Test on day 10 post-administration compared to
`baseline, and was also found to be undetectable
`in the cerebral spinal fluid of participants [Staskin
`et al., 2010]. In a study of darifenacin among 129
`older adults aged 65-84, no significant effects on
`cognition were observed (memory scanning sensi-
`tivity, speed of reaction time, and word recognition)
`compared with placebo [Lipton et al., 2005]. No data
`on fesoterodine and memory were found.
`
`New onset delirium also does not appear to be a
`significant concern in patients taking antimuscarinic
`agents. Although several published case reports
`have documented the acute onset of delirium fol-
`
`lowing initiation of tolterodine, in incontinent adults
`with and without dementia [Womack and Heilman,
`2003: Salvatore et al._ 2007; Edwards et al., 2002;
`Williams et al., 2004; Tsao et al., 2003], these defi-
`cits resolved upon discontinuation or dose reduction
`of tolterodine.
`In a randomized controlled study of
`extended-release oxybutynin in nursing-home resi-
`dents with mild to severe dementia, there was no
`incidence of delirium over the duration of the study
`[Lackner et al., 2008]. Furthermore, more recent ev-
`idence puts into question the traditionally held belief
`that new use of anticholinergic agents provokes in-
`cident delirium in hospitalized older patients [Camp-
`bell et al.. 2011: Luukkanen et al., 2011].
`
`increasing evidence suggests that
`Taken together,
`with the exception of oxybutynin, use of the other
`antimuscarinic agents poses little or no cognitive
`risk to otherwise healthy older adults with symptoms
`of overactive bladder. However, two caveats apply.
`First, the integrity of the blood brain barrier may be
`compromised in many older adults with cerebro-
`vascular disease, diabetes, or certain forms of de-
`mentia, with the results of studies in healthy older
`adults not generalizable to frailer individuals [Kay et
`al., 2005]. Second, long—term use of antimuscarinic
`agents over months or years may yield more detri-
`mental cognitive effects than single dose or short-
`term use. A number of large observational studies
`have linked chronic consumption of antimuscarinic
`drugs with an increased risk of cognitive impairment.
`although most studies simultaneously examined the
`cumulative effect of drugs with any antimuscarinic
`properties rather than each drug class alone. [An-
`celin et al., 2006; Campbell et al.. 2009; Fox et al.,
`2011]. The Eugenia study of aging randomly recruit-
`ed 372 adults 60 years and older from Montpellier,
`France, and showed that antimuscarinic drug users
`displayed significantly poorer reaction time, atten-
`tion, immediate and delayed visuospatial memory,
`narrative recall, and verbal fluency than did non drug
`users [Ancelin et al., 2006]. A 2-year longitudinal
`study of 13,000 participants enrolled in the Medical
`Research Council Cognitive Function and Ageing
`Study also showed that use of medication with anti-
`muscarinic effects was associated with a 0.33-point
`greater decline in the Folstein Mini Mental Status
`Exam score (95% confidence interval
`(Cl)=0.03-
`
`0.64, P=.03) than not taking antimuscarinics. Two-
`year mortality was also greater for those taking
`(OR=‘l.68; 95% Cl=1.30-2.16; P<.00‘l) anticho|iner-
`gics. Many commonly prescribed medications in the
`elderly possess antimuscarinic properties [Chew et
`al., 2008], so the results may not be specific to blad-
`der antimuscarinics. Other antimuscarinic medica-
`
`tion include, among others, amytriptyline, clozapine,
`olanzepine, paroxetine, furosemide. hydrocodone,
`lansoprazole, levofloxacin, and metformin.
