Medicines Management Programme Oral Medicines for the Management of Urinary Incontinence, Frequency & Overactive Bladder Medicines Management Programme, Version 1.0, 17th October 2014. Table of Contents 1. Introduction ................................................................................................................................................ 1 2. Aim .............................................................................................................................................................. 2 2.1 Definitions ............................................................................................................................................ 3 3. Preferred drug for urgency incontinence and and overactive bladder syndrome. .................................... 3 4. Consultation ................................................................................................................................................ 4 5. Selection criteria ......................................................................................................................................... 4 5.1 Clinical efficacy ..................................................................................................................................... 4 5.1.1 Meta-analyses ............................................................................................................................... 5 5.2 Patient factors ....................................................................................................................................11 5.2.1 Dosing and administration ..........................................................................................................11 5.2.2 Adverse effects ...........................................................................................................................11 5.2.3 Drug interactions ........................................................................................................................13 5.3 Cost .....................................................................................................................................................16 5.4 Clinical Guidelines ..............................................................................................................................19 5.5 National prescribing trends ................................................................................................................23 5.5.1 Market share ...............................................................................................................................23 5.5.2 Total expenditure .......................................................................................................................24 5.5.3 Duration of use ...........................................................................................................................25 6. Summary ...................................................................................................................................................29 7. References ................................................................................................................................................32 Appendix 1. Pivotal Clinical Trials .................................................................................................................37 Appendix 2. Prescribing Tips and Practice Points .........................................................................................43 Table of figures Figure 1. Estimated reimbursed cost per day (DDD). ...................................................................................17 Figure 2. Estimated reimbursed cost per 30 days’ treatment (DDD). ..........................................................17 Figure 3. Expenditure in terms of mean ingredient cost per dispensed item ..............................................18 Figure 4. Market share as per number of dispensing claims (June 2014). ...................................................23 Figure 5. Number of GMS patients dispensed drugs for UI, frequency and OAB .........................................24 Figure 6. Total monthly expenditure on drugs for UI, frequency and OAB (GMS). ......................................24 Figure 7. Duration of use (months) in patients who newly initiated drugs for UI, frequency & OAB ..........25 Figure 8. Percentage of patients continuing drug treatment for longer than 6 months after initiation ......26 Figure 9. Percentage of patients (GMS) switched to another drug for UI, frequency or OAB .....................27 List of tables Table 1. Clinical guidelines ............................................................................................................................19 Table 2. Pivotal clinical trials .........................................................................................................................37 Medicines Management Programme, Version 1.0, 17th October 2014. Abbreviations AUA American Urological Association ACP American College of Physicians CEBM Centre for Evidence-Based Medicine CYP Cytochrome P450 DDD Defined daily dose DPS Drug Payments Scheme GMS General Medical Services scheme EAU European Association of Urology EMA European Medicines Agency ER Extended-release IR Immediate-release HSE Health Service Executive LUTS Lower Urinary Tract Symptoms MMP Medicines Management Programme NICE National Institute of Health and Care Excellence OAB Overactive bladder syndrome PCRS Primary Care Reimbursement service P-gp P-glycoprotein QoL Quality of life RCT Randomised controlled trial RR Relative risk SMD Standardised mean difference UI Urinary incontinence UUI Urge urinary incontinence WMD Weighted mean difference Medicines Management Programme, Version 1.0, 17th October 2014. 1. Introduction The International Continence Society–International Urogynecological Association defines urinary incontinence (UI) as the complaint of any involuntary loss of urine.1 UI can have a significant detrimental impact on the physical, psychological and social wellbeing of a person.2 In general, UI is approximately twice as common in women as in men, and is more common in older than younger persons.3 There are three main subtypes of UI2: Stress urinary incontinence: involuntary leakage on effort or exertion, or on sneezing or coughing. The management of stress urinary incontinence is not addressed in this evaluation. Urgency incontinence (or urge urinary incontinence): involuntary leakage accompanied by, or immediately proceeded by, a sudden compelling desire to pass urine which is difficult to defer (urgency). Mixed urinary incontinence: involuntary leakage associated with both urgency and also physical stress (exertion, effort, sneezing, or coughing). Mixed UI may be stress or urge dominant. Urinary frequency is generally considered as ≥ 8 micturitions during waking hours, though this number is variable depending on hours of sleep, fluid intake and co-morbidities etc.4 Overactive bladder (OAB) syndrome is defined as urgency, usually with increased frequency and nocturia, which may occur with or without urgency incontinence.1, 2 About 20% of women aged 40 years or older have a “healthcare requirement” for OAB and this increases to 36% of women aged 80 years or older.5 Prevalence rates among men range from 7% to 27%.4 For women, conservative management options for OAB include lifestyle interventions such as reducing caffeine intake, altering fluid intake and losing weight; physical therapies such as pelvic floor muscle training; and pharmacological treatment.5 Although most studies have been conducted in women, behavioural therapies are also valuable in men. Troublesome lower urinary tract symptoms (LUTS) occur in up to 30% of men over the age of 65 years, and are categorised into voiding, storage or post-micturition symptoms.6 For 1 men with LUTS suggestive of OAB, or where OAB is the predominant symptom, supervised bladder training, advice on fluid intake, lifestyle advice and containment products may be offered. If such management options prove unsuccessful or are not appropriate, pharmacological therapy should be offered.6 Drugs for the treatment of urge urinary incontinence, frequency and overactive bladder syndrome represent a significant cost to the health service, approximately €16.5 million in 2013, representing a slight increase in expenditure since 2012.7 On average, 31,400 prescriptions for these medications are filled on the General Medical Services (GMS) scheme every month, with a further 4,200 prescriptions filled on the Drugs Payments Scheme (DPS).7 2. Aim There are eight oral drugs currently licensed and marketed for the treatment of urge urinary incontinence (UI), frequency and overactive bladder syndrome (OAB) in Ireland, all of which are reimbursed by the Health Service Executive (HSE) Primary Care Reimbursement Service (PCRS).8, 9 Seven of these drugs are antimuscarinics, which work through competitive antagonism of acetylcholine at postganglionic muscarinic receptors, causing a relaxation of bladder smooth muscle.10 By this action, they increase the maximum urinary capacity and the volume to the first detrusor contraction and decrease the urgency and frequency of 10 incontinence episodes and voluntary urination. Mirabegron, a beta3-agonist, is a novel agent first authorised in 2012.11 Mirabegron exerts it effect by activating beta adrenoceptors in the detrusor muscle and trigone area of the bladder, facilitating urine storage