meet the speakers - annual.ascp.com

10/19/21

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California

Urine Good Hands:Updates in Clinical Management of

Urinary IncontinenceMacayla Bartucca, PharmD, BCPS, BCGP

Assistant Clinical ProfessorNortheastern University

Catherine Liu, PharmD, BCPS, BCGPAssistant Professor of Pharmacy Practice

Touro College of Pharmacy

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Meet the Speakers

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Macayla Bartuccais an Assistant Clinical Professor atNortheastern University School ofPharmacy and a Geriatrics ClinicalPharmacist at Harbor Health ElderService Plan. Dr. Bartucca completedGeriatrics residency at VA ConnecticutHealthcare System. She is boardcertified in Pharmacotherapy and Geriatrics.

Catherine Liuspecializes in geriatrics and is aclinical ambulatory care pharmacist ather practice site at New-York PresbyterianHospital. Dr. Liu completed both herPGY-1 Pharmacy Practice Residency and PGY-2 Geriatrics Pharmacy Residencyat the VA Connecticut. Dr. Liu is also aboard-certified pharmacotherapy specialist and board-certified geriatric pharmacist.

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Disclosure

• Drs. Bartucca and Liu have no actual or potential conflicts of interest in relation to this program or presentation.

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Learning Objectives1. Review proper clinical assessment of urinary incontinence, inclusive and appropriate

language, and differentiating type of incontinence.

2. Identify outcomes from landmark trials involving antimuscarinic/anticholinergic agents, beta-3 adrenergic receptor agonists, and other pharmacotherapy agents used for treatment of urinary incontinence.

3. Compare risks and benefits of pharmacotherapy and devices/supplies used for urinary incontinence in older adults.

4. Given a patient case, utilize current guidelines and available clinical trial evidence to create a patient-centered care plan for management of urinary incontinence in older adults who may be at increased risk of adverse outcomes such as social isolation.

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Prevalence

Lightner DJ. J Urol. 2019; 202: 558.Gormley EA. J Urol. 2012; 188: 2455.5

● Urinary incontinence (UI) affects up to 27% of men and up to 43% of women§ Women > Men (until age 80 years)

§ Prevalence in community-living elders aged ≥ 65 years is 15-30%, rising to ≥ 50% in those who reside in LTC

● Overactive bladder (OAB) symptom prevalence and severity tend to increase with age

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Definitions

Lightner DJ et al. J Urol. 2019; 202: 558.Gormley EA et al. J Urol. 2012; 188: 2455.6

OAB

• Urinary urgency usually accompanied by frequency and nocturia with or without urge urinary incontinence (UUI), in the absence of UTI or other obvious pathology

Urgency

• Sudden, compelling desire to pass urine which is difficult to defer

• Hallmark symptom of OAB

Frequency

• Reliably measured with a voiding diary

• ≤7 micturition episodes during waking hours is normal

• Nocturia

Nocturia

• Interruption of sleep 1+ episode due to need to urinate

Urge urinary incontinence

(UUI)• Requires Urologist

diagnosis• Involuntary

leakage of urine, associated with a sudden compelling desire to void

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Implications of UI

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Social Implications

Sleep disturbance

Travel limitation

Frequency provider

visits

Financial burden

Isolation

Caregiver burden

Low self-esteem

Lack of sexual

intimacy

Associated Morbidity

Depression

Anxiety

Sexual dysfunction

Dehydration

UTIs

Skin breakdown & infection

Falls

Fractures

Lightner DJ et al. J Urol. 2019; 202: 558.Gormley EA et al. J Urol. 2012; 188: 2455.

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Risk Factors for Incontinence

• Cognitive impairment• Cerebral vascular accident• Chronic degenerative

diseases that impair mobility

• Diabetes• Environmental barriers• Smoking

• Estrogen depletion• High-impact physical

activities• Obesity• Pregnancy with vaginal

delivery and episiotomy

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Age-related Vulnerability to UI

DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 11e. 9

↓Bladder capacity

Detrusor overactivity

↓Detrusor contractility

Benign prostate

hyperplasia(BPH)

Atrophic vaginitis

(urge/stress incontinence)

↑Urine production later in the

day/overnight

Decrease in flow rate in men with prostatic enlargement.

Urethral resistance in women with loss of estrogen.

Present in ~20% of healthy, continent older persons.

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California 10

Normal Bladder Filling & Emptying

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Bladder Physiology

DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 11e.

