DRUG FORECAST. Select Conditions of the Lower Urinary Tract

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1 Transdermal Oxybutynin: Novel Drug Delivery for Overactive Bladder Vitalina Rozenfeld, PharmD, BCPS, Stanley Zaslau, MD, Kathleen New Geissel, PharmD, David Lucas, PhD, and Lili Babazadeh, PharmD INTRODUCTION The International Continence Society defines overactive bladder (OAB) as a symptom syndrome characterized by the presence of urgency, with or without urge incontinence, frequency, and nocturia (Table 1). 1 OAB is also referred to as the urge syndrome or urgency frequency syndrome. Because it is a syndrome, not all symptoms need to be present for patients to have the condition. The syndrome is often indicative of detrusor overactivity and can be referred to as Dr. Rozenfeld, Dr. Lucas, and Dr. Babazadeh are Medical Liaisons at Watson Laboratories in Morristown, New Jersey. Dr. Zaslau is Assistant Professor and Director of the Urodynamics Laboratory in the Section of Urology, Department of Surgery, at West Virginia University School of Medicine in Morgantown, West Virginia. At the time of this writing, Dr. New Geissel was a Medical Liaison at Watson Laboratories. Drug Forecast is regular department coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York. overactive bladder in the absence of infection or other pathological condition. 1 The number of patients with this disorder is estimated to be greater than the number of patients who have Alzheimer s disease, osteoporosis, and Parkinson s disease combined. According to a survey of 5, adults in the U.S by the National Overactive Bladder Evaluation (NOBLE) Program, 1.9% of women and 1.% of men were affected, representing approximately 33 million Americans. 3 These patients reported a diminished quality of life, and they had elevated depression scores. Similarly, a European study that collected data from 1,77 adults found a prevalence of 1.%. The management of overactive bladder reflects the multifactorial nature of this disorder and includes several options. 5 Both the storage and the elimination of urine are under the intricate control of the central and peripheral nervous systems. Multiple neurotransmitters are involved in regulating the micturition cycle; however, most of the detrusor muscle contraction results from muscarinic receptor stimulation via the parasympathetic release of acetylcholine. Coupled with relaxation of the external urinary sphincter, voiding can occur normally. Because of their ability to reduce detrusor contractility, anticholinergic agents are the mainstay of pharmacological management of patients with overactive bladder. A systematic review of published trials supports anticholinergic therapy as the pharmacological treatment of choice for urge urinary incontinence. PHARMACOKINETICS Rationale for Transdermal Delivery Oxybutynin (OXY), which has been commonly used for control of the overactive bladder, exhibits antimuscarinic and local anesthetic properties and acts as a smooth-muscle relaxant. When given orally, the drug undergoes extensive first-pass metabolism in the liver and the gastrointestinal tract via cytochrome P5 (CYP3A). The primary active metabolite, N-desethyl oxybutynin (), is formed in concentrations that are four to 1 times higher than the parent compound. Although OXY and have similar effects on the detrusor muscle, is more potent in the salivary Table 1 Select Conditions of the Lower Urinary Tract Term Increased daytime frequency Nocturia Urgency Urinary incontinence Stress incontinence Urge incontinence Mixed incontinence Normal detrusor function Detrusor overactivity Definition Data from Abrams P, Cardozo L, Fall M, et al. Neurourol Urodyn ;1: Patient considers voiding to be occurring too often during the day Waking up at night more than one time to void A sudden compelling desire to pass urine that is difficult to deter Any involuntary leakage of urine on effort or exertion or on sneezing or coughing accompanied by or immediately preceded by urgency associated with urgency and also with exertion, effort, sneezing, or coughing Bladder able to fill with little change in pressure; no involuntary phasic contractions despite provocation Urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may be spontaneous or provoked Vol. 9 No. June P&T 37

2 glands and has been associated with the additive effect of dry mouth. 7 Reducing the extent of first-pass metabolism, thereby ultimately reducing levels of, has been shown to improve tolerability and to diminish systemic anticholinergic side effects. 8 A transdermally administered OXY product that minimizes the extent of its first-pass metabolism and formation is now available as Oxytrol (Watson Pharmaceuticals). Oxytrol is indicated for patients with symptoms of urge urinary incontinence, urgency, and frequency. 9 Single-Dose Pharmacokinetics In a randomized, open-label, two-way crossover study, OXY was administered to 18 healthy volunteers as a single 39-cm transdermal system (OXY-TDS 3.9 mg/day) over 9 hours of wearing the patch or as a single 5-mg immediaterelease (OXY-IR) tablet. 