Editor's Commentary - LUTS update: Medical therapy for BPH and OAB

JM, a 76-year-old retired salesman who reports a 5-year history of urgency and frequency that has been worsening for 6 months. Frequency includes 3-4 nocturnal episodes of urination. Mr. H experiences occasional leakage of urine on the way to the bathroom but the amount of urine loss is small. He feels that his frequency is slowly worsening. It is taking him longer to urinate as he thinks the urine stream is “not as strong.” Coffee worsens his urinary symptoms. Nocturia is the most bothersome symptom, as sleep disruption affects his daytime performance. JM was told he had an enlarged prostate and was prescribed a medication that made him dizzy so he stopped taking it.

There are three major lower urinary tract symptoms (LUTS) categories: storage symptoms, voiding, and postmicturition symptoms (Abrams et al., 2002). JM exhibits both bladder storage and emptying symptoms. They are defined as:

• Storage or irritative symptoms resulting from bladder wall thickening and irritation due to increased bladder outlet resistance. These include:
  • Frequent urination - voiding more than 8 times in a 24-hour period
  • Urgency - sudden, compelling desire to urinate that is difficult to defer and possibly accompanied by urine leakage
  • Nocturia -awakening at night more than 2 times to urinate
• Voiding symptoms, also called obstructive symptoms, are due to an enlarged prostate intrusion into the bladder floor causing constriction of the bladder neck and urethra, which increases bladder neck urethral smooth muscle cell tone (contraction) (Issa & Regan, 2007). These symptoms include:
  • Slow, weak, or “poor” stream - decreased or reduced force of urine stream
  • Hesitancy -stopping and starting of urinary stream causing a delay in voiding
  • Straining by using abdominal or muscular effort to initiate voiding or to improve the urine stream
  • Intermittent stream - stream that stops/starts during urination
  • “Sprayed” or “split” stream - double stream or spraying of the urinary stream
  • Terminal dribble- prolonged final micturition
• Postmicturition symptoms are experienced right after voiding, and include:
  • Incomplete bladder emptying - the sensation that urine remains in the bladder after micturition
  • Post- void dribbling - intermittent urine loss immediately after voiding.

In male patients, it is important to determine the cause of the LUTS, because it is not uncommon to see storage symptoms being attributed to OAB, bladder outlet obstruction, or both (Abdel-Aziz & Lemack, 2002). In time, BPH can lead to benign prostatic enlargement (BPE), which can lead to bladder outlet obstruction (BOO) (Bushman, 2009). Men will report a weak stream and complain that it takes them a much longer time to urinate. There are effective pharmacological treatment for LUTS (benign prostatic hyperplasia and overactive bladder), specifically silodosin and oxybutynin transdermal gel, indicated for treating storage and voiding/postmicturition symptoms. These pharmaceuticals have demonstrated promise in their respective clinical trials and the following is a review of these medications.

Benign Prostatic Hyperplasia (BPH)

BPH is one of the most commonly diagnosed conditions in men aged > 50 years (Fenter, 2006). After age 60, BPH prevalence increases sharply, reaching almost 82% worldwide by age 80 (Lepor, 2004). BPH pathophysiology causing obstructive and irritative symptoms have both dynamic and static components. The dynamic component involves increased adrenergic tone (contraction) in the prostate, urethra, and bladder neck smooth muscle. The static component involves prostatic enlargement either from increased growth or dihydrotestosterone stimulation. Together, these lead to obstructive and/or irritative bladder outlet obstruction symptoms (Issa & Regan, 2007). Prostate size does not always determine the extent of symptom bother and not all patients with BPH will have an enlarged prostate (AUA Practice Guidelines Committee, 2003).

There are standard questionnaires that clinicians can use to determine the severity of BPH symptoms. They include the International Prostate Symptom Score (IPSS) or the American Urological Symptom Index (AUA-SI). The IPSS measures obstructive or irritative BPH symptoms. BPH-associated LUTS treatment is based on symptom severity, the extent of symptom bother, and patient preferences for treatment. Patients with bothersome moderate to severe symptoms are treatment candidates. Patients with moderate to severe symptoms (AUA-SI or total IPSS, 8-35) may choose watchful waiting, medical therapy, office-based minimally invasive therapy treatment, or traditional surgery performed in a hospital or surgical center.

Recommended medical therapies for BPH include alpha-blockers and 5-reductase inhibitors (5-ARIs), used as monotherapies or as combination therapies. Patients with refractory urinary retention or BPH-related persistent gross hematuria, bladder stones, recurrent urinary tract infections, or renal insufficiency are surgery candidates (AUA Practice Guidelines Committee, 2003).

Three structurally distinct α1-adrenergic receptor subtypes have been identified: α1A, α1B, and α1D (Schwinn, & Roehrborn, 2008) and they are as follows:

• α1A expressed in the prostate, regulates contraction of the smooth muscle in the prostate, bladder base and neck, urethra, seminal vesicles, and vas deferens (Nasu, Moriyama, Kawabe, et al., 1996; Kaplan, 2004).
• 1B receptors predominate in peripheral blood vessels, regulates contraction of arterial blood vessels in response to postural redistribution of vasculature (Murata, Taniguchi, Takahashi, et al. 2000; Townsend, Jung, Hoe, et al. 2004)
• α1D receptors expressed in the bladder, spinal cord, and nasal passages (Schwinn, & Roehrborn, 2008; Stafford-Smith, Bartz, Wilson, et al. 2007).

It is known that α1A adrenergic receptor subtypes regulate prostate smooth muscle and α1B receptor subtypes primarily regulate arterial blood vessel contraction. The exact α1D receptor role has not been established. . In men aged <55 years, α1A is the predominant subtype, whereas in men aged >65 years, α1B becomes predominant (Rudner, Berkowitz, Booth, et al. 1999). Given that α1B receptors regulate arterial smooth muscle contraction, particularly in response to blood volume postural redistribution (Townsend, Jung, Hoe, et al. 2004), this may explain why older patients may be more susceptible to orthostatic effects of α-blockers.

α-Blockers may be selective or nonselective in their α1-adrenergic receptor type binding affinity. Nonselective α-blockers bind to the three receptor subtypes with similar affinity:

• α-blocker prazosin interacts with the same amino acids, at the same binding pockets positions, in all of the α1-receptor subtypes (Ishiguro, Futabayashi, Ohnuki, et al. 2002).
• Terazosin, doxazosin, and alfuzosin are nonselective α-blockers (Schwinn, & Roehrborn, 2008).
• Tamsulosin binds more to α1D and α1A receptors than α1B receptors (Ishiguro, Futabayashi, Ohnuki, et al. 2002).
• Silodosin is highly receptor-subtype selective that has much more affinity to α1A receptors than α1D or α1B receptors. It effectively relaxes prostate, bladder, and urethra smooth muscle, but does not have a pronounced vascular smooth muscle effect, with low orthostatic hypotension incidence. The clinical significance of this is that it may provide rapid and sustained BPH symptom relief with a low incidence of orthostatic adverse events.

According to Yoshida and colleagues (2011), silodosin is a novel selective α(1A)-adrenergic receptor antagonist that is effective without causing obtrusive side effects. Silodosin has been shown to decrease the IPSS significantly from baseline with a mean reduction of 4.2 points and by the end of 12 weeks, the mean IPSS reduction was 6.4 points with significant reductions at all time points and relief of both irritative and obstructive symptoms (Marks, Gittelman, Hill, et al., 2009). The rate of urine flow increased significantly (P= 0.0007) from baseline within 2 to 6 hours of the first dose. Silodosin provides significant rapid symptom relief regardless of prostate size and in a population of 206 men, were relieved for 1-year in an open-label, uncontrolled study (Marks, Gittelman, Hill, et al. 2009). So the short and long-term benefits of silodosin in decreasing BPH symptoms has been established.

