Management of Overactive Bladder With Transdermal Oxybutynin
Treatment Update
RIU0283_08-12.qxd 8/12/06 3:09 PM Page 93 TREATMENT UPDATE Management of Overactive Bladder With Transdermal Oxybutynin Jonathan S. Starkman, MD, Roger R. Dmochowski, MD Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN In clinical trials, transdermal oxybutynin (OXY-TDS) has shown comparable efficacy and improved tolerability when compared with conventional pharmacotherapy. Systemic anticholinergic adverse effects are comparable to those with placebo, most likely owing to avoidance of first-pass hepatic metabolism and conversion of oxybutynin to N-desethyloxybutynin. OXY-TDS has predictable pharmacokinetic absorption and elimination parameters, as shown in both in vitro and in vivo studies. Consistent plasma concentrations of oxybutynin avoid labile peak and trough concentrations seen with immediaterelease formulations, paralleling extended-release drug delivery. This novel drug delivery system has unique dermatologic skin application site reactions, including erythema and pruritus. Skin reactions are usually mild and can be minimized by varying the site of patch application. Most eczematous dermatologic reactions can be appropriately treated with a moderately potent topical corticosteroid cream. A small percentage of patients will discontinue therapy as a result of bothersome application site skin reactions. [Rev Urol. 2006;8(3):93-103] © 2006 MedReviews, LLC Key words: Overactive bladder • Anticholinergic medications • Oxybutinin • Tolterodine • Transdermal drug delivery veractive bladder (OAB) is a common symptom complex of the lower urinary tract characterized by urinary frequency, urgency, urge incontinence, and nocturia.1 Although it is generally accepted that OAB symptomatology is widely under-reported for a variety of reasons, it is estimated that OAB affects up to 33 million adults in the United States, with a third experiencing urinary urge incontinence.2,3 Symptoms of OAB are known to have a negative impact on O VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 93 RIU0283_08-12.qxd 8/12/06 3:09 PM Page 94 Transdermal Oxybutynin continued health-related quality of life, leading to limitations in daily activities, withdrawal from social situations, embarrassment, anxiety, and depression.4-6 Furthermore, there are real health risks associated with OAB. It has been shown that postmenopausal women with urinary incontinence have a significantly higher risk of falling and sustaining a fracture.7 There is also a huge financial burden associated with the disorder, with total costs related to urinary incontinence exceeding $25 billion per year.8 effective.9 Pharmacotherapy for OAB is also extremely effective, with antimuscarinic agents demonstrating efficacy in the reduction of OAB symptoms in numerous randomized clinical trials. In addition, several studies have shown that combination therapy with antimuscarinics and behavioral therapy provides outcomes superior to those seen with either treatment alone.10,11 Despite the existence of effective treatments for OAB, at any given time only a fraction of patients are receiv- Patient compliance with these conservative, noninvasive treatments often declines with time because they require more effort on the part of the patient to be effective. Although OAB is a syndrome for which no identifiable cause has been identified, the pathophysiological abnormalities underlying detrusor overactivity are reasonably well understood, and a variety of effective treatments for OAB are currently available. However, it is extremely important to individualize therapy, with consideration given to each patient’s lifestyle, cognitive ability, and expectations. Realistic goals should be outlined and discussed with patients before the initiation of any form of therapy. The management of OAB has become standardized to some degree, and because it is the least invasive approach, behavioral therapy is often recommended as first-line treatment. Behavioral therapies include a combination of pelvic floor muscle exercises (with or without biofeedback), pelvic floor electrical stimulation, fluid restriction, dietary modification, and timed/prompted voiding. Patient compliance with these conservative, noninvasive treatments often declines with time because they require more effort on the part of the patient to be 94 VOL. 8 NO. 3 2006 ing therapy. Reasons for this disparity are likely multifactorial, including issues related to cost of therapy, patient and physician attitudes, a heterogeneous patient population with respect to symptom severity and response to therapy, and side effects related to medication. Furthermore, both neurogenic and myogenic mechanisms might play important roles in the bladder’s responsiveness to particular agents and interventions.12 Of the various pharmacotherapies for OAB, antimuscarinic agents are type is the most abundant receptor in the bladder, it seems that the M3 receptor subtype is most directly responsible for the symptoms of OAB because it mediates detrusor contractility.13-15 Oral immediate-release oxybutynin (OXY-IR) has had a proven track record with regard to both safety and efficacy in the treatment of OAB. In recent years, a number of newer agents have become available, including tolterodine, trospium, solifenacin, and darifenacin, thus adding to the therapeutic armamentarium and enhancing treatment options for patients. Extended-release formulations of oxybutynin and tolterodine result in controlled release of drug and steady plasma concentrations, improving tolerability compared with immediate-release dosing.16-18 Several drugs allow for flexible dosing and dose escalation, which serves to optimize efficacy and tolerability.19-21 Despite these improvements, the significant incidence of anticholinergic side effects continues to be a major cause of noncompliance and discontinuation of treatment, serving to negatively impact patient quality of life.22,23 Several novel methods of oxybutynin administration have been reported as means of reducing anti- Intrarectal, intravesical, and intravaginal oxybutynin have been administered in clinical trials in an attempt to avoid first-pass hepatic metabolism. currently considered the standard of care, with efficacy achieved through muscarinic receptor blockade. Five different receptor types (M1–M5) have currently been identified, which vary in distribution throughout the body, depending on the particular organ system. In the bladder the predominant receptors are the M2 and M3 subtypes. Although the M2 sub- REVIEWS IN UROLOGY cholinergic adverse effects. Intrarectal, intravesical, and intravaginal oxybutynin have been administered in clinical trials in an attempt to avoid first-pass hepatic metabolism.24-28 Despite observed therapeutic efficacy with these alternative oxybutynin regimens, a variety of factors have limited their clinical applicability and acceptance, including persistence of RIU0283_08-12.qxd 8/12/06 3:09 PM Page 95 Transdermal Oxybutynin anticholinergic side effects25 (dry mouth and constipation), inconvenient administration of medication (intravesical and intrarectal),25,27 lack of approved commercial drug preparation (intrarectal), and issues related to impurities and contaminants with aqueous oxybutynin preparations (intravesical). As a result, these modes of drug delivery have not gained the widespread acceptance achieved by more conventional routes of administration. Transdermal Drug Delivery Systems Human skin can be classified into 3 distinct layers: epidermis, dermis, and hypodermis. Although each layer has a distinct function, the lipid- and keratin-rich stratum corneum of the epidermis plays an important role as a barrier layer, acting as the ratelimiting step in transdermal drug absorption.29 Transdermal absorption requires that compounds traverse all 3 skin layers, entering the systemic circulation through the rich capillary network within the dermis. There are can facilitate the absorption of more hydrophilic compounds, thus acting as a vehicle that aids in drug transport and absorption.31 Transdermal systems are generally classified as rate-controlled liquid reservoir patches or diffusion-controlled matrix-type patches.32 Matrixtype patches are smaller and thinner, have superior adhesive properties, and cause less skin irritation when compared with reservoir patches, thus improving patient acceptance and compliance. There are several distinct advantages of transdermal drug delivery systems. First, transdermal systems follow zero-order kinetics, delivering a constant amount of drug per unit time at a predetermined rate. Most typical oral and intravenous medications follow first-order kinetics, which commonly leads to high peak and low trough serum concentrations. Zero-order kinetics can potentially decrease adverse events associated with high peak concentrations, can permit less frequent dosing, and can minimize subtherapeutic plasma concentrations.33 Second, Transdermal absorption requires that compounds traverse all 3 skin layers, entering the systemic circulation through the rich capillary network within the dermis. a wide variety of factors that influence the absorption of a particular drug, including biological factors (eg, skin permeability, local lipid and aqueous microenvironment, and local cutaneous metabolism) and physiochemical factors (eg, molecular weight, size, structure, transdermal concentration gradient, and lipophilicity/hydrophilicity of the specific compound).30,31 Lipophilic drugs are particularly well suited for transdermal delivery owing to their increased solubility. Agents that can reduce lipids by acting as a solvent transdermal administration avoids first-pass hepatic metabolism, which is particularly beneficial in cases in which the parent drug is metabolized to an active metabolite that might potentiate side effects or toxicity. Furthermore, studies have repeatedly shown that bioavailability is greater after transdermal delivery of agents subject to extensive hepatic metabolism, thus allowing drugs with relatively poor bioavailability to attain therapeutic serum levels at low dosages.34,35 Currently there are a number of transdermal medications commercially available, including testosterone, estrogen, fentanyl, scopolamine, clonidine, nicotine, and oxybutynin.36 The purpose of this review is to discuss the mechanism of action, pharmacokinetics, efficacy, and safety of transdermal oxybutynin (Oxytrol™, Watson Pharmaceuticals, Corona, CA) in the management of OAB. Oxybutynin: Mechanism of Action Oxybutynin is a tertiary amine that exists commercially as a racemic mixture of R- and S-enantiomers (R-OXY, S-OXY). The mechanism of action of oxybutynin is 2-fold, consisting of (1) its antimuscarinic properties; and (2) its spasmolytic action on detrusor smooth muscle cells.37,38 Oxybutynin exhibits stereoselectivity: R-OXY has greater anticholinergic activity compared with S-OXY. The spasmolytic effects on smooth muscle seem to be equal for the R- and S-isomers.39,40 Studies from animal experiments have demonstrated that detrusor contractility occurs by M3 receptor– mediated smooth muscle contraction through hydrolysis of phosphatidylinositol and release of intracellular calcium. Furthermore, there is also evidence that M2 receptor–mediated contractions occur through inhibition of cyclic adenosine monophosphate–mediated relaxation of detrusor smooth muscle.41 As a result, by binding to the M2 and M3 muscarinic receptors of urothelial and detrusor smooth muscle cells, oxybutynin exerts its therapeutic effect by interrupting signal transduction pathways that culminate with a detrusor contraction. Oxybutynin Metabolism Oxybutynin is extensively metabolized by first-pass hepatic metabolism after administration of an oral VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 95 RIU0283_08-12.qxd 8/12/06 3:09 PM Page 96 Transdermal Oxybutynin continued immediate-release dose. The cytochrome P-450 (CYP) isoenzymes are the most abundant drug-metabolizing cytochromes in the liver and small intestine, mediating phase I drug metabolism through oxidation, reduction, and hydrolysis. CYP-3A4 is a specific cytochrome that converts oxybutynin to its active metabolite, N-desethyloxybutynin (N-DEO). As a result, bioavailability after oral dos- transmission rate, which are important in maintaining skin hydration.45 In addition, the backing layer adds to the physical integrity of the matrix system protecting the adhesive/drug layer. These properties of the backing layer facilitate penetration and absorption of oxybutynin through the layers of the skin. The second layer consists of an adhesive film of acrylic containing oxybutynin and triacetin It is generally accepted that many of the anticholinergic adverse effects observed after oral dosing of oxybutynin are secondary to high circulating levels of its active metabolite, N-DEO. ing of oxybutynin is only 6%, with levels of N-DEO reaching peak plasma concentrations that are 4 to 10 times greater than the native compound.42,43 Because of the high affinity of N-DEO for muscarinic receptors, particularly in the parotid gland, it is generally accepted that many of the anticholinergic adverse effects observed after oral dosing of oxybutynin are secondary to high circulating levels of its active metabolite, N-DEO.44 Because there are only small amounts of CYP-3A4 found in the skin, transdermal delivery of oxybutynin offers a unique route of administration that maintains the efficacy of oral oxybutynin while demonstrating pharmacodynamic and pharmacokinetic advantages that improve tolerability. (permeation enhancer). The acrylic adhesive keeps the delivery system in contact with the skin surface for defined periods of time (96 hours), allowing easy wear and removal with minimal dermatologic reactions. Layer 3 is the release liner, which contains 2 overlapped siliconeFigure 1. The transdermal oxybutynin system. Transdermal Oxybutynin Patch Transdermal oxybutynin (OXY-TDS) was approved by the US Food and Drug Administration for the treatment of OAB symptoms in February 2003. OXY-TDS is a matrix-type transdermal system composed of 3 layers (Figure 1). The first layer consists of a backing film composed of a thin polyester/ethylene-vinyl acetate film. The backing layer exhibits excipient resistance and a low moisture vapor 96 VOL. 8 NO. 3 2006 coated polyester strips that are peeled off and discarded by the patient before use. OXY-TDS contains 36 mg of oxybutynin and triacetin dissolved in an acrylic block copolymer adhesive with a surface area of 39 cm2.46 The average daily dose of oxybutynin absorbed from the 39-cm2 OXY-TDS system is 3.9 mg/d (0.1 mg/cm2). As previously noted, absorption of drug requires penetration of the lipid-rich stratum corneum of the skin and the more aqueous epidermis and dermis. Thus, oxybutynin must possess both lipophilic and hydrophilic properties. Once contact is established between the skin and OXY-TDS, diffusion of oxybutynin and the permeation enhancer occurs across the stratum corneum, controlled by the interaction of oxybutynin and enhancer with lipids in the skin.46 Oxybutynin is then absorbed by the capillary microcirculation in the dermis and delivered into the systemic circulation, REVIEWS IN UROLOGY Backing film Matrix adhesive layer Overlapped release liner strip Oxybutynin patch RIU0283_08-12.qxd 8/12/06 3:09 PM Page 97 Transdermal Oxybutynin 4 Abdomen Buttock Hip Cp (ng/mL) 3 2 1 0 0 12 24 36 48 60 72 84 96 Time (hours post-system application) 108 120 Figure 2. Concentration versus time curve after single-dose (3.9 mg/d), 96-hour transdermal oxybutynin application to the abdomen, buttock, and hip (n 24). Adapted from Zobrist RH et al,46 with kind permission of Springer Science and Business Media. thus bypassing first-pass metabolism by the liver (Figure 1). Benefits of OXY-TDS include avoidance of presystemic metabolism in the gut and liver and continuous, controlled release of drug throughout the entire 3- to 4-day dosing interval.46,47 Twice-weekly dosing of OXY-TDS might also improve patient compliance and overall satisfaction. The OXY-TDS patch can also be incised or cut before application to improve tolerability without compromising efficacy. Pharmacokinetics of OXY-TDS Several studies have evaluated the initial and steady-state pharmacokinetic characteristics of oxybutynin after transdermal administration. One recent clinical study assessed measurable serum levels of oxybutynin and N-DEO through the transdermal formulation in 24 healthy volunteers.46 After patch application there is a consistent 2-hour delay before measurable levels appear in the serum, with a steady increase in oxybutynin and N-DEO concentrations over the following 24 to 36 hours. Maximum drug concentrations of 3 to 4 ng/mL are consistently observed, reaching a stable plateau for another 24 hours before a gradual decline throughout the remainder of the 96-hour dosing interval. After discontinuation of the patch, plasma drug concentrations transiently increase, followed by rapid clearance of drug until levels become undetectable (Figure 2). During the study,46 the site of patch placement was rotated between the abdomen, hip, and buttock, with each site demonstrating bioequivalence, given that no significant pharmacokinetic differences were observed with respect to patch location. Median maximum concentrations (Cmax) were reproducibly observed between 36 and 48 hours (Tmax) after patch placement for both oxybutynin and N-DEO. Furthermore, the N-DEO/ oxybutynin ratio was consistently 1.5, which demonstrates that circulating levels of N-DEO after transdermal therapy are much less than corresponding concentrations after oral administration. Cumulative and interval absorption rates from in vivo and in vitro experiments revealed contin- uous and comparable average absorption rates over the 96-hour application period, with higher absorption occurring during the first 24 hours and interval reductions in absorption for each additional 24-hour period. A dose-escalation phase of the study revealed that steady-state pharmacokinetic parameters increased in direct proportion to patch surface area, with the N-DEO/oxybutynin ratio and time to Cmax remaining unchanged. Overall, the study46 demonstrated consistent and