1 Sixteen subjects completed the study. Plasma OXY and levels were measured for six hours after oral administration and 18 hours after the patch was applied. Both routes of delivery achieved comparable OXY plasma concentrations, with the patch producing substantially lower levels. After OXY-IR administration, concentrations were 1 times greater Table Pharmacokinetics of Enantiomers: Focus on Average Ratios AUC -t Transdermal Oxybutynin C max R-:R-OXY 1. ±. 1. ±. S-:S-OXY.8 ±..8 ±. Immediate-Release Oral Oxybutynin R-:R-OXY 15.1 ± ±.5 S-:S-OXY.7 ±. 3.3 ± 1. P <.1 between corresponding transdermal and oral administration ratios. AUC -t = area under the concentration time curve; c max = maximum concentration; = N-desethyl oxybutinin; OXY = oxybutinin. Data from Zobrist RH, Schmidt B, Feick A, et al. Pharm Res 1;18: With permission of Kluwer Academic/ Plenum Publishers. 1 Mean Cp (ng/ml) OXY-TDS OXY than those of OXY-TDS (Figure 1). There are two enantiomers of OXY: R and S. The R-enantiomer has greater anticholinergic activity. The enantiomers exhibit similar patterns of potency, and R- potentially contributes to greater anticholinergic side effects during oral administration. With the extensive hepatic metabolism that follows oral administration, selective R-OXY metabolism is observed. This reduces systemic bioavailability of the more active R-OXY and produces relatively higher concentrations of the more active R- (Table ), potentially leading to a greater number of anticholinergic side events. After transdermal application, plasma levels of R-OXY and R- are approximately equal, thus potentially preserving efficacy while minimizing the potential for adverse anticholinergic reactions. Bioavailability of Oxybutynin at the Application Site To compare the pharmacokinetic properties of oxybutynin applications to the abdomen, buttock, or hip, Zobrist et al. conducted a randomized, open-label, three-way crossover study that enrolled volunteers. 1 A 39-cm patch was applied to one of these three sites, followed by sequential blood collections for 1 hours. Application to the buttock and hip were found to be bioequivalent with 1.8 OXY-IR 19.8 Figure 1 Average plasma concentrations (Cp) following single-dose oxybutynin transdermal (OXY-TDS) or oral administration. = N-desethyl oxybutynin; OXY-TDS = 39 cm (3.9 mg/day) system; OXY-IR = immediate-release oxybutynin 5 mg. (Courtesy of G. Willy Davila, MD, et al. 3rd annual scientific meeting of the American Urogynecologic Society, October 17 19,. 11 ). application to the abdomen (Figure ), thus allowing patients the option of rotating or alternating the application sites. Multiple Applications and Dose Proportionality The relationship between the transdermal system area and steady-state plasma OXY levels was determined in a randomized, open-label, three-way crossover study of healthy volunteers. 1 Three sequential doses of 13,, and 39 cm were applied to the lower abdomen. The first two patches were applied for 8 hours, and the third was applied for 9 hours. Blood samples were collected over 88 hours. Plasma concentration profiles of OXY increased proportionally to the augmented doses (Figure 3). On the basis of the residual analysis method, the 13-, -, and 39-cm patches delivered approximately 1.3,., and 3.9 mg/day of OXY, respectively. 1 Steady-State Pharmacokinetics and Salivary Production The steady-state pharmacokinetics, metabolism, and pharmacodynamics of transdermal and controlled-release (extended-release) oral oxybutynin chloride (OXY-ER) (Ditropan XL, Ortho-McNeil) were studied in 15 healthy volunteers. 13 In an open-label, two-way crossover design, the subjects were randomly selected to receive two 38 P&T June Vol. 9 No.

3 Mean Oxybutynin Cp (ng/ml) Mean Oxybutynin Cp (ng/ml) 3 1 Figure Application site bioequivalence. Cp = plasma concentration. (From Zobrist RH, Quan D, Thomas HM, et al. Pharm Res 3;: With permission of Kluwer Academic/Plenum Publishers.) Figure 3 Mean plasma concentrations (Cp) of oxybutynin following application of the 13-, -, and 39-cm transdermal system (TDS) dose. (From Zobrist RH, Quan D, Thomas HM, et al. Pharm Res 3;: With permission of Kluwer Academic/Plenum Publishers. 1 ) sequential applications of transdermal OXY 3.9 mg/day and six daily oral doses of OXY-ER 1 mg. Blood and saliva samples, a surrogate marker for dry mouth, were monitored, and 13 subjects completed the study. Steady-state plasma concentrations of OXY were achieved by 8 hours after the first TDS application and after the second oral tablet. Following OXY-TDS, the mean OXY plasma concentrations were generally greater and less variable than System removal Time (hours) System removal Abdomen Buttock Hip 1.3 mg/day TDS. mg/day TDS 3.9 mg/day TDS Time (hours post-third TDS application) those of OXY-ER. In addition, mean plasma concentrations were lower and less variable following OXY-TDS than OXY-ER (Figure ). The :OXY areaunder-the-curve concentration (AUC 8 ) ratio was 1. after the transdermal dose and.1 after the oral dose (P <.1). These findings are consistent with reduced first-pass metabolism during transdermal delivery. The total weight of saliva was greater with OXY-TDS administration (Figure 5). There was a significant correlation between mean plasma levels and total saliva production (P =.351; r =.585). There was no significant correlation between OXY plasma levels and saliva output (P =.1778; r =.398). Analyses of Plasma Concentrations Results from multiple clinical trials were combined to evaluate the pharmacokinetics of OXY in healthy volunteers and patients with overactive bladder. 