The safety of silodosin versus placebo was compared using adverse effects (AEs), vital signs, electrocardiogram (ECG) results, clinical laboratory tests, and physical examination evaluations. The most common adverse effect of silodosin is retrograde ejaculation (RE), seen in 28.1% of the participants in the Marks, Gittelman, Hill, et al. (2009) study. Other adverse effects reported in this study that occurred in at least 2% of participants included dizziness, orthostatic hypotension, diarrhea, nasopharyngitis, headache, and nasal congestion.

In clinical practice, retrograde ejaculation is a concern voiced by many patients, so it is important the clinician understand that in the clinical trials, RE referred to changes either in a reduction of or lack of semen that may/may not involve leakage of semen into the bladder. This is most likely due to seminal vesicle and vas deferens smooth muscle relaxation. As seminal vesicle and vas deferens smooth muscle contraction is mediated by α1A receptors (Moriyama, Nasu, Takeuchi, et al. 1997), one may expect a highly elective α1A-antagonist such as silodosin to be associated with RE. The side effect is reversible upon stopping the drug. There is a post hoc sub analysis that evaluated the relationship between silodosin efficacy and RE. Data obtained from spontaneous AE reports of 457 placebo and 466 silodosin patients noted that the majority (n=335) did not experience RE, with 131 experiencing retrograde ejaculation (Roehrborn, Lepor, Kaplan, 2009). But if they did, they were more likely to have improvement of ≥30% in IPSS and Q_max as well as an IPSS improvement of ≥3 points and a Q_max increase of ≥3 mL/s (P < .01) than those who did not have RE or those who received placebo (Data on file. Corona, CA: Watson Laboratories, Inc.).

Silodosin was reviewed for QT interval prolongation in a placebo-controlled, parallel group of 189 healthy men aged 18 to 45 years who received daily silodosin 8 mg or 24 mg, placebo, or a single 400-mg moxifloxacin dose (a QT-interval prolonging drug) (Rapaflo® (silodosin) [package insert]. Corona, CA:Watson Pharmaceuticals, Inc.; November 2009). Neither silodosin daily dose significantly affected ECG intervals or cardiac repolarization. No QTc prolongation or serious cardiac events occurred over the 9-month open-label extension period.

A common complaint by patient of this class of drugs is orthostatic hypotension. But in clinical trials of silodosin, orthostatic hypotension incidence was 2.3% in patients aged <65 years (1.2% for placebo), 2.9% in patients aged ≥65 years (1.9% for placebo), and 5.0% in patients aged ≥75 years (0% for placebo). with no other clinically significant safety differences or adverse effects. About one-third of patients in the trials took silodosin concomitantly with other antihypertensive agents (other than alpha-blockers) but whether or not taking antihypertensive medications, all patients taking silodosin had similar adverse event rates. But patients taking silodosin with a phosphodiesterase type 5 (PDE5) inhibitor should exercise caution with concomitant PDE5 or antihypertensive use and monitor for adverse effects.

The recommended dose of silodosin (Rapaflo®) is an 8-mg oral capsule, once daily with a meal. For patients with moderate renal impairment, a 4-mg capsule is available. Silodosin (Rapaflo®) is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min), hepatic impairment (Child-Pugh score ≥10), and with use of strong CYP3A4 inhibitors (eg, itraconazole, ritonavir). Silododsin (Rapaflo®) should be used with caution in patients with moderate renal impairment and who are planning cataract surgery.

Overactive Bladder (OAB)

LH is a 53-year-old attorney who reports urgency several times throughout the day. She complains of urinary frequency 3× in morning, 4× in afternoon, and 5× in evening and at least once during the night. She also will have occasional urine leakage associated with urgency. LH avoids sexual intercourse with spouse because of the fear of urine leakage.

