Editing AUA: Overactive Bladder (2019) (section)

=== Second-line: Pharmacologic Management ===

==== Options ====

* '''<span style="color:#ff0000">Recommended</span>'''
** '''<span style="color:#ff0000">Oral anti-cholinergic</span>'''
** '''<span style="color:#ff0000">Oral β3-adrenoceptor agonists</span>'''
* '''<span style="color:#ff0000">May be offered</span>'''
** '''<span style="color:#ff0000">Transdermal oxybutynin (patch or gel)</span>'''
*'''Consider beginning with the lowest possible dose and titrate slowly while carefully assessing for the balance between symptom control and AEs.'''
**In older patients who may metabolize drugs differently, it is advisable to start with a minimal dose and titrate as tolerated.
**Optimizing medication tolerability is critical to obtaining patient compliance in the treatment of this chronic condition.
*Compliance with a once daily dosing is greater than with medications taken more than once a day.

==== Anti-cholinergics ====

===== Options =====
# '''<span style="color:#ff0000">Oral</span>'''
##'''<span style="color:#ff0000">Oxybutynin</span>'''
##'''<span style="color:#ff0000">Tolterodine</span>'''
##'''<span style="color:#ff0000">Fesoterodine</span>'''
##'''<span style="color:#ff0000">Darifenacin</span>'''
## '''<span style="color:#ff0000">Solifenacin</span>'''
## '''<span style="color:#ff0000">Trospium</span>'''
#'''<span style="color:#ff0000">Transdermal oxybutynin (patch or gel)</span>'''

===== Efficacy =====
*'''Similar efficacy observed for all oral anti-cholinergic medications'''
**Choice of medication is patient dependent
**'''Adverse event profiles for dry mouth and constipation vary with medications'''
* Patients with more severe symptoms, on average, experience greater symptom reductions. 
**Only patients with relatively low baseline symptom levels are likely to experience complete symptom relief

===== Contraindications =====
#'''<span style="color:#ff0000">Narrow angle glaucoma</span>''' (unless approved by the treating ophthalmologist)
#'''<span style="color:#ff0000">Dementia</span>'''
#*Anti-cholinergics may be contraindicated entirely depending on the level of cognitive impairment.
#'''<span style="color:#ff0000">Impaired gastric emptying</span>'''
#*Prior to initiation of anti-cholinergics, a patient at risk for gastric emptying problems should receive clearance from a gastroenterologist
#'''<span style="color:#ff0000">Use of solid oral forms of potassium chloride</span>'''
#*Reduced gastric emptying potentially caused by the anti-cholinergics may increase the potassium absorption of these agents.
#*Anti-cholinergic therapy may be used with caution with alternative forms of potassium chloride.
#'''<span style="color:#ff0000">History of urinary retention</span>'''
##Prior to initiation of anti-cholinergics, a patient with history of urinary retention should receive clearance from a urologist.
##*A PVR may be useful in any patient suspected of a higher risk of urinary retention.
#'''<span style="color:#ff0000">Use caution in prescribing anti-cholinergics in patients who are already using''' '''other medications with anti-cholinergic properties.</span>'''
#* '''<span style="color:#ff0000">Medications with anti-cholinergic properties include (3)</span>'''
#*#'''<span style="color:#ff0000">Tricyclic antidepressants</span>'''
#*#'''<span style="color:#ff0000">Medications for Parkinsonism, other extra-pyramidal diseases and Alzheimer’s disease</span>''' (benzotropine, biperiden HCl, galantamine, rivastigmine and trihexyphenidyl HCl)
#*#'''<span style="color:#ff0000">Acetylcholinesterase inhibitors (donepezil)</span>'''
#*'''Certain anti-nausea medications and those with atropine-like properties may also potentiate adverse events.'''
#**Examples include trimethaphan, methscopolamine bromide and ipratropium
#'''<span style="color:#ff0000">Use caution in prescribing anti-cholinergics or β3-adrenoceptor agonists in the frail OAB patient.</span>'''
#* '''Frail patients are defined as patients with mobility deficits (i.e., require support to walk, have slow gait speed, have difficulty rising from sitting to standing without assistance), weight loss and weakness without medical cause and who may have cognitive deficits'''
#*'''OAB medication trials generally are not conducted in the frail elderly''', resulting in a lack of efficacy and AE data in this group. 
#**Additional AEs are reported in this group, including impaired thermoregulation with dangerous core temperature elevation.
#* Polypharmacy is common in frail community-dwelling patients, placing them at higher risk for AEs, including impaired cognition.