`
`Clinicians who remain wary of prescribing antimus-
`carinic agents for frail older adults with symptoms of
`overactive bladder are suggested to proceed with
`caution in prescribing these medications and fully
`weigh the risk—benefit ratio in light of other therapeu-
`tic options that can be equally effective for urgency
`and mixed incontinence in the elderly. If antimusca-
`rinics are to be prescribed, a short cognitive screen
`(such as the Montreal Cognitive Assessment http:/I
`www.mocatest.org) or even a full neuropsychologi-
`cal test battery for those patients who are concerned
`or at risk, before and after initiating therapy might
`reveal whether subtle impairments have been in-
`duced. This is especially pertinent because patients
`are often unaware of their memory deficits [Kay et
`al., 2006]. A proxy informant, such as the patient's
`spouse or a relative, may be able to provide more
`reliable information on possible cognitive changes
`resulting from the drugs.
`
`A frequently asked clinical question is whether anti-
`muscarinic agents used to treat incontinence should
`be contraindicated in patients with dementia already
`taking cholinesterase inhibitors. as the mechanisms
`of these two medications are diametrically opposed.
`A number of small studies have shown that cholines-
`
`terase inhibitors used to improve cognition in Alzheim-
`er's disease precipitate urinary incontinence [Hashi-
`moto et al., 2000]. A Japanese study followed 94
`patients with mild to moderate dementia treated with
`donepezil [Hashimoto et al.. 2000]. Seven patients
`developed urinary incontinence, although the event
`was transient in most patients.
`In Scotland, among
`216 patients with Alzheimer's disease initiating treat-
`ment with a cholinesterase inhibitor,
`incontinence
`was precipitated in 6.6%, and those with existing
`incontinence worsened [Starr, 2007]. Epidemiologic
`studies also show associations between cholines-
`
`terase inhibitors and incontinence [Gill et al.. 2005;
`Roe et al., 2002]. In a large population—based cohort
`study of 44,884 adults with dementia carried out in
`Canada, those who were dispensed cholinesterase
`inhibitors were more likely to subsequently receive
`an antimuscarinic drug for incontinence compared to
`those not receiving cholinesterase inhibitors (hazard
`ratio 1.55, 95% confidence interval 1.39-1.72) [Gill
`et al., 2005]. This finding was confirmed by a sepa-
`rate study in the U.S. documenting a two-fold risk of
`taking oxybutynin in dementia patients treated with
`donepezil compared to those not treated with done-
`pezil [Roe et al., 2002]. A Japanese study examined
`
`702
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0276
`
`

`
`the addition of a 3-month trial of propiverine 20 mg!
`day to donepezil in twenty-six cognitively impaired
`older adults, and found improved dryness rates with
`no deleterious effect on cognition [Sakakibara et al..
`2009]. A 6-month study also compared the effects of
`trospium, galantamine, or trospium plus galantamine
`in 178 older adults with urge incontinence (n=99), de-
`mentia (n=43) or dementia and incontinence (n=36)
`respectively [lsik et al., 2009]. Treatment with 45-60
`mg/day of trospium chloride and combined use of
`trospium with galantamine 24 mgfday was found to
`have no adverse effect on cognitive or physical func-
`tion scores in this group of patients. A larger obser-
`vational study of 3,563 long-term care residents with
`dementia also failed to document an increased rate
`
`of cognitive decline with combined use of a cholin-
`esterase inhibitor and antimuscarinic therapy (oxy-
`butynin or tolterodine) compared to cholinesterase
`therapy alone [Sink et al., 2008]. However, a 50%
`faster rate of physical function decline was observed
`in higher-functioning participants on dual
`therapy
`compared to cholinesterase inhibitor therapy alone.
`This evidence suggests the competing mechanisms
`of the antimuscarinics and cholinesterase inhibitors
`
`may indeed have clinical consequences in some.
`but not all patients.
`
`3. Cardiac safety. Another serious side effect of anti-
`muscarinic drugs in the elderly is the risk of cardiac
`adverse effects and increased mortality, particularly
`due to increases in heart rate, prolongation of the
`QT interval, and induction of polymorphic ventricu-
`lar tachycardia. These have been previously dis-
`cussed, and it has been noted that studies specific
`to the elderly are lacking [Andersson et al., 2011].