LH’s symptoms appear to be related to overactive bladder (OAB), which is characterized as “urgency, with or without urge incontinence, usually with increased daytime frequency and nocturia,” occurring in the absence of infection or other obvious pathology (Abrams et al., 2002). Urinary incontinence (UI) is relatively common and is seen in > 40% of women aged between 50-70 years – yet <50% of people with UI seek treatment. These symptoms may occur individually or in combination with other OAB symptoms and other types of UI. Stress UI may occur combined with other OAB symptoms, but is not itself a part of the formal OAB definition.

The major treatments for OAB include three broad categories: behavioral interventions, pharmacotherapy, and surgery. Two major approaches to nonpharmacological therapy are behavioral modification and physiotherapy (Crespi-Lofton, 2001; Payne, 2009). Behavioral modification may include voiding and fluid/dietary modification. Physiotherapy can include pelvic floor muscle exercises, biofeedback, and functional electrical stimulation. Optimal OAB pharmacological management depends on a UI evaluation, including physical history, urinalysis, and a bladder diary. Pharmacological therapy should focus on specific comorbidities and functional limitations to evaluate pharmacologic therapy compliance.

One of the drug therapies available for OAB is a novel transdermal oxybutynin chloride (Gelnique®) gel that is applied to the skin daily. The skin has easy accessibility while protecting against harmful substances and microorganisms; it has low permeability to most molecules (Nitti, Sanders, Staskin, et al. 2006). The major protective barrier is the top epidermis layer, the stratum corneum, which is approximately 100 microns thick. It is composed of dead keratinized epidermal cells surrounded by a lipid matrix, forming a brick-and mortar structure, behaving as a tough, flexible membrane (Scheindlin, 2004) Nearly all molecules penetrate the stratum corneum; whereas hydrophilic drugs permeate the skin too slowly to be effective, lipophilic drugs are better suited for transdermal delivery. Oxybutynin is a lipophilic compound and when applied as a gel, drug delivery bypasses gastrointestinal (GI) absorption which may confer several benefits. It avoids first-pass metabolism that may reduce bioavailability and decreases oral medication–associated GI upset and irritation. Because of its delivery, there was no reported severe dry mouth or application site dermatitis of transdermal oxybutynin chloride gel (Gelnique®) (Staskin, Dmochowski, Sand, et al., 2009). The skin’s protective features result in steady transdermal drug permeation and absorption, allowing for consistent serum drug levels and avoidance of oral dosing–associated peaks and troughs.

Oxybutynin chloride Gelnique® (Watson Pharmaceuticals, Inc., Corona, CA) is a transdermal gel indicated for the treatment of OAB with symptoms of urgency UI, urgency, and frequency. The most commonly reported adverse events seen with administration included dry mouth (7.5%), urinary tract infection (6.9%), and application site reactions (5.4%). Gelnique is contraindicated in patients with urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, or known hypersensitivity. It should be used cautiously in patients with hepatic or renal impairment, clinically significant bladder outflow obstruction, myasthenia gravis, and gastrointestinal obstructive disorders, and other conditions such as ulcerative colitis, intestinal atony, gastroesophageal reflux, and esophagitis.

Transference of Gelnique to another person can occur when vigorous skin-to-skin contact is made with the application site (Dmochowski, Newman, Sand, et.al., 2011). Patients should avoid open fire or smoking until the gel has dried.

Gelnique has been evaluated in a single phase III double-blind, placebo-controlled study in OAB patients that provided sufficient evidence of efficacy and safety (Staskin, Dmochowski, Sand, et al., 2009). The primary endpoint of the study was the change from baseline to the end of treatment (week 12) in mean UI episodes per day and 3-day urinary diaries completed by the patients. Secondary endpoints included mean urinary frequency, void volume, quality of life (measured by the Kings Health Questionnaire [KHQ] and Incontinence Impact Questionnaire [IIQ]), nocturia, and safety measures. The study design included practice of some behavioral interventions including bladder and fluid management techniques taught to all patients at the first study visit. Patients were educated about OAB, enabling them to accurately complete the diary prior to randomization.

