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Case Study Activity: Managing in the Community Pharmacy Answers to Interactive Questions and Resources

Case 3: Updates on Overactive Bladder Treatments

Activity Preview Overactive bladder (OAB) is a defined as “ (except in the absence of sensory input), with or without urge incontinence, usually with frequency and ” and in the absence of a known pathologic condition (uncommon) that may cause similar symptoms (e.g., ). When inadequately treated, OAB has a significant detrimental effect on patients’ quality of life including bothersome symptoms, inferior health-related quality of life, and higher rates of depression, , and insomnia due to nocturia and the fear of .

The first-line treatment for OAB is nonpharmacologic management, consisting of lifestyle modifications, behavioral therapies (e.g., bladder and/or pelvic floor muscle training) and other toilet scheduling regimens. Anti-incontinence devices and supportive interventions are adjunctive or used to manage residual OAB symptoms. If these measures do not adequately control symptoms, pharmacotherapy with antimuscarinic is initiated.

Antimuscarinic agents, currently the mainstay of OAB pharmacotherapy, include , , , , trospium, and fesoterodine. These agents are available in a variety of dosage forms, ranging from transdermal patches and topical gels to oral medications (immediate-release and extended-release formulations). Still, many patients do not achieve adequate symptom relief or experience intolerable -related adverse events from the currently available medications.

Fortunately, new treatment options for OAB with different mechanisms of action are now available. In addition, other agents, including a novel pharmacologic class of medications, are in various stages of development; the manufacturer of one of these medications has filed a New Drug Application for U.S. Food and Drug Administration (FDA) approval.

Antimuscarinic Agents Oxybutynin Dosage Forms One of the first antimuscarinic agents, oxybutynin is available for administration via transdermal patch or topical gel in addition to oral forms. Like the transdermal patch formulation, the oxybutynin topical gel avoids first-pass liver metabolism of oxybutynin to the active metabolite © 2011 by the American Pharmacists Association. All rights reserved.

N-desethyloxybutynin. This approach produces lower concentrations of the active metabolite, which (like the parent medication) has effects. Benefits of this characteristic include lower rates of the adverse anticholinergic effects of dry mouth and compared with non-transdermal forms of oxybutynin, especially immediate-release oxybutynin. In contrast to the transdermal patch form of oxybutynin, the rates of local skin reactions to the gel are lower due to elimination of the patch delivery system. These improvements in tolerability are achieved while retaining the effectiveness of the oral and patch forms. Nevertheless, the same contraindications and precautions applicable to other antimuscarinics apply to the gel formulation of oxybutynin.

Flexible Dosing Strategy for Antimuscarinics OAB symptoms have a variable, subjective effect on different patients. In consultation with the prescribing physician, patients have the opportunity to request increases or decreases of their medication to determine the dose that achieves the optimal balance between effectiveness and tolerability of adverse effects. In fact, this flexible dosing regimen approach has been shown to improve OAB urgency and other symptoms. Antimuscarinics that are available in multiple strengths (i.e., darifenacin, solifenacin, oxybutynin extended-release, and tolterodine), enable dose titration to patient response and therefore are candidates for flexible dosing.

Patients using this approach must be cognitively intact and committed, must understand the principles of dose titration, and must be willing to assume a central role in requesting and accepting dose changes in consultation with their physician. In preparation, these patients are counseled on what to expect regarding drug effectiveness and adverse effects. They are informed of available drug strengths and encouraged to discuss the planned dose titration with their care provider. Starting with the lowest recommended dose, patients are informed that a dose increase may be needed. If intolerable adverse effects occur, patients can request a dose decrease without concern about resistance from their physician. Regardless of some improvement in the risk-to- benefit ratio using this strategy, the same contraindications and precautions apply.