reproducible drug delivery, absorption, and pharmacokinetics. Bioequivalence with respect to the site of patch application should allow for flexible and convenient drug administration. A separate study47 demonstrated stereoselective metabolism of oxybutynin and further revealed that the metabolite profile varies depending on the route of drug administration. Although in vitro experiments showed no difference in absorption for R- and S-isomers of oxybutynin, the in vivo phase of the trial clearly revealed stereoselectivity. After transdermal administration, the R-enantiomer of oxybutynin attained lower plasma concentrations compared with the S-enantiomer at the following values: S-OXY S-DEO ROXY R-DEO. The ratio of DEO to oxybutynin was less than 1 for both R-OXY and S-OXY. A different profile was observed after oral oxybutynin therapy: R-DEO S-DEO SOXY R-OXY. Furthermore, DEO concentrations were significantly higher for both the S- and R-enantiomers, with measured S- and RDEO/OXY ratios of 3.25 and 8.93. Because the R isomer possesses greater muscarinic receptor affinity and NDEO is thought to play an important role in anticholinergic side effects, the distinct differences in metabolite profile after both transdermal and oral administration support the possibility VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 97 RIU0283_08-12.qxd 8/12/06 3:09 PM Page 98 Transdermal Oxybutynin continued of improved tolerability and comparable efficacy with the transdermal delivery system. In another study, Appell and colleagues48 compared pharmacokinetic parameters and saliva output after patients treated with OXY-TDS for OAB. A comparative review of the pharmacokinetic parameters of OXY-IR, OXY-ER, and OXY-TDS is provided in Table 1. The distinct differences in metabolite profile after both transdermal and oral administration support the possibility of improved tolerability and comparable efficacy with the transdermal delivery system. 98 VOL. 8 NO. 3 2006 Results from Clinical Trials The efficacy and tolerability of OXYTDS have been evaluated in several clinical trials. Figure 3. Steady-state oxybutynin and N-desethyloxybutynin plasma concentrations after transdermal and extended-release oral administration. Adapted with permission from Appell RA et al.48 REVIEWS IN UROLOGY Plasma concentration (ng/mL) 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 1st dose 2nd dose 0.5 Oxybutynin N-desethyloxybutynin 0 0 84 96 108 120 132 144 156 168 Time (hours after first transdermal application) 180 14 Plasma concentration (ng/mL) administration of both OXY-TDS and extended-release oxybutynin (OXYER). Steady-state plasma concentrations were attained after the first transdermal application and the second extended-release oral tablet. Although plasma concentrations were comparable for both agents, OXYTDS showed less fluctuation and greater stability over the course of the dosing interval when compared with OXY-ER. N-DEO levels were noted to be much higher after OXY-ER dosing when compared with OXY-TDS, and corresponding N-DEO/oxybutynin ratios were 4.1 0.9 (OXY-ER) and 1.2 0.3 (OXY-TDS) (Figure 3). Stereoselective metabolism was observed for both the R- and S-isomers of oxybutynin and N-DEO, which paralleled data previously reported.47 Previous studies have demonstrated that saliva output is an excellent surrogate marker of dry mouth symptomatology.49,50 As would be expected given the pharmacokinetic data, measurable saliva output (weight in grams) was greater in patients receiving transdermal therapy, which most likely reflects the avoidance of firstpass hepatic metabolism. As substantive evidence of this effect, an inverse relationship was observed between NDEO levels and saliva output, with lower levels of N-DEO correlating with greater total saliva weight. Data such as these corroborate the low incidence of dry mouth observed in A short-term, multicenter, doubleblind, dose titration study evaluated the respective safety and efficacy of OXY-TDS (maximum dose of 5.2 mg/d) and OXY-IR (maximum dose of 7.5 mg/d 3 times daily) in patients with urinary urge incontinence.51 After a 2-week washout phase, 76 patients with pure urge or mixed urinary incontinence responsive to OXY-IR were randomized to OXY-TDS (n 38) or OXY-IR (n 38). Outcomes were determined according to a 3-day bladder diary and a visual analogue scale measuring urinary control. Tolerability and side effects were assessed with a non-validated 12 10 8 6 Oxybutynin 4 N-desethyloxybutynin 2 0 * * 0 12 24 * 48 * * * 60 72 84 96 108 120 Time (hours after first oral administration) 132 