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Assessment of OAB

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History, physical, UA

Patient Education

Behavioral Modifications

Pharmacotherapy based on type

Additional workup needed

PVR

Urine culture

Bladder diary

Not OAB or complicated OAB consider referral

Treatment goals met

START

S/sx of OAB(-) UA


UA = Urinalysis; PVR = Post void residual; OAB = Overactive bladder;S/Sx = Signs and symptoms; AEs = adverse effects; PTNS = peripheral

tibial nerve stimulation; SNS = sacral neuromodulation

Uncleardiagnosis

S/sx OAB

Monitor efficacy

Monitor AEs

Treatment goals not met after appropriate

duration*

*8-12 weeks for behavioral modification; 4-8 weeks for most pharmacotherapy

For select patients:Intra-detrusor botulinum

toxin, PTNS, SNS

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Gathering a Patient History

Thirugnanasothy S. BMJ 2010;341:c383513

Urinary Symptoms

•Storage symptoms: frequency, nocturia, urgency•Voiding symptoms: hesitancy, poor urinary stream, dribbling•Precipitants of urinary leakage (cough, exertion)•History of hematuria and recurrent UTI

Bowel Symptoms

•Constipation, straining, fecal incontinence

Fluid Intake

•Specific drinks (such as caffeinated drinks) and volume

Drug History

•Sedatives and hypnotics, antimuscarinics, diuretics, alcohol

Medical History

•Previous surgery (e.g., hysterectomy, prostatectomy)•Women: pregnancy history, mode of delivery, birth weight of children

Social History

•Access to toilets and aides• Mobility•Impact on quality of life

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Gathering a Patient History: Transgender CareTransgender Women &

Urinary Health• Individuals who were

designated male at birth• Exposure to high-levels of

estradiol and anti-androgen medications • Limit prostate growth, relax

pelvic floor à Stress +/- urge incontinence

• Removal of testes (before age 50) à Reduced risk of BPH

Transgender Men & Urinary Health

• Individuals who were designated female at birth

• Exposure to high-levels of testosterone• Reduced estrogen à Vaginal

dryness, urinary urgency, frequency, dysuria, pelvic pain, and UTIs

• Atrophic vaginitis

Fosnight A. Hormone Therapy and Urinary Health for Transgender Individuals. https://aeroflowurology.com/blog/hormone-therapy-and-urinary-health-for-transgender-individuals. Accessed 8/2/21 14

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https://aeroflowurology.com/blog/hormone-therapy-and-urinary-health-for-transgender-individuals

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Types of Urinary Incontinence

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Urge Stress Overflow Functional


MIXED

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Prevalence by Type

MEN WOMEN

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Mixed (12%)

Overflow (29%)

Urge (59%)


Mixed (5%)

Overflow (12%)

Stress (21%)

Urge (62%)

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Identifying Causes

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• Delirium• DrugsD• Restricted mobilityR• Infection• Inflammation• Impaction (fecal)

I• Polyureic stateP

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Medication Regimen Review

Agent Potential Impact on Urination/IncontinenceAlcohol Increased frequency, urgency, sedation, immobility

Alpha agonists Outlet obstruction (men)

Alpha blockers Stress leakage (women)

ACE-inhibitors Cough can worsen stress incontinence

Anticholinergics Impaired emptying, retention, delirium, sedation, constipation

Calcium channel blockers

Impaired detrusor contractility and retention;Dihydropyridine agents can also cause pedal edema (nocturnal polyuria)

Cholinesterase inhibitors Urinary incontinence, interactions with antimuscarinic

Gabapentin and pregabalin Edema causing nocturia and nighttime incontinence

Loop diuretics Polyuria, frequency, urgency

Narcotics Urinary retention, fecal impaction, sedation, delirium

NSAIDs Pedal edema causing nocturnal polyuria

Sedative hypnotics Sedation, delirium, immobility

Thiazolidinediones Pedal edema causing nocturia polyuria


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Clinical Assessment by Type


URGE•Characteristics: Leakage of large volume urine due to inability to delay voiding after sensation of bladder fullness is perceived

•Causes: Detrusor overactivity (e.g., GU tumors, stroke, dementia, Parkinson’s)

STRESS•Characteristics: Involuntary loss of small volume urine with increasing abdominal pressure (e.g., coughing, laughing, exercise)

•Causes: Weak pelvic floor muscles (e.g., childbirth, menopause)

OVERFLOW•Characteristics: Leakage of urine caused by mechanical forces of overdistended bladder or bladder/sphincter dysfunction (large or small volume)

•Causes: Anatomic obstruction (prostate); Contractile issues due to diabetes, spinal cord injury; medications; MS and other neurologic disorders

FUNCTIONAL•Characteristics: Inability to toilet due to cognitive or physical impairment, environmental barriers