`Only one study prospectively examined the effect of
`anticholinergic drug use in 400 community—dwe|ling
`older people (aged 75-90 years) with stable cardio-
`vascular disease in Helsinki. Finland [Uusvaara et
`al., 2011]. Bladder antimuscarinic agents were not
`examined individually, but were considered in a cu-
`mulative assessment of all drugs with antimuscarinic
`properties being taken by the same individual. The
`unadjusted follow-up mortality was 20.7% and 9.5%
`among users and non-users of antimuscarinic drugs,
`respectively (p =0.010). However, the use of drugs
`with antimuscarinic properties was not a significant
`predictor of mortality in multivariate analysis after ad-
`justment for age, sex and other comorbidites (hazard
`ratio 1.57; 95% Cl 0.78, 3.15).
`
`4.Drugldrug interactions in the elderly. Rates of poly-
`pharmacy (> 5 drugs per patient) are high in the ge-
`riatric population, and cause potential for drug—drug
`interactions that increase toxicity or reduce the ef-
`ficacy of antimuscarinic agents [Chancellor and
`Miguel, 2007]. The relationship between the number
`of drugs and potential drug—drug interactions in the
`elderly is alarming. Consumption of 5 to 7 and 8 to
`10 drugs places older adults at a 4-fold and 8-fold
`increased risk of potentially serious drug—drug inter-
`actions respectively, compared with consumption
`
`of 2 to 4 drugs [Johnell 8: Klarin, 2007]. Drug drug
`interactions frequently involve isoenzymes of the
`hepatic cytochrome CYP450 system [Zakrzewski-
`Jakubiak et al., 2011]. Of the antimuscarinic drugs.
`tolterodine, darifenacin, solifenacin, and oxybutynin
`are extensively metabolized by CYP450 and are at
`greater risk of having altered drug metabolism due
`to hepatic-based drug-drug interactions. Trospium
`is eliminated renally as unchanged drug, suggest-
`ing that it has lower potential for CYP450 drug—drug
`interactions [Sand et al., 2011]. Trospium may there-
`fore represent a safer treatment option in the context
`of polypharmacy in the elderly.
`
`ll. DESMOPRESSIN -- EFFICACY AND
`SAFETY IN THE ELDERLY
`
`Desmopressin (DDAVP) (01-02 mg) reduces noc-
`turia in older persons [Rezakhaniha et al., 2011;Fu
`et al., 2011; Johnson et al., 2006], but has been as-
`sociated with significant dose-related hyponatremia
`in 2-20% of older patients [Fu et al., 2011;Johnson
`et al., 2006; Weatherall 2004]. Both female sex and
`increasing age are risk factors for the development
`of hyponatremia [Callreus et al., 2005; Rembratt et
`al., 2006; Juul et al., 2010]. A lower starting dose
`(0.025 mg) for the melt form has been suggested for
`older women [Juul et al., 2010] but requires further
`study. Caution is recommended for the initiation of
`desmopressin in adults aged 65 years and older at
`the current time.
`
`III. BOTULINUM TOXIN A IN OLDER
`ADULTS
`
`To date no studies have stratified the results of tri-
`
`als using BoNTA for the treatment of urinary inconti-
`nence in patients with neurogenic bladder according
`to age. The risk of catheterization due to high post-
`void residual urine volumes following treatment with
`botulinum toxin may be higher in older adults, as
`they are at higher risk of elevated residuals, but this
`requires systematic investigation.
`
`IV. OTHER
`
`None of the other drug classes have undergone
`rigorous evaluation in the elderly, however a num-
`ber of general guidelines apply. Use of o1-AR ago-
`nists and tricyclic antidepressants are discouraged
`in the elderly due to blood pressure considerations.
`Uncontrolled systolic hypertension could occur
`with the former agents and orthostatic hypotension
`leading to falls with the latter. There is no evidence
`that hormonal agents are of benefit for urgency or
`stress incontinence in older women, although local
`estrogens may be indicated to treat symptomatic
`vaginal atrophy. Finally, removal of any offending
`agents that could be contributing to incontinence
`should be considered.
`
`703
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0277
`
`

`
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