matched. In this case,
`the frequency is appropriate because of the intake
`volume and the patient does not have OAB. Frequency
`due to polydipsia is physiologically self-induced OAB
`and should be managed with education, with
`consideration of fluid management. Similarly, diabetes
`insipidus (DI) also is associated with frequent, large
`volume voids and should be distinguished from OAB.
`
`
`The clinical presentation of interstitial cystitis/ bladder
`pain syndrome shares the symptoms of urinary
`frequency and urgency, with or without urgency
`incontinence; however, bladder and/or pelvic pain,
`including dyspareunia, is a crucial component of its
`presentation
`in contradistinction to OAB.
` Other
`conditions also can contribute to OAB symptoms and
`should be assessed. For example, in the menopausal
`female patient, atrophic vaginitis can be a contributing
`factor to incontinence symptoms. There is some
`evidence for symptom improvement with the use of
`vaginal (but not systemic) estrogen.29
`
`Section 5: Diagnosis
`
`The Diagnostic Approach. Insufficient literature was
`identified to constitute an evidence base for diagnosis
`of OAB in clinical practice. For this reason, the section
`titled Diagnosis is based on Clinical Principles or Expert
`Opinion with consensus achieved using a modified
`Delphi technique when differences of opinion emerged.
`This section is intended to provide clinicians and
`patients with a framework for determining whether a
`diagnosis of OAB is appropriate; it is not intended to
`replace the judgment and experience of the individual
`clinician faced with a particular patient.
`
`Guideline Statement 1.
`
`in a diagnostic
`The clinician should engage
`process to document symptoms and signs that
`characterize OAB and exclude other disorders
`that could be
`the cause of the patient’s
`symptoms; the minimum requirements for this
`
`Guideline Statements
`
`process are a careful history, physical exam and
`urinalysis. Clinical Principle
`
`Discussion. History. The clinician should carefully
`elicit the patient’s bladder symptoms to document
`duration of symptoms and baseline symptom levels, to
`ensure that symptoms are not the consequence of
`some other condition and to determine whether the
`patient constitutes a complex OAB presentation that
`may require referral. Questions should assess bladder
`storage symptoms associated with OAB (e.g., urgency,
`urgency
`incontinence,
`frequency, nocturia), other
`bladder storage problems (e.g., stress incontinence
`episodes) and bladder emptying (e.g., hesitancy,
`straining to void, prior history of urinary retention,
`force of stream, intermittency of stream). The
`symptom

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket