Unravelling the puzzle of lower urinary tract symptoms to optimize management of overactive bladder: An experience-sharing interview
• A 67-year-old male had frequent urination, poor stream and occasional urgency for 3 years. He also experienced nocturia, waking up 3-4 times to urinate.
• He had mild hypertension, which was controlled with an antihypertensive.
• He consulted at another hospital, where his International Prostate Symptom Score (IPSS) was noted as 24 points.
• Physical examination showed mild enlargement of the prostate gland. Results of laboratory tests were normal.
• He was treated with an alpha-blocker for benign prostatic hyperplasia (BPH), but he experienced only some symptom relief. He was switched to another alpha-blocker, with no improvement.
• At our clinic, physical examination and other test findings were consistent with previous results.
• However, his IPSS was 27 points. Points were mainly derived from questions for storage symptoms (frequency, urgency and nocturia; Figure 1).
• A voiding diary showed that his intake was approximately 3 L and urine output was approximately 2.1 L per day; he urinated every 1.5 hours, with an output of 70-160 mL each time. Uroflowmetry was not performed because he could not postpone urination, but no residual urine was observed.
• Tolterodine 4 mg was prescribed as monotherapy. At follow-up, IPSS improved to 16, and all storage symptoms were reduced
• A 35-year-old female experienced urgency, urge incontinence and nocturia for 3 years. She would wake up 3 times per night to urinate.
• She was very uncomfortable at work because she could not reach the toilet on time during busy hours, and used diapers (4 pads/day) due to these symptoms.
• She had no other medical conditions.
• Her gynecologist prescribed tolterodine 4 mg for overactive bladder (OAB). Urgency and urinary incontinence were reduced, and she only needed one diaper per day.
• However, after 2 weeks, she discontinued medication due to side effects of dry mouth and constipation. Her symptoms worsened and she resumed the use of four pads per day.
• At our clinic, a review of her symptoms included urinary frequency, urgency and urge incontinence. She woke up twice per night to urinate.
• Physical examination showed normal findings.
• A voiding diary revealed her intake was approximately 2 L and her urine output was approximately 1.6 L per day; her voiding volume was 100-140 mL each time. Frequent occurrences of urgency and urge incontinence were also noted.
• At our clinic, the diagnosis of OAB was confirmed. Treatment options were discussed, such as the use of a beta 3-receptor agonist, reducing the dose of the anticholinergic, and intravesical botulinum toxin injection.
• The patient preferred treatment with an anticholinergic but was concerned about side effects.
• Tolterodine 2 mg was prescribed.
• Her symptoms improved after 2 weeks. She only needed one pad during the day and another at night. She continued to use tolterodine 2 mg and experienced a mild degree of dry mouth, but no constipation.
1. How can we improve the diagnosis of OAB and lower urinary tract symptoms (LUTS)? How important are the use of voiding diaries and the IPSS questionnaire?
A voiding diary and the IPSS questionnaire are important tools in the diagnosis and management of OAB and LUTS. LUTS are defined by the patients themselves or described by their caregivers. These symptoms are divided into storage, voiding, and post-micturition symptoms and may indicate changes in the bladder or an enlarging prostate (BPH).1,2 OAB is defined by the International Continence Society as a symptom complex of “urgency, with or without urge incontinence, usually with frequency and nocturia”.1 Variables of a voiding diary show significant correlation with symptoms of OAB,3 such that information from a diary may help in the differential diagnosis when patients complain of urgency, frequency and urge incontinence. IPSS is another simple tool for the management of OAB and LUTS (Figure 1).2,4 We can separate scores for storage and voiding symptoms for analysis. Most patients with predominantly storage symptoms based on IPSS may have OAB.5
2. How do you make the decision to use an anticholinergic agent for patients with OAB-LUTS?
Anticholinergic medications are part of the first-line pharmacological treatment for OAB,6,7 and extended-release formulations are preferred because of lower rates of dry mouth.6 Side effects should be considered prior to prescription. Vigilance should be particularly given to the selection of anticholinergic drugs for elderly patients with or at risk of cognitive dysfunction.8
3. Is tolterodine more effective for your patients with OAB-LUTS, compared with other agents? Are there certain patients who may benefit more from treatment with tolterodine than with other agents?
Studies have provided information that tolterodine is an effective medication in the management of OAB.