•Causes: Dementia, neurologic conditions, psychologic factors (e.g., depression)

MIX

ED C

HARA

CTER

ISTI

CS

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Assessment of OAB

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Patient Education




PVR

Urine culture

Bladder diary


Treatment goals met

START

S/sx of OAB(-) UA




Uncleardiagnosis

S/sx OAB

Monitor efficacy

Monitor AEs


duration*



toxin, PTNS, SNS

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Lifestyle Interventions

• Adjust fluid intake timing (e.g., avoid after 5pm)

• Manage constipation• Use pads/protective garments• Reduce alcohol intake• Reduce carbonated beverages (with or without caffeine), coffee or

tea (with or without caffeine), citrus juice and fruits, tomatoes and tomato-based products, spicy foods, artificial sweetener, chocolate, corn syrup, sugar or honey

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Behavioral Interventions

• Voluntary voiding to keep bladder volume low

• Bladder retraining with timed voiding• Timed voiding while awake with initial

frequency based on the smallest time interval between voids (e.g., obtained from the bladder diary or every two hours)

• Double voiding (repeat voiding after 5 minutes by changing position; lean forward more and gently press the abdomen)

• Especially helpful in detrusor hyperactivity with impaired contractile function

• Pelvic floor muscle-strengthening exercises• Moderate repetitions of the strongest contraction

for progressively longer times (e.g., 3 sets of 10 contractions held for 6 seconds; 3x/week)

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Behavioral Interventions in Cognitively Impaired

• Habit training: Use timed voiding with the interval based upon the individual's usual voiding schedule as evident on the bladder diary

• Scheduled voiding: Use when unable to toilet independently (timed voiding using an arbitrarily set interval, usually every 2-3 hours)

• Prompted voiding: Regular monitoring with encouragement for patients to report their continence status; Prompting to toilet on a scheduled basis; praise and positive feedback when individuals are continent and attempt to toilet

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Pelvic Floor Muscle Strengthening/Kegel Exercises

Pelvic Floor Muscles in Women• Pretend you are trying to avoid passing gas.• Pretend to tighten your vagina around a

tampon.

• Pretend you are trying to avoid passing gas.• While urinating, try to stop your urine

stream.

Pelvic Floor Muscles in Men

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Why Behavioral Interventions?

25 Burgio KL, et al. JAMA. 1998;280(23):1995–2000.

RCT comparing behavioral vs drug therapy for UUI in older women (n=197)

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Absorbent Products

26 Newman DK. 2004;24(4):316-33.

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Non-pharmacologic Options

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Toilet Risers

Bedside Commode

Handheld Urinal

Support Pessaries

Bladder Support DevicesPenile Clamps

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External Urine Collection

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Condom Catheter for Men PureWick by BD for Women

https://youtu.be/ztGblBFHQeE

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https://youtu.be/ztGblBFHQeE

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Assessment QuestionA 70-year-old woman comes to your pharmacy reporting urinary symptoms of urgency, frequent urination, and urination when coughing or sneezing.

What type of urinary incontinence does this patient likely have?A. Urge incontinenceB. Stress incontinenceC. Mixed incontinenceD. Overflow incontinence

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Assessment QuestionA patient comes to your pharmacy stating she has urge urinary incontinence. Her past medical history is significant for hypertension, diabetes, and a history of mild dementia.

Which of the following behavioral therapies should be initiated to manage her incontinence?A. Reduce the patient’s daily fluid intakeB. Create scheduled voiding with patient promptingC. Instill habit training with the patientD. Counsel the patient on pelvic floor exercises

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Assessment of OAB

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Patient Education




PVR

Urine culture

Bladder diary


Treatment goals met

START

S/sx of OAB(-) UA




Uncleardiagnosis

S/sx OAB

Monitor efficacy

Monitor AEs


duration*



toxin, PTNS, SNS

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Add

phar

mac

othe

rapy

base

d on

type

StressDuloxetine

Topical estrogensα-adrenergic agonists

Imipramine

Pelvic floor physical therapyPessaries

Minor surgical interventions

Urge Antimuscarinicsβ3-adrenoceptor agonists

In select patients:Intra-detrusor botulinum toxin

PTNS or SNS

Overflow α-blockers5-alpha reductase inhibitors

Functional Implement further lifestyle interventions

After initial evaluation ruling out reversible causes and implementation of lifestyle and behavioral modifications without reaching treatment goals, pharmacotherapy should be trialed.

Jayarajan J, et al. Res Rep Urol. 2013;6:1-16.

