Efficacy and safety of tamsulosin OCAS

Original Article EFFICACY AND SAFETY OF TAMSULOSIN OCAS SPEAKMAN Efficacy and safety of tamsulosin OCAS MARK SPEAKMAN Taunton and Somerset Hospital, Taunton, UK The efficacy and safety of a new tablet formulation of tamsulosin (the oralcontrolled absorption system: OCAS ) have been assessed in several clinical trials. In a phase IIb and a phase IIIa trial, the appropriate dose of the tamsulosin tablet for clinical practice was determined. All tested doses of tamsulosin OCAS (.4,.8 and 1. mg) improved the lower urinary symptoms (LUTS) of benign prostatic enlargement to a statistically significantly greater extent than placebo, with no differences between the doses. However, treatment with tamsulosin OCAS.4 mg was associated with a lower incidence of treatment-emergent adverse events (AEs) than the.8 mg and 1. mg doses. The incidence of the two most frequently reported AEs, dizziness and abnormal ejaculation, was similar for tamsulosin OCAS.4 mg and placebo. As the.4 mg tablet had the most favourable efficacy/safety profile, it was selected as the most appropriate dose to use in further clinical research studies. In a phase IIIb trial, the.4 mg dose of tamsulosin OCAS improved nocturia, quality of sleep and quality of life. Cardiovascular safety studies showed that tamsulosin OCAS.4 mg has a better cardiovascular safety profile, even under conditions that stress the cardiovascular system and in older people. Overall, these studies confirm the assumption that the improved pharmacokinetics of tamsulosin OCAS together with tamsulosin s α 1A -/α 1D - adrenoceptor subtype selectivity and its selective distribution to the LUT, translate into a superior safety profile. KEYWORDS BPH, cardiovascular safety, efficacy, LUTS, tamsulosin OCAS, nocturia, randomized clinical trials INTRODUCTION LUTS suggestive of BPH (LUTS/BPH) is a prevalent condition in elderly men [1]. Medical treatment is currently considered the mainstay of care for most men with LUTS/ BPH. Treatment with α 1 -adrenoceptor (α 1 - AR) antagonists such as alfuzosin, doxazosin and tamsulosin is recommended as the firstline pharmacological therapy for men with LUTS/BPH []. Basically, α 1 -AR antagonists relax smooth muscle in the bladder neck, urethra and prostate. This results in an improvement of the urinary flow and symptoms of BPH [3]. In addition, α 1 -AR antagonists might have a beneficial effect on the clinical progression of LUTS/BPH [4,5]. All currently available α 1 -AR antagonists are similarly effective, but their safety profiles differ [3]. These differences in tolerability are mainly because α 1 -ARs are not only situated in the LUT, but also in other tissues such as the vascular system. CARDIOVASCULAR SIDE-EFFECTS OF α 1 -AR ANTAGONISTS The presence of α 1 -ARs in the cardiovascular system might explain the most bothersome side-effects of α 1 -AR antagonists. When α 1 -AR antagonists bind to α 1 -ARs in the vasculature, they interfere with the counterregulatory system of the sympathetic nervous system that is responsible for the adaptation of venous tone during postural change. This rapid response of the body to changes in blood pressure prevents people from becoming dizzy or even fainting when standing up. Vasodilatation induced by α 1 -AR antagonists might worsen orthostatic changes in blood pressure and increase the risk of postural hypotension and syncope [6]. Men with LUTS/BPH are generally older, and tend to have a reduced cardiac output and a reduced sensitivity of the baroreflex [7]. Consequently, they might be more susceptible to cardiovascular side-effects of α 1 -AR antagonists. Moreover, orthostatic hypotension in the elderly increases the risk of falls and fractures [6]. Although all three subtypes of α 1 -ARs (α 1A -, α 1B - and α 1D -ARs) are present in the vasculature, it has been suggested that ageing is associated with a specific up-regulation of the α 1B -AR subtype [8]. Therefore, inhibition of α 1B -ARs is thought to have the strongest impact on the incidence of cardiovascular side-effects in patients with LUTS/BPH [7]. Tamsulosin s greater selectivity for α 1A -AR and α 1D -AR subtypes over the α 1B -AR subtype, its preferential distribution to LUT tissues, and its controlled-release formulation probably explain the favourable efficacy/safety ratio of this drug over other α 1 -AR-antagonists [9]. Nevertheless, the pharmacokinetics (PKs) of the tamsulosin modified-release (MR) formulation are dependent on food intake [1]. The exposure to the drug, and hence the risk of adverse events (AEs), is higher when tamsulosin MR is taken under fasting conditions than when it is taken after the first meal of the day [1]. As not all patients comply with the dosing recommendations in the patient leaflet, the independence of PKs of food intake might considerably improve the tolerability of tamsulosin. In addition, further smoothing of the plasma concentration time curve, with a lower maximum plasma concentration (C max ), might result in a more favourable tolerability profile and a lower incidence of (cardiovascular) AEs [11]. NOCTURIA A more flattened PK profile with more constant 4-h plasma concentrations might also provide better control of bothersome night-time symptoms of LUTS/BPH, such as nocturia. Nocturia, or the complaint of waking at night once or more to void, is one of the most bothersome storage symptoms of BPH [1]. The need to void several times during a night reduces the period of undisturbed sleep, which can have a profound negative impact on quality of sleep (QoS) and on the general feeling of well-being [1,13]. 6 BJU INTERNATIONAL 98, SUPPLEMENT, 13 17 13

SPEAKMAN TAMSULOSIN ORAL-CONTROLLED ABSORPTION SYSTEM (OCAS ) A novel tablet formulation of tamsulosin which uses the OCAS technology was specifically designed to give a more continuous 4-h drug release [11]. The OCAS technology consists of a gel matrix, containing a gel-forming and a gelenhancing component. The tamsulosin OCAS tablet undergoes substantial hydration in the stomach and the small intestine, so that complete hydration occurs before arrival at the colon. The gel matrix then has enough gel strength to allow drug release in the colon. By scintigraphy, it was shown that tamsulosin OCAS was released throughout the entire gastrointestinal tract, including the colon, confirming consistent and continued 4-h release [14]. This results in a more consistent PK profile, as shown in two phase I studies in healthy young volunteers [11]. Tamsulosin OCAS showed a lower C max and less fluctuation in 4-h plasma concentrations. Furthermore, the PK profile of tamsulosin OCAS was independent of food intake [11]. The benefits of this improved profile were determined in clinical phase II and III studies, as discussed below. EFFICACY OF TAMSULOSIN OCAS The efficacy of the new tablet formulation of tamsulosin was assessed in three randomized controlled trials. Two of these, a phase IIb and a phase IIIa study, were completed for submission of the registration form [15,16]. An additional phase IIIb study was completed after submission [17]. The most appropriate dosage for clinical use was assessed in the phase IIb and the phase IIIa trials [15,16]. The phase IIIb study was designed to assess the effect of tamsulosin OCAS on nocturia, quality of life (QoL) and QoS. ASSESSING THE MOST EFFECTIVE DOSE The efficacy and safety of tamsulosin OCAS at three different dosages (.4,.8 and 1. mg) was first evaluated in a double-blind, randomized, placebo-controlled phase IIb dose response study [15]. The study randomized 839 men (aged 45 years) with LUTS/BPH to one of the three dosages or placebo [15]. All tested doses of tamsulosin OCAS reduced the IPSS to a statistically significantly greater extent than did placebo (Fig. 1). The percentage change in total IPSS % change in total I-PSS 6 4 Change in I-PSS nocturia from baseline to endpoint 4 3 1 Placebo (n = 13) Tamsulosin OCAS.4 mg (n = 6) from baseline to endpoint was similar for all three doses. Tamsulosin OCAS had a rapid onset of action, after weeks of treatment, 6% of the total improvement was achieved, and 8% was achieved after treatment for 4 weeks. The improvement of urinary symptoms was accompanied by a statistically significant improvement in the IPSS QoL score with all tested doses. The efficacy of the.4 mg and.8 mg doses of tamsulosin OCAS were also evaluated in a phase IIIa study in 15 men with LUTS/BPH [16]. Again, both doses statistically significantly improved the total IPSS vs placebo and had a similar rapid onset of action. Taken together, these studies show that tamsulosin OCAS.4 mg is statistically significantly superior to placebo in relieving LUTS/BPH. Increasing the dose to.8 mg does not increase efficacy. EFFECT ON NOCTURIA P=.16 P<.1 P<.1 Tamsulosin OCAS.8 mg (n = 9) 3 3.1.3 Placebo -.7 Baseline Endpoint The effect of tamsulosin OCAS.4 mg on nocturia, QoS and QoL was assessed in a phase IIIb pilot study in 117 men (aged 45 years) with LUTS/BPH and two or more nocturnal voids [17]. To evaluate the effect of tamsulosin OCAS on QoS, the concept of hours of undisturbed sleep (HUS) was introduced. HUS refers to the time from Tamsulosin OCAS 1. mg (n = 11) -1.1* Tamsulosin OCAS.4 mg falling asleep to the first awakening to void. The idea to develop HUS as a tool to evaluate QoS was based on the finding that waking up during the first 3 4 h of the night, when deep restorative sleep predominates, has a profound affect on wakefulness and performance during the following day [1]. Consistent with the results of the phase IIb and IIIa studies, tamsulosin OCAS.4 mg was superior to placebo in reducing the mean total IPSS, and more specifically the mean IPSS nocturia (Fig. ) and QoL subscores. This was accompanied by an increase in the HUS from a baseline of 8 min (6%) with tamsulosin OCAS, compared to 6 min (4%) with placebo, with the difference not being statistically