144 RIU0283_08-12.qxd 8/12/06 3:09 PM Page 99 Transdermal Oxybutynin Table 1 Comparative Steady-State Pharmacokinetic Parameters of OXY-IR, OXY-ER, and OXY-TDS Agent Dosage Mean Tmax (h) OXY-IR 5 mg t.i.d. 5.0 (4.2) Mean Cmax (ng/mL) Mean AUC (ngh/mL) Mean T 1/2 (h) N-DEO/OXY References 12.4 (4.1) 81 (43) 9.0 (2.4) 5.5:1 46, 57 OXY-ER 15 mg q.d. 5.2 (3.7) 6.7 (2.1) 109 (43) 13.8 (2.9) 4.1:1 (0.9) 48, 57 OXY-TDS 3.9 mg q.d. 10 6.6 (2.4) 408 (108) 7-8 1.3:1 (0.3) 46, 56 3–4 d OXY, oxybutynin; IR, immediate release; ER, extended release; TDS, transdermal; Tmax, time to maximum concentration; Cmax, maximum concentration; AUC, area under the curve; T 1/2, half-life; N-DEO, N-desethyloxybutynin. Numbers in parentheses are standard deviation of the mean. anticholinergic symptom questionnaire. Dose titration was initiated at levels based on previous OXY-IR dosage and escalated upward until the maximal dose balancing efficacy and tolerability was achieved. Each active treatment cohort saw a significant reduction in average daily incontinence episodes compared with baseline ( 5; P .0001), although no significant difference was observed between treatment arms (OXY-TDS from 7.2 to 2.4, OXY-IR from 7.2 to 2.6; P .39). Eight patients were continent with patch treatment, whereas 10 patients were continent with oral therapy at study completion. Differences in mean visual analogue scale scores measuring urinary control were insignificant (P .9). With respect to measured cystometric parameters, both average volume at first contraction and average bladder capacity increased relative to baseline for both OXY-TDS (P .0055 and P .0011, respectively) and OXY-IR (P .1428 and P .0538). Although study outcome endpoints were similar between the 2 treatment groups, tolerability profiles differed, with patients receiving OXY-TDS reporting fewer and more mild adverse effects. During dose escalation/titration, 39% of the OXY-TDS group and 94% of the oral group reported the side effect of dry mouth. Because the majority of the patients receiving OXY-TDS experienced fewer and milder adverse effects related to therapy, more patients were able to achieve the maximal daily dose during the dose titration phase compared with patients receiving oral therapy (68% vs 32%). With the non-validated anticholinergic symptom questionnaire, side effects were rated as mild, moderate (tolerable), and severe (intolerable). Dry mouth was rated as absent, mild, including somnolence, dizziness, blurred vision, and impaired urination. Adverse dermatologic reactions were unique to patch therapy (active treatment and placebo). Mild, moderate, and severe erythema were observed in 18%, 4%, and 1%, respectively, of placebo patches and in 30%, 7%, and 1% of active-therapy patches. One patient developed allergic contact dermatitis with active transdermal treatment. Most importantly, no patients discontinued therapy secondary to dermatologic side effects related to the patch. Conclu- No patients discontinued therapy secondary to dermatologic side effects related to the patch. tolerable, and intolerable in 62%, 27%, 11%, and none, respectively, of patients treated with OXY-TDS. The respective values for patients treated with OXY-IR were 6%, 26%, 59% and 9%. Constipation was the next most frequent adverse event recorded in the questionnaire, being documented by 21% of patients in the transdermal group and 50% of patients in the oral group. Other side effects were described by fewer patients with less variance between treatment cohorts, sions from this study revealed comparable efficacy and increased tolerability with OXY-TDS compared with OXY-IR. In another multicenter, double blind study,52 520 patients with overactive bladder were randomized to receive 3 doses of OXY-TDS (1.3 mg/d, 2.6 mg/d, or 3.9 mg/d) or placebo applied twice weekly for 12 weeks. This was followed by a 12-week openlabel, dose titration period to further evaluate safety and efficacy parameters. VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 99 RIU0283_08-12.qxd 8/12/06 3:09 PM Page 100 Transdermal Oxybutynin continued The 3.9-mg/d transdermal dose led to significant improvements in incontinence episodes per week (median change 19 vs 14.5; P .0165), mean daily frequency (mean change 2.3 vs 1.7; P .0457), and average voided volume (median increase of 24 mL vs 6 mL; P .0063). There were also significant improvements in Incontinence Impact Questionnaire scores (39% improvement vs 28%; P .0327) compared with placebo. Forty-five patients achieved complete continence at study completion, with 16 receiving the 