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Antimuscarinic AgentsMechanism of action: Antagonist of muscarinic receptor which blocks acetylcholine and thereby limiting contractions of detrusor muscle

Jayarajan J. Res Rep Urol. 2013;6:1-16.DiPiro JT. Pharmacotherapy: A Pathophysiologic Approach, 11e. 33

•Brain (cortex, hippocampus), salivary glands, sympathetic gangliaM1

•Heart, hindbrain•Smooth muscle (80% of detrusor)

•Salivary glands, brain, eye (lens, iris)•Smooth muscle (20% of detrusor)

•Brain (forebrain, striatum)M4•Brain (substantia nigra), eyeM5

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Uroselectivity & Binding Affinities

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Agent Chemical Property M1 M2 M3 M4 M5 Uroselectivity

Oxybutynin Tertiary amine 8.7 7.8 8.9 8.02 7.4 Higher M1M3>M2, minimally

Tolterodine Tertiary amine 8.8 8.0 8.5 7.7 7.7 None

Trospium Quaternary amine 9.2 9.2 9.3 9.0 8.7 None; theoretical low penetration across blood-brain barrier

Darifenacin Tertiary amine 8.2 7.4 9.1 7.3 8.0 M3 selective

Solifenacin Tertiary amine 7.6 6.9 8.0 NA NA Some M1M3>M2, minimally

Festoterodine Tertiary amine 9.5 9.2 8.9 8.7 9.2 None

VA PBM. Anticholinergic Agents for Overactive Bladder Syndrome: Drug Class Review. 2011.

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Agent Dose Geriatric Dosing Renal Impairment Dosing

Hepatic Impairment Dosing

Administration

Oxybutynin IR 2.5-5 mg BID-TID; Max dose 5 mg QID

2.5-5 mg BID-TID NR NR Dose titration over 1 -3 months. Best if taken on an empty stomach.

Oxybutynin ER 5-10 mg once a day; Max dose 30 mg once a day

5-10 mg daily NR NR Can be taken without regard to meals. Dose titration no faster than weekly intervals. Do not crush, chew or split.

Oxybutynin TDS 3.9 mg/day patch applied q3-4 days

3.9 mg/day applied q3-4 days

NR NR Apply to dry, intact skin on the abdomen, hip or buttocks. Apply each patch to a new site; avoid reapplying to the same site within 7 days.

Tolterodine IR 1-2 mg BID 1-2 mg BID CrCl 10-30 mL/min: 1 mg BID

1 mg BID Use 1 mg BID for patients taking concurrent CYP3A4 inhibitors. Food increases bioavailability 53%.

Tolterodine ER 2-4 mg once daily

2-4 mg daily CrCl 10-30 mL/min: 2 mg daily

2 mg daily Use 2 mg once daily for patients taking concurrent CYP3A4 inhibitors.

NR = dose adjustment not required


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Agent Dose Geriatric Dosing

Renal Impairment Dosing

Hepatic Impairment Dosing

Administration

Trospium IR 20 mg BID >75 years: 20 mg daily

CrCl <30 mL/min: 20 mg daily; XR not recommended

Moderate-severe: Use caution

Take on an empty stomach.

Trospium XR 60 mg once daily

Darifenacin 7.5-15 mg daily

NR NR Moderate: Maximum dose 7.5 mg daily

Starting dose 7.5 mg daily, increase to 15 mg daily no sooner than 2 weeks after starting. May be taken without regard to food. Do not crush, chew or split.

Solifenacin 5 mg daily; Max dose 10 mg daily

NR CrCl<30 mL/min: Maximum 5 mg daily

Moderate: Max dose 5 mg dailySevere: Avoid

May take without regard to food.

Festoterodine 4 mg daily; Max dose 8 mg daily

NR CrCl <30 mL/min:Maximum 4 mg daily

Moderate: NRSevere: Avoid

May take without regard to food. Do not crush, chew or split.


NR = dose adjustment not required

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AUA/SUFA 2012/2019 Guidelines• In patients unwilling or unable to adhere to behavioral

interventions, it is appropriate to use pharmacotherapy• Antimuscarinics ↓ symptoms but have A/Es that limit use

• Dry mouth, constipation, dry eyes, blurred vision, dyspepsia, urinary retention, impaired cognitive function

• Rarely arrhythmias and QTc prolongation may occur• If treatment failure and/or AEs with one antimuscarinic

agent → try at least one other agent with consideration of side effect profile


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Efficacy of Antimuscarinics

• No difference in efficacy between agents (e.g., 24-hour frequency, urgency incontinence, symptom level or reduction)

• Severe symptoms at baseline à Greater symptom improvement with antimuscarinics vs. lifestyle/behavioral interventions alone

• Less severe symptoms at baseline à Possible complete relief of symptoms and incontinence episodes with antimuscarinics

• No apparent relationship between baseline symptom level and symptom reduction for urgency and nocturia

38Lightner DJ. J Urol. 2019; 202: 558.