In this large study (N total = 789 total enrolled, N=389 Gelnique®, N=400 placebo, N=701 completed) (Staskin, Dmochowski, Sand, et al., 2009). Among these patients, 216 entered the 14-week extension trial. Patient demographic and clinical characteristics were similar in both groups, with populations composed primarily of middle aged, non-Hispanic white women, an average age of 59.4 years, and an average UI duration of 8.5 years. Slightly more placebo group patients (27.3%) received previous pharmacological OAB therapy compared with Gelnique® group patients (23.4%). Patients had a high mean BMI and relatively low previous/current use of other OAB medical therapies. The mean baseline OAB symptom values were similar in each group. Primary efficacy endpoint results, the change from baseline to study endpoint (week 12) in UI episodes per day, showed Gelnique® patients experienced a significant decrease from baseline in mean number of UI episodes compared with placebo. Gelnique® had a significant effect, ranging from P=.0004 to P<.0001, which occurred within 4 weeks of initiating treatment and which was sustained for the remaining 8 weeks. In addition, 27.8% of the Gelnique group patients achieved complete continence compared with 17.3% of placebo patients. Among secondary endpoints, the urinary frequency episodes were more significantly reduced (P=.0017) with Gelnique® (-2.7) versus placebo (-2.0).

Certain treatment-emergent AEs occurred in < 2% of the patients, more frequently with Gelnique than with placebo. The most common were dry mouth, urinary tract infections, and upper respiratory infection. There were no significant differences in application site pruritus, constipation, and dizziness, although these occurred more frequently with Gelnique®. Overall, most AEs were of mild/moderate intensity; no serious AE was considered treatment related and there was no reported severe dry mouth or application site dermatitis.

Thus, Gelnique has good safety, tolerability, and efficacy as an OAB treatment and would be a good choice of drug therapy for LH in the case study. Gelnique® potentially increases treatment convenience and has a 90.7% compliance rate (vs. 91.2% with placebo). It had a low discontinuation rate: 4.9% versus 3.3% with placebo.

Important Safety Information: RAPAFLO® (silodosin)

RAPAFLO® (silodosin) capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) RAPAFLO® is not indicated for the treatment of hypertension. RAPAFLO® is contraindicated in patients with severe renal impairment (Cir. <30 ml/min), severe hepatic impairment (Child-Pugh score ≥10), and with use of strong CYP3A4 inhibitors. Postural hypotension with or without symptoms (e.g., dizziness) may develop when beginning treatment with RAPAFLO®. As with all alpha-blockers, there is a potential for syncope. Patients should be warned of the possible occurrences of such events and should avoid situations where injury could result. RAPAFLO® should be used with caution in patients with moderate renal impairment. Patients should be assessed to rule out the presence of prostate cancer prior to starting treatment with RAPAFLO® . Patients planning cataract surgery should inform their ophthalmologist that they are taking RAPAFLO®.

The most common side effects are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion.

Important Safety Information: Gelnique® (oxybutynin chloride) Gel 10%

Gelnique is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

The most commonly reported adverse events with the use of Gelnique included dry mouth (6.9%), urinary tract infection (6.9%) and application site reactions (5.4%). Gelnique is contraindicated in patients with urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, or known hypersensitivity to Gelnique, including skin hypersensitivity and in patients who are at risk for these conditions. Gelnique should be used with caution in patients with hepatic or renal impairment, clinically significant bladder outflow obstruction, myasthenia gravis, and gastrointestinal obstructive disorders. Gelnique should also be used with caution in patients with conditions such as ulcerative colitis, intestinal atony, gastroesophageal reflux and those concurrently taking drugs that can cause or exacerbate esophagitis. Patients who develop skin hypersensitivity to Gelnique should discontinue drug treatment. Transference of oxybutynin to another person can occur when vigorous skin-to-skin contact is made with the application site. Patients should be instructed to avoid open fire or smoking until the gel has dried.

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