Antimuscarinics Alone or Combined With an α-Adrenergic Antagonist for Men Historically, antimuscarinic drugs were avoided in men with OAB symptoms and benign prostatic obstruction (BPO). This precaution was due to concern about the risk of acute urinary retention characterized by worsening voiding lower urinary tract symptoms , uncomfortable or painful effort to urinate without success, and abdominal pressure/bloating. However, recent research in this population concluded that antimuscarinic monotherapy is safe and effective in decreasing OAB symptoms and improving quality of life in men with OAB storage lower urinary

tract symptoms ( see OAB Lexicon) due to primary bladder conditions (e.g., detrusor overactivity), with minimal or no voiding lower urinary tract symptoms. Conversely, antimuscarinic monotherapy is not recommended for the treatment of benign prostatic hyperplasia (BPH) without obstruction. Nor should this approach be used in men with baseline post-void residual urine volume greater than 200 mL or clinically significant bladder outlet obstruction, history of acute urinary retention due to BPH, high serum -specific antigen (PSA), or low urine flow rate (as determined by urodynamic measurement).

Antimuscarinic therapy may be added to α-adrenergic antagonist treatment in men with BPO and predominant OAB symptoms due to a concomitant or secondary bladder condition (e.g., BPH) or when these storage symptoms persist despite relief of voiding symptoms with an α-adrenergic antagonist alone or in combination or monotherapy with a 5-α-reductase inhibitor. However, concomitant therapy of an antimuscarinic and an α-adrenergic antagonist is not recommended for the treatment of BPH or in men with OAB symptoms with no significant bladder voiding lower urinary tract symptoms or significant bladder outlet obstruction. While the effectiveness and safety of the combined therapy does not appear to be affected by prostate size or PSA level, further research is needed to determine the effect of antimuscarinics in men with larger prostate glands or higher PSA levels. Also in need of investigation is whether criteria composed of these parameters would better identify suitable candidates for combined therapy. Therefore, while these parameters may help to guide treatment strategy, treatment should be chosen according to individual patient response. Post-void residual urine volume should be assessed before and after an antimuscarinic is started, especially during the first month of therapy.

OAB Lexicon Term Definition Voiding lower urinary Slow or intermittent urinary stream, splitting or spraying, hesitancy, tract symptoms straining, terminal dribble Storage lower urinary Urinary urgency, frequency, nocturia, tract symptoms BPH Benign prostatic hyperplasia BPO BPH with bladder outlet obstruction BTX-A OnabotulinumtoxinA, recently FDA-approved OAB treatment, for injection

OnabotulinumtoxinA The FDA recently approved onabotulinumtoxinA (BTX-A) for injection to treat urinary incontinence due to detrusor overactivity associated with neurologic conditions such as post- , , and multiple sclerosis in adults inadequately controlled or intolerant of an anticholinergic medication. Two double-blind, randomized controlled trials demonstrated a significant reduction in urinary incontinence episodes and increased bladder capacity in patients who received BTX-A. Cure rates of up to 38% have been achieved after a single intradetrusor injection administered under local or general . Although BTX-A has been shown to be effective in controlling urologic symptoms in idiopathic OAB, it is not FDA-approved for this indication at this time. BTX-A achieves its therapeutic effects in OAB by inhibiting acetylcholine and adenosine 5'-triphosphate (ATP) release at the parasympathetic presynaptic nerve terminal. The duration of BTX-A effects is approximately 9 months; repeated injections may be necessary.

BTX-A does not produce anticholinergic symptoms. The most common adverse effects with BTX-A bladder injection are urinary tract infection and urinary retention. Therefore, intermittent self-catheterization may be necessary to empty the bladder in individuals who develop urinary retention and who are willing and able to perform this procedure. BTX-A has a boxed warning for the possible and potentially life-threatening distant spread of toxin effect. In addition to contraindications and precautions with other forms of BTX-A used, intradetrusor administration is contraindicated with acute urinary tract infection or urinary retention. Furthermore, BTX-A should be administered only with caution in individuals with urinary retention and only with monitoring of post-void residual urine volume in those who do not catheterize routinely, particularly patients with multiple sclerosis. BTX-A should be administered with caution due to its relatively invasive administration, lack of direct comparative trials with antimuscarinic drugs, and the uncommon but serious risk of distant spread of toxin indicated by the following : breathing problems, or tightness, rapid irregular pulse, dysphagia, speech problems, unusual weakness, numbness, or eye problems. Hence, the use of this agent should be restricted to patients who are inadequately controlled with nonsurgical, nonpharmacologic, and antimuscarinic therapy.

β3-Adrenoceptor Agonists A new class of drugs, β3-adrenoceptor agonists, is demonstrating viability for the treatment of OAB. These agents improve OAB symptoms by selectively binding and activating β3- adrenoceptors on the detrusor muscle and perhaps by additional mechanisms.