A randomized trial showed that tolterodine improved storage symptoms in patients with OAB and already on alpha-blocker therapy.9 Systematic reviews have also confirmed the efficacy of tolterodine over placebo for OAB-LUTS.7,10
However, there is no consistent evidence that any one anticholinergic agent is superior to another in terms of efficacy and safety.6
4. Patients are often concerned about the risk of side effects with OAB treatment. How often do your patients experience side effects associated with anticholinergic treatment? How do you balance treatment efficacy with the risk of side effects
In my experience, adverse effects can occur in 25% of patients with some OAB treatments. The most common adverse events are dry mouth, constipation and palpitations but after continuing with treatment, most patients are able to tolerate the side effects. From my experience, withdrawal from tolterodine is approximately 5%, while results from a previous systematic review showed tolterodine to have the lowest rate of discontinuations among antimuscarinics (Figure 2).11
Importantly, some anticholinergics may cause a greater risk of central nervous system adverse effects such as dizziness, insomnia and cognitive impairment,7 or cardiovascular adverse effects such as QT interval prolongation.12 These side effects should be considered prior to initiating treatment, particularly among more vulnerable populations such as the elderly.6,7
5. Please explain the importance of counselling patients on the available treatment options and their associated side effects
Counselling is important because patients may stop taking medications due to side effects. The most common side effect of anticholinergics is dry mouth, reported by approximately 20-30% patients.12 With tolterodine sustained release (SR), other common side effects can include headache, fatigue, dyspepsia, constipation, dry eyes, and abnormal vision; impaired cognition is uncommon.13,14,15 All treatment options should therefore be explained and discussed, including other medication classes and minimally invasive treatment.
6. What key messages do you want physicians to take away from these cases?
As shown in the first case, almost all doctors treat male patients who presents with LUTS as BPH. Some prescribe medication and after treatment failure, usually perform surgery. If we pay attention to IPSS, especially storage symptoms, and ask patients to keep a voiding diary, the diagnosis of OAB may be clarified for appropriate management.
The second is a simple case of OAB. However, the patient could not tolerate the full dose of tolterodine so the dose was reduced and she was able to continue treatment with reduced side effects.
Abbreviated Prescribing Information1
Composition: Tolterodine Tartrate
Indications: For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
Recommended dosage: Taken 4mg daily with water and swallowed whole. The dose may be lowered to 2mg daily based on individual response and tolerability; however, limited efficacy data is available for DETRUSITOL® SR 2mg.
Contraindications: Contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets.
Drug interaction: Concomitant use with potent CYP3A4 inhibitors (macrolides/ antifungals/antiproteases) is not recommended due to a risk of overdosage in poor CYP2D6 metabolizers.
Special warning and precautions for use: Angioedema: In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETRUSITOL® SR should be discontinued and appropriate therapy promptly provided. Administer with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention, in patients with gastrointestinal obstructive disorders because of the risk of gastric retention, in patients with conditions associated with decreased gastrointestinal motility or in patients being treated for narrow-angle glaucoma. DETRUSITOL® SR is associated with anticholinergic CNS effects including dizziness and somnolence. Advise patients not to drive or operate heavy machinery until the drug’s effect has been determined. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), the recommended dose is 2mg once daily. Use is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).
Reduce dose to 2mg once daily in patients with severe renal impairment. Use of DETRUSITOL® SR in patients with CCr<10mL/min is not recommended. Administer with caution in patients with myasthenia gravis. Administer with caution in patients with a known history of QT prolongation or patients taking Class IA or Class III antiarrhythmic medications.
Side effects: Dry mouth, headache, fatigue, dizziness, constipation, abdominal pain, dyspepsia, xerophthalmia, abnormal vision, somnolence, anxiety, sinusitis and dysuria.
Formulation and preparation: 4mg capsules in bottles of 30’s.
Full prescribing information is available upon request.
1. Pfizer (Malaysia) Detrusitol SR Prescribing Information : DETRUSITOL SR-0917
Abbreviated Prescribing Information14
Composition: Tolterodine Tartrate
Indications: For the treatment of overactive bladder with symptoms of urinary urgency, frequency or urge incontinence.
Recommended dosage: The recommended total daily dose is 4 mg. Dosage with tolterodine tablets is 2 mg twice daily. The total daily dose may be reduced to 2 mg, based on individual tolerability.