significant. TAMSULOSIN OCAS SAFETY AND TOLERABILITY TOLERABILITY FIG. 1. The percentage change in total IPSS from baseline to endpoint was similar for tamsulosin OCAS.4,.8 and 1. mg and statistically significant vs placebo [15]. FIG.. The mean change in IPSS nocturia from baseline to endpoint for placebo and tamsulosin OCAS.4 mg. The mean reduction at endpoint with tamsulosin OCAS.4 mg (1.1 points) was statistically significantly greater than that with placebo (.7 points). *P =.8 vs placebo [17]. A first impression of the tolerability of tamsulosin OCAS was provided by the phase IIb and IIIa studies described above. In these, all three doses of tamsulosin OCAS (.4,.8 and 1. mg) were well tolerated, but the.4 mg dosage had the lowest incidence of AEs, which was similar to placebo [15,16]. On average, 6% of men in the placebo group 14 6 BJU INTERNATIONAL

EFFICACY AND SAFETY OF TAMSULOSIN OCAS FIG. 3. The incidence of the two most commonly reported treatmentemergent AEs after treatment with tamsulosin OCAS.4 mg is similar to that with placebo [15,16]. and 6 9% of men treated with tamsulosin OCAS.4 mg had AEs, which were treatmentrelated in 7% and 9 11% of men, respectively. The two most frequently reported treatmentemergent AEs were dizziness and abnormal ejaculation. Basically, the incidence of dizziness was similar for tamsulosin OCAS.4 mg and placebo (Fig. 3), but was higher with the.8 mg and 1. mg doses of tamsulosin OCAS. The incidence of abnormal ejaculation was only slightly but not statistically significantly higher with tamsulosin OCAS.4 mg than with placebo (Fig. 3) and showed a clear dose response relationship with tamsulosin OCAS.8 mg and 1. mg. As in both efficacy studies tamsulosin OCAS.8 mg and 1. mg were no better than.4 mg but were associated with a higher incidence of AEs, tamsulosin OCAS.4 mg was recommended as the optimum dose for the treatment of LUTS/BPH. CARDIOVASCULAR SAFETY % of patients 1 The phase IIIa study also evaluated the effect of treatment on blood pressure [16]. Both placebo and tamsulosin OCAS.4 mg induced very small changes in systolic (SBP) and diastolic (DBP) blood pressure that were not clinically significant. Also, there was no major difference between tamsulosin OCAS.4 mg and placebo in their effect on blood pressure changes. However, standard clinical trials, such as the phase IIIa study, might underestimate the occurrence of AEs and therefore overestimate the real safety of α 1 -AR antagonists in daily life. This is partly because the very elderly and patients with cardiovascular comorbidity and/or taking vasodilatory co-medication (e.g. antihypertensives or phosphodiesterase-5 inhibitors), are in particular prone to interference with blood pressure control 8 6 4 1.9 1.4 1.4 1.4.9.5.3 n = 356 n = 1 n = 3 n = 1 n = 3 n = 356 n = 36 n = 36 dizziness Phase IIb Placebo dizziness Phase IIIa Tamsulosin OCAS.4 mg abnormal ejaculation Phase IIb abnormal ejaculation Phase IIIa by α 1 -AR antagonists, and are largely excluded from most randomized clinical trials. Furthermore, in normal daily life, the cardiovascular system is often stressed by situations such as standing up, exercising, a heavy meal, etc., which are not often observed during routine hospital visits (in clinical trials). Therefore a more profound evaluation of the cardiovascular safety was needed to obtain reliable data on this issue. Several studies were specifically designed to test the cardiovascular safety of tamsulosin OCAS. Cardiovascular safety during graded infusions of phenylephrine In one of these studies, the cardiovascular safety of tamsulosin OCAS.4 mg was evaluated in 18 male volunteers (aged 18 45 years) by measuring the degree of vascular α 1 -AR antagonism under fasting conditions [18]. Cardiovascular stress can occur during a posture change, which results in α 1 -AR stimulation by endogenous noradrenaline. In the studies cardiovascular stress was mimicked by graded infusions of the α 1 -AR agonist phenylephrine. Infusion of this α 1 -AR agonist increases DBP and total peripheral resistance (TPR). The more this increase in DBP and TPR is inhibited by an α 1 - AR antagonist, the more it blocks the effect of the α 1 -AR antagonist at vascular α 1 -ARs. Phenylephrine-induced increases in DBP and TRP were less inhibited in men treated with tamsulosin OCAS than in men treated with tamsulosin MR up to 1 h after dosing. This is probably due to the better PK profile (lower C max ) of the OCAS formulation. Although it is recommended to take tamsulosin MR capsules after the first meal of the day, the study was done under fasting conditions. However, because in real life patients do not always comply with the recommended mode of dosing, especially in the elderly population, the cardiovascular risk shown in the study will be representative for at least some clinical situations. In a subsequent study, using the same study procedures, the degree of vascular α 1 -AR antagonism was tested after