3.9-mg dose, 7 the 2.6-mg dose, 12 the 1.3-mg dose, and 10 the placebo patch. During the open-label, dose titration period, 51% of patients achieved the maximal allowable daily dose of 3.9 mg/d. Patients consistently achieved reductions of 3 incontinence episodes per day at all 3 dosages of OXY-TDS; however, those patients titrated to 3.9 mg/d tended to have more severe incontinence before study entry. Safety was evaluated in all patients completing the double-blind (n 520) and dose titration (n 411) phases of the trial.52 Local skin reactions were the most frequently observed adverse events related to transdermal treatment, with the vast majority being mild to moderate in intensity. The percentage of patients experiencing a dermatologic complication increased in direct proportion to the administered OXY-TDS dose (1.3 mg/d, 2.6 mg/d, or 3.9 mg/d), with erythema observed in 3.1%, 4.5%, and 5.6% (placebo 2.3%) of patients and pruritis reported in 10.8%, 13.5%, and 16.8% (placebo 6.1%) of patients, respectively. Corticosteroids and antihistamines were administered to 4.4% and 1.9% of patients in the double-blind and dose titration periods. Study withdrawal was most commonly related to skin reactions and was seen in 10.2% of patients in the double-blind period and 7.3% of pa- 100 VOL. 8 NO. 3 2006 tients during the dose titration period. An important endpoint with respect to transdermal delivery shown in the trial was that anticholinergic side effects, particularly dry mouth, did not differ between active treatment and placebo (7% vs 8.3%; P ns). Thus, successful treatment of OAB symptoms with OXY-TDS can be accomplished with an anticholinergic side effect profile comparable to that with placebo. The comparative efficacy and safety of OXY-TDS, oral extendedrelease tolterodine (tolterodine ER), and placebo were assessed in another double-blind, multicenter study.53 A total of 361 patients with OAB symptoms responsive to standard antimuscarinic medications underwent a washout phase with subsequent randomization to OXY-TDS (3.9 mg/d, twice weekly), tolterodine ER (4 mg daily), or placebo. Study outcomes were based on voiding diaries, incontinence-specific quality of life, and tolerability/safety. The 2 active treatment groups were both similar in terms of efficacy, demonstrating statistically significant changes in daily incontinence episodes, average voided volume, and disease-specific quality of life compared with placebo. Upon completion of the study 120 patients were continent, including 47 (39%), 47 (38%), and 26 (22%) patients receiving OXY-TDS, tolterodine ER, and placebo, respectively (both P .014 vs placebo). Whereas all measured efficacy outcomes showed comparable improvement, systemic adverse events occurred more frequently with tolterodine ER (23.6%) compared with OXY-TDS (19%) and placebo (12%). The majority of these were classified as mild and moderate. Dry mouth occurred in 4.1% of patients receiving OXY-TDS and 7.3% of patients receiving tolterodine ER, compared with 1.7% with placebo (OXY-TDS, REVIEWS IN UROLOGY P .2678; tolterodine ER, P .0379). Constipation occurred in 3.3% and 5.7% of OXY-TDS– and tolterodine ER–treated patients, respectively. As has been shown in the previous OXYTDS clinical trials, the most significant adverse effects directly attributable to transdermal therapy were dermatologic, including pruritis (14% with transdermal therapy vs 4.3% with placebo) and erythema (8.3% with transdermal therapy vs 1.7% with placebo). Dermatologic adverse effects were rated by patients as mild or moderate in 81% of cases. Twelve patients discontinued treatment in the OXY-TDS group as a result of skin site reactions, whereas 2 patients withdrew because of tolterodine ER–related side effects. The study53 demonstrated that OXY-TDS is similar to tolterodine ER in the treatment of patients with OAB symptoms, while maintaining a low anticholinergic side effect profile that is comparable to that with placebo. Another study54 analyzed pooled data from the 2 double-blind, phase III trials52,53 to better determine the safety and efficacy of OXY-TDS. The 241 patients who received 3.9 mg/d transdermal oxybutynin and 244 patients who received placebo treatment were included in the data analysis. As has already been discussed in the individual trials, significant improvements were noted with respect to incontinence episodes per day, daily urinary frequency, average voided volume, and quality of life scores. Adverse events determined to be related to therapy occurred in 100 (41.3%) and 61 (24.9%) patients receiving active