===== Adverse events (9) =====
#'''<span style="color:#ff0000">Dry mouth (20-40%)</span>'''
#'''<span style="color:#ff0000">Constipation (7-9%)</span>'''
#'''<span style="color:#ff0000">Dry or itchy eyes</span>'''
#'''<span style="color:#ff0000">Blurred vision</span>'''
#'''<span style="color:#ff0000">Dyspepsia</span>'''
#'''<span style="color:#ff0000">UTI</span>'''
#'''<span style="color:#ff0000">Urinary retention</span>'''
#'''<span style="color:#ff0000">Impaired cognitive function</span>'''
#'''<span style="color:#ff0000">Arrhythmias (rare)</span>'''
*'''<span style="color:#ff0000">Dry mouth</span>'''
**<span style="color:#ff0000">'''Dry mouth rates for oxybutynin (61%) significantly higher''' </span>than tolterodine (24%)
**'''<span style="color:#ff0000">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.</span>'''
*** ER formulations of oxybutynin and tolterodine result in significantly fewer patient reports of dry mouth than the IR formulations of either medication.
***Compliance with a once-daily treatment has been shown to be greater than with medications that are taken more than once a day
**<span style="color:#ff0000">'''Management'''</span>
***<span style="color:#ff0000">'''Can be mitigated with (4):'''</span>
***#<span style="color:#ff0000">'''Oral lubricants'''</span>
***#<span style="color:#ff0000">'''Small sips of water'''</span>
***#<span style="color:#ff0000">'''Sucking on sugar-free hard candies and chewing sugar-free gum'''</span>
***#<span style="color:#ff0000">'''Avoiding mouthwashes with alcohol'''</span>
***<span style="color:#ff0000">'''Transdermal preparations of oxybutynin may be offered instead of oral anti-muscarinics to patients who are at risk of or who have experienced dry mouth with oral agents'''</span>
****<span style="color:#ff0000">'''The use of transdermal anti-muscarinics should be monitored to ensure that the skin where the medication is applied remains intact.''' </span>
*'''<span style="color:#ff0000">Constipation</span>'''
**<span style="color:#ff0000">'''Can be mitigated with'''</span> 
***<span style="color:#ff0000">'''Adequate dietary fiber and fluid'''</span>
***<span style="color:#ff0000">'''Psyllium-based fiber supplements'''</span>
***<span style="color:#ff0000">'''Regular exercise and normal bowel habits.'''</span>
**<span style="color:#ff0000">'''Constipation rate significantly higher for darifenacin (17%) and oxybutynin (12%)</span>''', compared to tolterodine (5%)
*'''<span style="color:#ff0000">Constipation and dry mouth should be managed before abandoning effective anti-cholinergic therapy.</span>'''
**'''<span style="color:#ff0000">Management may include bowel management, fluid management, dose modification or alternative anti-cholinergics.</span>'''
*'''<span style="color:#ff0000">Cognitive impairment</span>'''
**Patients may not recognize that memory deterioration has occurred, making it essential for the clinician, family members and caregivers to monitor for these effects
**While newer agents (eg, darifenacin) are reported to be less likely to produce cognitive deficits in elderly patients, the literature is limited; the two-week drug administration period in these studies is not long enough to yield definitive conclusions.

==== β 3-adrenoceptor agonists: Mirabegron ====
*<span style="color:#ff0000">'''Similar efficacy profile to the anti-muscarinics and a relatively lower adverse event profile.'''</span>
**Lower incidence of bothersome adverse events may inform the selection of medications for patients who already present with dry mouth (e.g., secondary to Sjogren's syndrome) and/or constipation or for patients who experience efficacy from the anti-muscarinics but cannot tolerate these adverse events.

===== Efficacy =====
*Significant symptom reductions for voids per day and incontinence episodes per day
*Improvements in UUI, urgency episodes, and QOL measures also occur but were not as consistently statistically significant. 
*Among studies with an active control group administered tolterodine ER 4 mg/daily, mirabegron generally performed similarly to tolterodine. Higher doses of mirabegron did not produce greater effects.

===== Adverse events =====

#<span style="color:#ff0000">'''Increased heart rate'''</span>
#<span style="color:#ff0000">'''Increased blood pressure'''</span>
#*Changes in blood pressure and pulse rate are usually minor
#<span style="color:#ff0000">'''Constipation'''</span>
#*May produce lower/similar rates of constipation than some of the anti-muscarinics, except for solifenacin (5 mg and 10 mg), fesoterodine (8 mg) and trospium (60 mg), all of which had a higher risk of constipation.

==== Failure of medical therapy ====
*'''<span style="color:#ff0000">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.</span>'''
**Patients who had prior unsatisfactory symptom control and/or unacceptable adverse events with older medications (tolterodine or oxybutynin) reported better efficacy and/or more acceptable adverse event profiles with new medications (fesoterodine, solifenacin or darifenacin).
**Non-responders to anti-muscarinics should be tried on at least one other anti-muscarinic or mirabegron and/or dose modification attempted to determine if a better balance between efficacy and adverse events occurs. 
***Failure and/or the experience of adverse events with one medication should usually be addressed by trying at least one other medication before third-line therapies are considered.
**If adverse events are severe enough to compromise patient QOL, then strategies to manage specific adverse events, such as ameliorating constipation with appropriate bowel management, should be implemented before abandoning anti-muscarinic treatment.
*'''<span style="color:#ff0000">Clinicians may consider combination therapy with an anti-muscarinic and β3-adrenoceptor agonist for patients refractory to monotherapy with either anti-muscarinics or β3-adrenoceptor agonists.</span>'''
**Studies have demonstrated improved efficacy with combination therapy without any significant effect on the safety profile when compared to monotherapy
**Combination therapeutic approaches should be assembled methodically, beginning with the establishment of confidence in the partial efficacy of one therapy, continuing with an adequate trial of any additional therapies one at a time until the patient experiences adequate symptom control in the context of tolerable adverse events.
*'''Patients who are refractory to behavioral''' '''and medical therapy should be evaluated''' '''by an appropriate specialist if they desire additional'''
**The refractory patient as the patient who has failed a trial of symptom-appropriate behavioral therapy of sufficient length to evaluate potential efficacy and who has failed a trial of at least one anti-muscarinic medication administered for 4 to 8 weeks. Failure of an anti-muscarinic medication may include lack of efficacy and/or inability to tolerate adverse drug effects.