Gormley EA. J Urol. 2012; 188: 2455.

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Figure 1. Baseline UUI (episodes/day and UUI Reduction (episodes/day) for randomized trials by drug

Figure 2. Baseline urgency (episodes/day and urgency reduction (episodes/day) for randomized trials by drug


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Adverse Effects

Anticholinergic Use

Patient Preference

Medication Adherence

Drug Interactions

Comorbid Conditions

Availability of

resources

Cost/ formulary

Given similar efficacy across agents, choice of agent depends on patient-specific factors.

Agent SelectionFactors

Goals of care

Disease interactions

Ability to apply patch

Ability to crush,

chew, split

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Antimuscarinics: Agent Selection

• Treatment for OAB is generally required long-term• Optimizing medication tolerability is crucial to adherence

• Side effects are major contributors to discontinuation of therapy• Consider prior medication trials, cost and pill burden• Extended-release (ER) tend to be better tolerated but if tolerating

immediate-release (IR) with good symptom control, no need to change to an ER formulation


Choosing an agent and formulation with the lowest likelihood of AEs may improve adherence and outcomes.

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Antimuscarinics: Adverse Effect Profiles

Jayarajan J. Res Rep Urol. 2013;6:1-16.

Improved with ER vs. IR formulations

Dose dependent change in dry mouth symptoms

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Anticholinergic Adverse Effects

“Hot as a hare” à Increased body temperature“Blind as a bat” à Mydriasis (dilated pupils)

“Dry as a bone” à Dry mouth, dry eyes, decreased sweat“Red as a beet” à Flushed face

“Mad as a hatter” à Delirium, confusion

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IR vs. ER Formulations

• If IR and ER formulations are available, ER should be preferentially prescribed due to lower rates of dry mouth (SOE, B)

○ Meta-analysis of AEs showed ER formulations of oxybutynin, tolterodine, and trospium resulted in significant reductions in dry mouth:


Agent ER IR

Oxybutynin 40.0% (95% CI: 28% to 53%) 69% (95% CI: 60.6% to 76.5%)

Tolterodine 18% (95% CI: 14.8% to 21.4%) 28.8% (95% CI: 25.1% to 32.8%)

Trospium 8.7-12.9% 19.8-41.4%

SOE = strength of evidence

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Patch Formulations

• Transdermal (TDS) oxybutynin patch may be offered (SOE, C)○ TDS may be offered to those at risk of/who experience dry mouth with PO○ TDS reduces incontinence episodes with lower rates of dry mouth (9.6%)

vs. oral oxybutynin ER (40%) and oral oxybutynin IR (68%)• Dmochowski et al. compared 3.9 mg TDS oxybutynin (q4 days) vs.

placeboo ↓ incontinence episodes (3.3 vs 2.8 episodes with placebo)o ↓ in 24-hour frequency (2.3 vs 1.7 episodes with placebo)

Lightner DJ. J Urol. 2019; 202: 558.Gormley EA. J Urol. 2012; 188: 2455.

Dmochowski RR. J Urol. 2002; 168 (2):580-86.45SOE = strength of evidence

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Drug-Disease Considerations

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Use extreme caution in prescribing

anticholinergics in elders with:

History of urinary retention

Urology consult should be considered

Use caution in patients with a PVR >250-300 mL

Taking solid oral forms of potassium chloride

Reduced gastric emptying caused by anticholinergics

may ↑K+ absorption

Switch to alternative forms of potassium

Narrow-angle glaucoma Get approval of use from treating ophthalmologist/optometrist

Impaired gastric emptyingPatient should be seen by and get clearance for use from gastroenterologist

Patients may not recognize cognitive decline à clinician,

family, caregivers must monitor


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Drug-Disease Considerations

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Use extreme caution in prescribing

anticholinergics in elders with:

Taking other medications with anticholinergic

properties

Frailty

Begin with lowest dose and increase slowly while

assessing for balance between symptom

control/AEs

Use of TD anticholinergics should be monitored for

intact skin with use

Cognitive impairmentNewer agents may be less likely to worsen cognition,

but literature is limited

Patients may not recognize cognitive

decline à clinician, family, caregivers must monitor

PVR >250 to 300 mLPossible outlet obstruction or overflow urinary incontinence, antimuscarinics may worsen;

further workup needed


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Drug-Drug ConsiderationsPrescribers should be aware that concurrent use of additional medications with

antimuscarinic/anticholinergic activity may potentiate AEs.