treatment compared with placebo (Table 2). Twenty-seven patients (11.2%) discontinued OXY-TDS secondary to side effects, compared with 3 patients (1.2%) who withdrew from placebo treatment. Study withdrawal among those treated with OXY-TDS were almost always related to local RIU0283_08-12.qxd 8/12/06 3:09 PM Page 101 Transdermal Oxybutynin able results of OXY-TDS even more impressive. Another unique aspect of the pooled data analysis54 was the variance in patient population. Eighty percent of the participants in one of the studies52 were naïve to antimuscarinic therapy, whereas 100% of participants in the other study53 were known to be previous responders. Despite these differences, the clinical response of OXY-TDS was similar regardless of previous sensitization to pharmacotherapy. Thus, the pooled data analysis yielded results that might be more representative of the expected efficacy observed in actual clinical practice, in which a more heterogeneous patient population might be the norm. The results of the pooled data analysis further corroborate the efficacy and safety data of previous OXY-TDS clinical trials.51–53 Table 2 Common Systemic Anticholinergic Side Effects of OXY-TDS (3.9 mg/d) Versus Placebo Adverse Event OXY-TDS (n 241) (%) Placebo (n 244) (%) Any Event 12.8 11.0 .5421 Dry Mouth 7.0 5.3 .4303 Constipation 2.1 2.0 .9843 Nausea 1.2 0.8 .6631 Abnormal Vision 1.2 0.8 .6431 Dysuria 1.2 0.4 .3904 P Abdominal Pain 0.8 0.8 .9901 Dizziness 0.8 1.2 .6631 Somnolence 0.8 0.4 .5553 Xerophthalmia 0.4 1.6 .1820 OXY-TDS, transdermal oxybutynin. Adapted from Dmochowski RR et al,54 with kind permission of Springer Science and Business Media. skin application reactions—there were no discontinuations secondary to dry mouth. Dermatologic complications experienced by the 241 patients treated with OXY-TDS are summarized in Table 3. Although the benefit of placebo therapy in OAB clinical trials is well documented, the observed improvements have been attributed to behavioral therapy regimens that often accompany the studies.55 Patients in the pooled data analysis study54 were instructed to maintain normal fluid intake and continue with all nonpharmacologic modalities (eg, timed voiding and pelvic floor muscle exercises). Furthermore, implementation of structured voiding diaries could translate into the placebo group being viewed as an “active” control group. This would seem to make the favor- Table 3 Application Site Events of OXY-TDS (n 241) Severity Erythema* Pruritis† Mild 4 (1.7) 20 (8.3) Moderate 8 (3.3) 17 (7.0) Severe 7 (2.9) 6 (2.5) Data are presented as n (%). OXY-TDS, transdermal oxybutynin. *Erythema: mild faint or barely perceptible; moderate bright pink or sunburned in appearance; severe beet-red appearance. † Pruritis: mild no inconvenience/minimal or no treatment; moderate low level of inconvenience/ some interference with functioning; severe interference with functioning/interruption of daily schedule/typically requiring systemic drug therapy. Adapted from Dmochowski RR et al,54 with kind permission of Springer Science and Business Media. Conclusions In clinical trials, OXY-TDS has shown comparable efficacy and improved tolerability when compared with conventional pharmacotherapy. Systemic anticholinergic adverse effects are comparable to those seen with placebo, most likely owing to avoidance of first-pass hepatic metabolism and conversion of oxybutynin to N-DEO. OXY-TDS has predictable pharmacokinetic absorption and elimination parameters, as shown in both in vitro and in vivo studies. Consistent plasma concentrations of oxybutynin avoid labile peak and trough concentrations seen with immediaterelease formulations, paralleling extended-release drug delivery. This novel drug delivery system has unique dermatologic skin application site reactions, including erythema and pruritus. Skin reactions are usually mild and can be minimized by rotating patch location to different areas of the body. Most eczematous skin reactions can be appropriately treated VOL. 8 NO. 3 2006 REVIEWS IN UROLOGY 101 RIU0283_08-12.qxd 8/12/06 3:09 PM Page 102 Transdermal Oxybutynin continued with a moderately potent topical corticosteroid cream. Despite this, a small percentage of patients will discontinue therapy as a result of bothersome application site skin reactions. In conclusion, OXY-TDS is an excellent treatment option for patients who find the side effects of oral antimuscarinics intolerable, as well as those patients who do not wish to administer their medication on a daily basis. 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