Mirabegron is the most highly developed agent in this new class of drugs. Two Phase 3 randomized controlled trials demonstrated that significantly decreased the mean

micturition frequency and number of urinary incontinence episodes, while improving quality of life in patients with OAB. Mirabegron was well tolerated with a small number of adverse events. However, it should be noted that possible adverse effects with long-term use have not been studied. The most common medication-related adverse effects that exceeded those observed with placebo in Phase 3 studies were headache, nasopharyngitis, dry mouth, and urinary tract infection (approximately 3% each). Anticholinergic adverse effects are reported to occur much less often than with antimuscarinic medications.

In August 2011, the manufacturer of mirabegron submitted a New Drug Application to the FDA. In addition to the anticipated indication as a first-line pharmacotherapeutic agent for OAB, mirabegron may serve as an alternative in patients intolerant of antimuscarinic anticholinergic effects and as a primary or secondary treatment for patients with cognitive impairment, poorly controlled or severe gastroesophageal reflux disease, closed-angle glaucoma, constipation, and vision disorders, and for patients in whom antimuscarinic agents should be avoided.

Phosphodiesterase Type 5 Inhibitors Phosphodiesterase type 5 (PDE-5) inhibitors have been shown to relax the prostate and bladder neck, likely by increasing the concentration of nitric oxide in smooth muscle. A small number of randomized controlled trials consistently showed that treatment with sildenafil, tadalafil, and vardenafil improved lower urinary tract OAB storage symptoms as well as voiding symptoms in men with BPH. Conversely, the only randomized controlled trial of an investigational PDE-5 inhibitor, UK-369003, in men with OAB but no bladder outlet obstruction found no difference in improvement in urgency episodes, frequency, nocturnal frequency, mean voided volume, or incontinence episode frequency compared with placebo. Only one small study of this treatment included women, and while the results for all participants showed improved urologic outcomes, the investigators did not distinguish the findings by the sex of the participants. The most common medication-related adverse events observed with PDE-5 inhibitors are headache, flushing, dyspepsia, nasopharyngitis, and diarrhea. The use of these agents is contraindicated with concomitant therapy with nitrates and nitrites, and there are many precautions for their use including ischemic heart disease and heart failure.

Case Study Larry Smith, a 68-year-old man who visits the pharmacy today, requests an over-the-counter (OTC) medication for “troublesome, sudden strong urges to urinate.” When you ask about additional symptoms, Mr. Smith reports that his symptoms began about 3 years ago with difficulty starting the urine stream, feeling that his bladder is never empty, and a weak stream. Then his symptoms worsened with sudden urges to urinate and frequent during the day and night, which began about 1 year ago. He states that the new symptoms bother him much more than his initial symptoms.

Mr. Smith states that his physician diagnosed him as having an “overactive bladder” and he has been practicing the lifestyle modifications and behavioral therapies as his physician recommended. However, he has not experienced much relief from his symptoms.

After checking the pharmacy record for Mr. Smith’s current medications, you ask him about any other prescription or OTC products he uses. Mr. Smith currently takes 0.4 mg after dinner for benign prostatic hyperplasia with obstruction (BPO), metoprolol 50 mg twice daily for , isosorbide mononitrate extended-release tablet 60 mg daily, nitroglycerin 0.4 mg sublingual every 5 minutes up to 3 doses as needed for chest pain, artificial tears 1 to 2 drops in both eyes 3 to 4 times daily for dry eyes, lovastatin 40 mg with each evening meal for high cholesterol, and aspirin 81 mg daily for heart protection. He knows of no other health problems. Mr. Smith quit smoking cigarettes 25 years ago. He drinks 1 to 3 alcoholic beverages on holidays but rarely during the rest of the year.

You review his medications to be sure that the OAB symptoms are not related to his medications and identify none that could contribute to his OAB. Therefore, you refer him to see his primary care physician for further treatment. Mr. Smith asks whether there is any medication you can suggest that he can discuss with his physician to relieve these OAB symptoms. Mr. Smith indicates that his physician is concerned that prescribing medication for OAB can cause his kidneys to stop working, and he does not want to take that chance. You explain that while you agree there is some risk for adverse effects, most people are at low risk for this effect and assure him that his risk can be determined from his medical history and some simple urinary tract tests. You tell Mr. Smith that you will send a summary of your discussion and treatment information to his physician.