Antihistamines• Diphenhydramine• Hydroxyzine• Meclizine

Tricyclic antidepressants• Amitriptyline• Imipramine

Parkinson’s treatment• Benztropine

Antipsychotics• Prochlorperazine

Skeletal muscle relaxants• Cyclobenzaprine• Carisoprodol

GI antispasmodics• Dicyclomine• Belladonna• Hyoscyamine

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*List is not all-inclusive.


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Management of Adverse Effects

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Counsel on adequate dietary fiber and fluid; psyllium-based fiber supplements; regular exercise

Bowel Management

Utilize oral lubricants (e.g., artificial saliva); avoid mouthwashes with alcohol; take small sips of water; sugar-free hard candies; sugar-free gum

Dry Mouth

Provide education that dose reduction may provide relief from AEs while retaining some therapeutic effect

Dose Modification

Start on low dose and titrate slowly if toleratedSlow Titration

Try alternative antimuscarinic agents to identify an agent that patient can tolerate or change to β3-adrenoceptor agonist

Alternative Agents


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Approach to Antimuscarinic Use

• Recommended duration is 8-12 weeks for behavioral therapies; 4-8 weeks for pharmacologic therapies

• High rates of discontinuation weeks to months after initiation due to AEs• Manage constipation and dry mouth before discontinuing effective

therapy• If inadequate symptom control and/or significant AEs with

one agent → dose modification, agent rotation, or β3-adrenoceptor agonist should be trialed

50Lightner DJ. J Urol. 2019; 202: 558.

Gormley EA. J Urol. 2012; 188: 2455.

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Assessment Question

KK is a 63-year-old woman with PMH significant for OAB and HTN. She has been taking oxybutynin IR 5mg PO BID for 3 weeks and reports some improvement in symptoms but continues to have 10 micturitions/day with 8 episodes of urgency/day. She reports having “a bitter taste” and bothersome dry mouth. Last BP = 160/92mmHg.

Which of the following is the best option for KB at this time?A. Continue current regimen of oxybutynin IR 5mg PO BIDB. Switch oxybutynin IR 5mg PO BID to oxybutynin ER 10mg PO dailyC. Decrease oxybutynin IR from 5mg PO BID to oxybutynin IR 2.5mg PO BIDD. Switch oxybutynin IR 5mg PO BID to mirabegron 25mg PO daily

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β3-Adrenoceptor Agonists

Mechanism of Action:• Activates beta-3 adrenergic

receptors in the bladder • Causes relaxation of detrusor

smooth muscle during the urine storage phase à increases bladder capacity

• Mirabegron (Approved 6/2012)• Vibegron (Approved 12/2020)

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Mirabegron (Myrbetriq®)Efficacy and Safety of Mirabegron in Patients With Symptoms of OAB

Design 12-week, double-blind, RCT; multicenter; patients with symptoms of OA ≥3 months; 94% White; 72% Female; Mean age 59 years; 48% no prior antimuscarinic use, 52% prior antimuscarinic use

Intervention and Endpoints

Intervention: Mirabegron 25 mg daily vs. mirabegron 50 mg daily vs. placeboCo-primary endpoints:• Change in mean number of incontinence episodes/day• Change in mean number of micturitions/day

Results • Statistically significant improvements in # of incontinence episodes and micturition frequency/day in mirabegron 25 mg and 50 mg groups vs. placebo

• Mirabegron was well tolerated vs placebo; 25 mg dose was effective in treating the symptoms of OAB within 8 weeks; 50 mg dose was effective within 4 weeks

53Herschorn S, et al. Urology. 2013;82(2):313-20.

MYRBETRIQ [Package Insert]. Astellas Pharma. Northbrook, IL..