dosing with tamsulosin OCAS.4 mg and the prolongedrelease (XL) formulation of alfuzosin 1 mg in 18 healthy subjects [19]. Despite the XL formulation of alfuzosin being associated with a lower incidence of cardiovascular AEs than its immediate-release formulation [], tamsulosin OCAS.4 mg caused a statistically significantly lower inhibition of the phenylephrine-induced increase in DBP at h after dosing, and in TRP at and 4 h after dosing. This might be due to the selectivity of tamsulosin for α 1A - and α 1D -ARs in the LUT over α 1B -ARs in the blood vessels and because tamsulosin is selectively distributed to the LUT. Cardiovascular safety during orthostatic stress testing Exercising and conditions that reduce the effective circulating blood volume, such as hot climates or bathing and dehydration, might stress the cardiovascular system and increase the risk of cardiovascular related AEs, especially in the elderly [7]. The cardiovascular safety of tamsulosin OCAS under circumstances that stress the cardiovascular system was evaluated in two studies in healthy men aged 6 years [19,1]. Orthostatic stress tests were done to stress the cardiovascular system; changes in vital signs (BP and heart rate) were assessed after the subjects had been asked to lie down for at least 5 min, then to sit up for min, and then to stand for 3 min. An orthostatic stress test was considered positive if at least one of the following conditions was fulfilled: (i) symptoms such as light-headedness, dizziness, or faintness, etc. upon standing up; (ii) a decrease in SBP of mmhg between supine and standing; (iii) a decrease in DBP of 1 mmhg between supine and standing or a standing DBP of <6 mmhg; (iv) an increase in standing pulse rate of beats/min between supine and standing or a standing pulse rate of 1 beats/min [19,1]. The first study evaluated the interaction of single doses of tamsulosin OCAS.4 mg and tamsulosin MR.4 mg with the adaptive orthostatic response to cardiovascular stress in 4 healthy men (aged 6 years) under 6 BJU INTERNATIONAL 15

SPEAKMAN fasting conditions. The incidence of positive orthostatic stress tests was lower in men treated with tamsulosin OCAS.4 mg than in men treated with tamsulosin MR.4 mg (Fig. 4). These results imply that the new formulation of tamsulosin has less cardiovascular α 1 -AR antagonism, i.e. is associated with a lower incidence of orthostatic hypotension than with the tamsulosin MR capsule under circumstances that stress the cardiovascular system in an age group representative of that likely to be treated with tamsulosin. This is probably related to the improved PK profile of the OCAS formulation. The second study assessed the effect of tamsulosin OCAS.4 mg and a comparator (alfuzosin XL 1 mg) during orthostatic stress testing, according to the summary of product characteristics (SmPC)/ labelling of alfuzosin, i.e. under fed conditions [19]. The incidence of positive orthostatic stress tests was lower in men treated with tamsulosin OCAS.4 mg than with alfuzosin. The more favourable cardiovascular tolerability of tamsulosin OCAS.4 mg is of particular value in real-life situations such as in patients with cardiovascular comorbidity and/or taking vasodilatory co-medication, who are more vulnerable to orthostatic hypotension [19]. CONCLUSIONS The novel formulation of tamsulosin was developed primarily to provide a 4-h control of day- and night-time symptoms of LUTS/ BPH and to reduce the risk of potentially dangerous cardiovascular side-effects. Efficacy studies showed that tamsulosin OCAS.4 mg induces a rapid and effective reduction of symptoms, including nocturia, and an improvement in QoL. This was accompanied by an improvement in QoS. It was expected that, due to its smoother PK profile, which is independent of food intake, tamsulosin OCAS would have better tolerability. Indeed, treatment with tamsulosin OCAS was associated with a minimal risk of treatment-induced morbidity with a low incidence of AEs (at placebo level). Studies specifically designed to evaluate the cardiovascular safety showed that tamsulosin OCAS.4 mg has a reduced cardiovascular α 1 -AR antagonism, regardless of food intake, and even in situations that stress the cardiovascular system and in the elderly. The observed improvements in cardiovascular safety are especially relevant in men with % of patients with positive OTs 5 4 3 1 LUTS/BPH at risk of cardiovascular sideeffects such as older men and those with concomitant cardiovascular disease or those taking vasodilatory medication. As the studies did not include patients at increased cardiovascular risk, it can be expected that the improvements observed in the present studies might be even greater in real-life practice. REFERENCES Tamsulosin OCAS.4 mg (N=4) Pre-dose 1 McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care 6; 1 (Suppl. 5): S1 8 AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (3). 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