Answer to Question #1

1. Which of the following medication changes do you recommend the physician consider in treating Mr. Smith’s OAB symptoms? a. Add an antimuscarinic. b. Replace tamsulosin with an antimuscarinic medication. c. Add sildenafil. d. Replace tamsulosin with sildenafil.

The correct answer is “a.” The use of an antimuscarinic agent in men with BPH with known or uncertain bladder outlet obstruction was formerly considered a relative contraindication due to risks of worsening urinary retention symptoms and acute urinary retention and renal failure. More recently, it has been shown that OAB storage symptoms such as urgency, frequency, nocturia, and urinary incontinence refractory to treatment with an α-adrenergic antagonist or 5-α- reductase inhibitor can be safely and effectively improved by an antimuscarinic medication. Answer “b” is incorrect because treatment with an antimuscarinic alone would not decrease urethral muscle sphincter tone as does tamsulosin. Therefore, the voiding symptoms of bladder outlet obstruction such as hesitancy, dribbling after urinating, and others would not be adequately managed.

Answers “c” and “d” are incorrect because there is no evidence that sildenafil alone or in combination with an α-adrenergic antagonist is effective in treating OAB symptoms. There is evidence from several randomized controlled trials that PDE-5 inhibitors such as sildenafil can decrease both OAB storage symptoms and voiding symptoms of BPH. However, one recent study of an investigational PDE-5 inhibitor in patients with OAB showed no significant symptom improvement.

Answer to Question #2

One month later, Mr. Smith tells you his physician started him on oxybutynin gel once daily (verified in his pharmacy record), and his urinary symptoms are much improved.

Case Question #2: 2. What symptom of potential acute urinary retention should Mr. Smith be counseled to monitor? a. Diarrhea. b. Abdominal cramping. c. Inability to urinate. d. Priapism.

The correct answer is “c.” Acute urinary retention results in patients being unable to urinate or experiencing pain or discomfort when attempting to urinate. They may feel abdominal pressure, bloating, and/or voiding symptoms of slow or intermittent urinary stream, splitting or spraying, hesitancy, straining, and a terminal dribble.

Answers “a,” “b,” and “d” are incorrect because diarrhea, abdominal cramping, and priapism are not established symptoms of acute urinary retention.

Answer to Question #3

Mr. Smith asks if there are any other drugs to treat OAB. You tell him that there are oral formulations of antimuscarinic agents, but that they frequently cause constipation and dry mouth which many patients find intolerable.

Case Question #3: 3. Which of the following medications currently available is least likely to cause intolerable anticholinergic effects? a. Solifenacin. b. Oxybutynin extended-release. c. OnabotulinumtoxinA (BTX-A). d. Tolterodine extended-release.

The correct answer is “c.” BTX-A, unlike the other choices, is not an antimuscarinic agent, a class associated with multi-organ anticholinergic activity. The most common adverse effects of BTX-A are urinary tract infection and urinary retention.

Answers “a,” “b,” and “d” are incorrect. All three are antimuscarinic medications and associated with multi-organ anticholinergic effects including the gastrointestinal tract. While the extended- release forms are associated with relatively low rates of adverse anticholinergic effects compared with oxybutynin immediate-release tablets, many patients report anticholinergic effects including dry mouth and constipation, and drug discontinuation due to these adverse effects is common.

Answer to Question #4

You inform Mr. Smith that there is a new option, BTX-A, that is injected into the bladder wall. It does not have anticholinergic side effects. You explain its benefits and risks, particularly the warning about the potentially life-threatening spread of the agent’s toxin effect.

Case Question #4: 4. For what potential adverse effect of intradetrusor injection of BTX-A should patients be instructed to immediately contact their physician? a. Headache. b. Sensitivity to light. c. Dysphagia. d. Diarrhea.

The correct answer is “c.” BTX-A has a boxed warning for the possible and potentially life- threatening distant spread of toxin effect; dysphagia, the most common severe adverse reaction due to toxin spread, can be fatal. For this reason, dysphagia is included in the boxed warning. Patients who experience this symptom should immediately contact their physician.