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Efficacy of MirabegronMean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours

Placebo Mirabegron 25mg

Mirabegron50mg

Baseline # of incontinence episodes/day

2.43 2.65 2.51

Decrease -0.96 -1.36 -1.38

Difference from placebo -0.40 -0.42

p-value 0.005 0.001

Baseline # of micturitions/day

11.48 11.68 11.66

Decrease -1.18 -1.65 -1.60

Difference from placebo

-0.47 -0.42

p-value 0.007 0.015

54 MYRBETRIQ [Package Insert]. Astellas Pharma. Northbrook, IL..

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Mirabegron Considerations for Use

• Not recommended for use in patients with severe uncontrolled HTN (SBP ≥180 mmHg and/or DBP pressure ≥110 mmHg)

• Avoid in patients with history of angioedema • Rare reaction with onset as early as 1st dose of mirabegron; mechanism

not clearly established

• Dose adjustment may be necessary for narrow therapeutic index CYP2D6 substrates

• Prolonged QTc at baseline or in combination with other QTc prolonging medications

55 MYRBETRIQ [Package Insert]. Astellas Pharma. Northbrook, IL..

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Vibegron (Gemtesa®)Efficacy and Safety of Vibegron for Treatment of OAB in Patients Aged ≥65 and ≥75 Years

Design 12-week, double-blind, randomized, placebo-controlled, and active-controlled trial in patients with OAB and symptoms ≥3 months

Interventions and Endpoints

Randomized 5:5:4 to receive once-daily for 12 weeks, respectively:• Vibegron 75mg • Placebo • Tolterodine ER 4mg Co-primary endpoints:• Change in mean number of UUI episodes/day• Change in mean number of micturitions/day

Results Statistically significant improvements in # of incontinence episodes and micturition frequency/day in vibegron group vs. placebo; rates were similar when compared with tolterodine group but better tolerability vs. tolterodine group

56 Varano S, et al. Drugs & Aging. 2021;38:137–146

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Efficacy of Vibegron

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Change from baseline in average daily number of UUI episodes for patients aged (a) ≥ 65 years and (b) ≥ 75 years

Varano S, et al. Drugs & Aging. 2021;38:137–146

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Mirabegron vs. Vibegron Administration & Dosing Mirabegron (Myrbetriq®) Vibegron (Gemtesa®)

Dosing and Administration

• Dose titration required• Starting dose: 25 mg daily, alone or in combination with

solifenacin 5 mg daily; May titrate to 50 mg daily, alone or in combination with solifenacin 5 mg daily, after 4-8 weeks

• Do not chew, divide, crush

• No dose titration• Dose: 75 mg daily• Can crush tablets and mix in applesauce

Renal Dose Adjustment

• Dose adjustment for GFR 15 to <30 mL/min/1.732: Do not exceed 25mg daily

• Use not recommend in GFR <15 mL/min/1.732

• Use not recommend in GFR <15 mL/min/1.732

Hepatic Dose Adjustment

• Moderate impairment (Child-Pugh B): Do not exceed 25 mg daily

• Severe impairment (Child-Pugh C): Not recommended

• Severe impairment (Child-Pugh C): Not recommended

Considerations for Use

• Not recommended in severe uncontrolled HTN (SBP ≥180 and/or DBP ≥110 mm Hg); dose-dependent ↑ in BP

• QTc prolongation at supratherapeutic doses• Angioedema in rare cases• CYP2D6 drug-drug interactions (e.g., metoprolol)

• Adverse effects were rare but similar to anticholinergics: headache (4%), hot flashes (2%), constipation (2%), xerostomia (2%), increased PVR/urinary retention (<2%); UTI (6% in patients treated x1 year)

58 MYRBETRIQ [Package Insert]. Astellas Pharma. Northbrook, IL..GEMTESA [Package Insert]. Urovant. Irvine, CA.

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Switching from Antimuscarinics to β3-Adrenoceptor Agonists• Systematic review evaluated 94 trials and showed antimuscarinics had only a small

benefit vs. placebo in achieving continence and improving UI symptoms; absolute risk difference in continence was <20%

• A high proportion of patients discontinue antimuscarinics due to adverse effects, except for, trospium and solifenacin (*trospium and solifenacin 5mg have shown better tolerability vs. other antimuscarinics):

• Less than 50% continue treatment after 6 months• Less than 25% continue treatment after 1 year• Less than 10% continue treatment beyond 2+ years

• Most patients enrolled in mirabegron and vibegron trials experienced a wash-out period before the introduction or were treatment naive

Shamliyan T, et al. Ann Intern Med. 2012;156:861-74.Liao CH. Medicine (Baltimore). 2016;95(45):e4962.