Contraindications: Contraindicated in patients with urinary retention, uncontrolled narrow angle glaucoma, myasthenia gravis, known hypersensitivity to tolterodine or excipients, severe ulcerative colitis and toxic megacolon.
Special warning and precautions for use: Tolterodine shall be used with caution in patients with significant bladder outlet obstruction at risk of urinary retention, gastrointestinal obstructive disorders, renal impairment, hepatic disease, autonomic neuropathy, hiatus hernia and risk for decreased gastrointestinal motility. Multiple oral total daily doses of immediate release 4 mg (therapeutic) and 8 mg (supratherapeutic) tolterodine have been shown to prolong the QTc interval. Tolterodine should be used with caution in patients with risk factors for QT-prolongation including congenital or documented acquired QT prolongation, electrolyte disturbances, bradycardia, relevant pre-existing cardiac diseases and concomitant administration of drugs known to prolong QT-interval including Class IA and Class III anti-arrhythmics.
Drug Interaction: Concomitant systemic medication with potent CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin and claritromycin), antifungal agents (e.g. ketoconazole and itraconazole) and antiproteases is not recommended due to increased serum concentrations of tolterodine in poor CYP2D6 metabolisers with (subsequent) risk of overdosage.
Side effects: Mild-to-moderate antimuscarinic effects like dryness of the mouth, dyspepsia and reduced lacrimation. Clinical trials: Infections and Infestations: bronchitis. Immune System Disorders: allergic reactions. Psychiatric Disorders: confusion. Nervous System Disorders: dizziness, headache, somnolence. Eye Disorders: abnormal vision (including abnormal accommodation), dry eyes. Ear and Labyrinth Disorders: vertigo. Vascular Disorders: flushed skin. Gastrointestinal Disorders: dry mouth, abdominal pain, constipation, dyspepsia, flatulence, gastroesophageal reflux. Skin and Subcutaneous Tissue Disorders: dry skin. Renal and Urinary Disorders: dysuria, urinary retention. General Disorders and Administration Site Conditions: chest pain, fatigue. Investigations: increased weight. Post marketing surveillance: Immune System Disorders: anaphylactoid reactions. Psychiatric Disorders: disorientation, hallucinations. Nervous System Disorders: memory impairment. Cardiac Disorders: tachycardia, palpitations. Gastrointestinal Disorders: diarrhea. Skin and Subcutaneous Tissue Disorders: angioedema. General Disorders and Administration Site Conditions: peripheral edema.
Formulation and preparation: Blisters of 56’s tablets.
Full prescribing information is available upon request.
2. Pfizer (Malaysia) Detrusitol Prescribing Information, DET-M-0407
1. Abrams P, et al; Standardisation Sub-Committee of the International Continence Society.
2. Rosenberg MT, et al. Can J Urol 2014;21(Suppl 2):12-24.
3. Brown JS, et al. Urology 2003;61:802-809.
4. Barry MJ, et al. J Urol 1992;148:1549–1557.
5. Hsiao SM, et al. Int Urogynecol J 2013;24:263-267.
6. European Association of Urology (EAU). EAU Guidelines on Urinary Incontinence 2016. Available at: http://uroweb.org/guideline/urinary-incontinence/. Accessed: 3 July 2017.
7. Chapple CR, et al. Eur Urol 2008;54:543–562.
8. Chancellor M, Boone T. CNS Neurosci Ther 2012;18:167-174.
9. Chapple C, et al. Eur Urol 2009;56:534-543.
10. Gacci M, et al. BMC Urol 2014;14:84.
11. Shamliyan T, et al. Nonsurgical treatments for urinary incontinence in adult women: Diagnosis and comparative effectiveness. Agency for Healthcare Research and Quality, 2012. Rockville, MD, US.
12. Hesch K. Proc (Bayl Univ Med Cent) 2007;20:307-314.
13. Pfizer (Malaysia) Detrusitol SR Prescribing Information : DETRUSITOL SR-0917
14. Pfizer (Malaysia) Detrusitol Prescribing Information, DET-M-0407
15. Electronic Medicines Compendium (eMC). Detrusitol XL 4mg [Summary of Product Charateristics]. Updated August 2015. Available at: http://www.medicines.org.uk/emc/medicine/7685/SPC/Detrusitol+XL+4mg/. Accessed 31 August 2017.