Answers “a” and “b” are incorrect because, while they are adverse effects related to BTX-A injection, they generally do not require medical attention. If they persist, worsen, or are bothersome, the patient may contact the physician for management recommendations.

Answer “d” is incorrect because it is an uncommon adverse effect and generally does not require medical attention.

Fast Facts About Antimuscarinic Agents • Antimuscarinic agents improve bladder capacity by reducing detrusor activity. • Individual patient response to antimuscarinic agents is highly variable. • The full benefits of antimuscarinic therapy may not be realized for several weeks after initiation of therapy. • Successive trials with different antimuscarinic agents may be required to maximize effectiveness.

Sources Lackner T, Reed K. Understanding the impact of overactive bladder from a patient perspective. Pharmacy Today. 2009;15(6):54–65.

Resources Botox [package insert]. Irvine, CA: Allergan; August 2011.

Carr LK. Botulinum toxin A should not be first-line therapy for overactive bladder. Can Urol Assoc J. 2011;5:204–5.

Chapple C, Wyndaele JJ, Van Kerrebroeck P, et al. Dose-ranging study of once-daily mirabegron (YM178), a novel selective β3-adrenoceptor agonist, in patients with overactive bladder (OAB) [abstract 774]. Eur Urol. 2010;9(2 suppl):249.

Chapple CR, Yamaguchi O, Ridder A, et al. Clinical proof of concept study (Blossom) shows novel β3-adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder [abstract 674]. Eur Urol. 2008;7(3 suppl):239.

Dmochowski RR, Peters KM, Morrow JD, et al. Randomized, double-blind, placebo-controlled trial of flexible-dose fesoterodine in subjects with overactive bladder. . 2010;75:62–8.

Giuliano FA, Lamb J, Crossland A, et al. A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder. BJU Int. 2010;106:666–73.

Herschorn S, Swift S, Guan Z, et al. Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo-controlled trial. BJU Int. 2009;105:58–66.

Kanai A, Wyndaele JJ, Andersson KE, et al. Researching bladder afferents—determining the effects of β3-adrenergic receptor agonists and botulinum toxin type-A. Neurourol Urodynam. 2011;30:684–91.

Kaplan SA, Roehrborn CG, Abrams P, et al. Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a systematic review. Int J Clin Pract. 2011;65:487–507.

Kaplan SA, Schneider T, Foote JE, et al. Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective, head-to-head, placebo-controlled trial. BJU Int. 2010;107:1432–40.

Kennelly MJ. A comparative review of oxybutynin chloride formulations: pharmacokinetics and therapeutic efficacy in overactive bladder. Rev Urol. 2010;12:12–9.

Khullar V, Cambromero J, Stroberg P, et al. The efficacy and tolerability of mirabegron in patients with overactive bladder: results from a European-Australian phase III trial [abstract 886]. Eur Urol. 2011;10(2 suppl):278–9.

Kuo HC, Liao CH, Chung SD. Adverse events of intravesical botulinum toxin A injections for idiopathic detrusor overactivity: risk factors and influence on treatment outcome. Eur Urol. 2010;58:919–26.

McVary KT, Monnig W, Camps JL Jr., et al. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007;177:1071–7.

McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177:1401–7.

Michel MC, Ochodnicky P, Homma Y, et al. β-Adrenoceptor agonist effects in experimental models of bladder dysfunction. Pharmacol Ther. 2011;131:40–9.

Nitti V, Herschorn S, Auerbach S, et al. The efficacy and safety of mirabegron in patients with overactive bladder syndrome—results of a North-American phase III trial [abstract 885]. Eur Urol. 2011;10(2 suppl):278.

Roehrborn CG, McVary KT, Elion-Mboussa A, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180:1228–34.

Schmid DM, Sauermann P, Werner M, et al. Experience with 100 cases treated with botulinum- A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to . J Urol. 2006;176:177–85.

Stief CG, Porst H, Neuser D, et al. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2008;53:1236–44.

Tyagi P, Tyagi V. Mirabegron, a β3-adrenergic receptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder. IDrugs. 2010;13:713–22.

Tyagi P, Tyagi V, Chancellor M. Mirabegron: a safety review. Expert Opin Drug Saf. 2011;10:287–94.

Vella M, Cardozo L. Review of fesoterodine. Expert Opin Drug Saf. 2011;10:805–8.