Brostrøm S. Eur J Clin Pharmacol. 2009;65(3):309-14. 59

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Direct Switch of Stable Antimuscarinic Therapy to β3-Adrenoceptor AgonistsHigh satisfaction with direct switching from antimuscarinics to mirabegron in patients receiving stable antimuscarinic treatment

Objective Observational study to assess efficacy and safety directly switching from antimuscarinics to mirabegron in patients with OAB from 2014-2015

Design • 282 (209 men, 73 women); mean age, 74.4 years• On stable antimuscarinic treatment >3 months • Primary end-point was global response assessment (GRA) at baseline and 1 month after switching

Results Change in GRA at 1 month: 19.1% = marked improvement; 10.6% = moderate improvement; 25.5% = mild improvement; 31.2% = no significant change; 5.3% = mild worsening; 1.1% = moderate worsening; 3.9% = marked worsening• 237 patients (84%) kept mirabegron use without antimuscarinics• 17 patients (6%) discontinued mirabegron and resumed antimuscarinics• 16 patients (5.7%) received “add-on” antimuscarinics with mirabegron after 1 month

Liao CH. Medicine (Baltimore). 2016;95(45):e4962.60

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Antimuscarinic + β3-Adrenoceptor Agonist Combination Therapy

• AUA/SUFU 2019 Guidelines updated to include:“Clinicians may consider combination therapy with an anti-muscarinic and β3-adrenoceptor agonist for patients refractory to monotherapy with either antimuscarinics or β3-adrenoceptor agonists”

• Increased risk of bladder outlet obstruction and urinary retention; xerostomia, UTI, constipation, tachycardia with combination therapy

What is the degree of benefit?Who are the appropriate candidates for therapy?

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Change in UI Episodes with Combination Therapy

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Mirabegron50mg

Solifenacin5mg

Mirabegron 25mg + Solifenacin 5mg


Baseline # of incontinence episodes/day

3.40 3.42 3.16 3.59 3.21 3.15

Decrease -1.34 -1.70 -1.76 -1.79 -2.04 -1.98

Difference from mirabegron monotherapy (same dose)

-0.34 -0.23

p-value 0.002 0.023

Difference from solifenacinmonotherapy (same dose)

-0.25 -0.20

p-value 0.035 0.009

Herschorn S. SYNERGY study. BJU international. 2017.

• DESIGN: 18-week, multinational, multicenter, randomized, double-blind, placebo- and active-controlled in patients with wet OAB for ≥3 months & self-recorded ≥8 micturitions/day, ≥1 urgency episode/day and ≥3 incontinence episodes/week

• BASELINE DEMOGRAPHICS: 77% female; Mean age 57.4 years (33% ≥65 yrs, 8% ≥75 yrs); 79% White; 65% UUI, 35% Mixed with UUI predominance; 46% previous OAB medication.

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Change in Frequency with Combination Therapy

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Mirabegron50mg

Solifenacin5mg



Baseline # of micturitions/day 10.97 10.81 11.19 10.74 10.72 10.72

Decrease -1.64 -2.00 -2.03 -2.20 -2.49 -2.59

Difference from mirabegron monotherapy (same dose)

-0.48 -0.56

p-value 0.004 <0.001

Difference from solifenacinmonotherapy (same dose)

-0.29 -0.39

p-value 0.044 0.006

Herschorn S. SYNERGY study. BJU international. 2017.

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Rates of Adverse Reactions with Combination Therapy

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Placebo (%) Mirabegron 25mg (%)

Mirabegron50mg (%)

Solifenacin5mg (%)

Mirabegron 25mg + Solifenacin 5mg (%)

Mirabegron 50mg + Solifenacin 5mg (%)

Number of patients 510 500 500 1288 997 1706

Dry mouth 2.2 3.8 3.6 6.5 9.3 7.2

UTI 5.3 4.0 4.2 3.6 7.0 4.0

Constipation 1.2 1.2 2.8 2.4 4.2 3.9

Tachycardia 0.8 1.6 1.6 0.7 2.2 0.9

Dyspepsia 0.6 0.4 0.2 0.7 1.1 1.3

Dizziness 0.4 0.8 1.2 1.2 1.3 0.4

Blurred vision 0.4 0.2 0.2 0.9 0.7 1.1

Arthralgia 0.8 0.8 0.8 0.8 0.5 1.1

MYRBETRIQ [Package Insert]. Astellas Pharma. Northbrook, IL..

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Assessment Question

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GB is a 78-year-old woman with PMH significant for OAB, dementia and narrow-angle glaucoma. With the approval of her ophthalmologist, she has been taking solifenacin 5 mg daily for 8 weeks along with behavioral modifications. Since starting solifenacin, her number of micturitions per day has reduced from 15 to 8 and number of incontinence episodes per day have reduced from 4 to 3. She continues to find her symptoms bothersome and impactful on quality of life. She asks about next steps. Last BP = 140/80mmHg.

Which of the following is the best recommendation for GB?A. Switch solifenacin to oxybutynin ER B. Increase solifenacin to 10mg dailyC. Add mirabegron 25 mg dailyD. Switch solifenacin to vibegron

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Questions?

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