15 This assessment included healthy volunteers from two randomized crossover studies 1,1 and 555 patients from phase 1 and phase 3 17 studies. Plasma concentrations demonstrated dose proportionality in the volunteers and in the patients with overactive bladder (Table 3). The transdermal system delivered OXY levels comparable to those given orally, with reduced formation. OXY concentrations were sustained over the 9-hour wearing period, thereby allowing for twice-weekly administration, and they remained consistent over weeks of therapy (Figure ). EFFICACY AND SAFETY IN CLINICAL TRIALS Initial Proof-of-Concept Trial: Transdermal vs. Immediate- Release Oxybutynin In an effort to confirm the rationale behind transdermal delivery of oxybutynin (OXY-TDS), Davila et al. conducted a six-week multicenter, doubleblind, forced dose titration study of 7 patients with a history of urge incontinence. 1 The trial was designed to assess the degree of anticholinergic adverse drug events (ADEs) between OXY-TDS and the current market formulation at the time of study initiation, OXY-IR. Patients were asked to list any anticholinergic ADEs via a questionnaire, with dose titration to higher doses based on tolerability, not efficacy. Participants had to be on stable doses of oral OXY and had to have at least three incontinence episodes daily and a recurrence of symptoms of incontinence after a two-week washout period. The patients were randomly assigned to receive OXY-TDS or overencapsulated, immediate-release tablets (OXY- IR). Treatment was begun at one of the continued on page 373 Vol. 9 No. June P&T 39

4 Table 3 Plasma Concentrations During Administration of Transdermal and Oral Immediate-Release Oxybutynin (ng/ml, mean + SD) OXY-TDS three dosing levels, depending on the pre-study OXY dose. The dose was titrated according to the patients reported anticholinergic ADEs, with the goal of achieving the maximal tolerable dose. The highest dose level (level 3) was defined as OXY-IR.5 mg/day divided, or OXY-TDS 5. mg/day. The patients were predominantly women, and OXY-IR 1.3 mg/day. mg/day 3.9 mg/day 5 mg/day 15 mg/day Single dose (C max ) OXY 3. ±.8 7. ± 5..5 ± ± 1. Steady state (C max ) OXY.3 ±.8. ± 1.3. ±..7 ± ± ± 5. Chronic treatment OXY ( weeks) 1. ±.5. ± 1..1 ±.1.8 ±.3 ( weeks).1 ± 1.. ± ±. 15. ± 13.8 OXY (1 weeks) 1. ±.. ± ± 1.9 OXY ( weeks) 1. ±.8.5 ± ±. C max = maximum concentration; OXY-IR = immediate-release oxybutynin; OXY-TDS = oxybutynin transdermal system; SD = standard deviation. Courtesy of David Guay, PharmD, and K. New, PharmD. 37th midyear clinical meeting of the American Society of Health-System Pharmacists, December 8 1,. 15 Mean Plasma Concentration (ng/ml) Transdermal system Oxybutynin Time (hours) Extended-release Oxybutynin nd OXY-TDS application 3rd OXY-ER tablet Figure Steady-state mean plasma concentrations of oxybutynin and N-desethyl oxybutynin () after transdermal (TDS) or oral oxybutynin. OXY-TDS = 3.9 mg/day of the oxybutynin transdermal system; OXY-ER = extended-release oxybutinyn chloride tablets (Ditropan XL ) 1 mg/day. (Courtesy of Rodney Appell, MD, et al. 3nd annual meeting of the International Continence Society,. 1 ) follow-up evaluations were conducted every two weeks. Seventy-four patients completed at least four weeks of treatment. Even though most patients began the study at the first dose level, 8% of OXY-TDS users reached the maximum dose, compared with 3% in the oral group, because of the formulation s increased tolerability. The most common anticholinergic side effect (dry mouth) occurred in fewer patients who received OXY-TDS (38%) than OXY-IR (9%) (P <.1). No patients in the OXY-TDS group rated the degree of dry mouth as severe, although 9% receiving OXY-IR did. Daily incontinence episodes were reduced by % in the groups receiving the transdermal system and by 7% in the groups receiving oral therapy (P =.39 between groups and P <.1 for both groups from washout to end of treatment). No erythema was reported by 78% of patients receiving a placebo transdermal system and by 1% who received active transdermal application. Transdermal Oxybutynin vs. Placebo In a large trial that compared the efficacy and safety of OXY-TDS with those of placebo, 5 adults with urge incontinence and mixed urinary incontinence were enrolled and evaluated for up to 5 weeks. 17 Patients were either treatmentnaive (78%) or had previously experienced a washout period from earlier anticholinergic therapy (%). Participants had at least 1 urge incontinence episodes and 5 voids per week. In the double-blind, 1-week portion of the trial, patients were randomly assigned to receive twice-weekly doses of 1.3,., 3.9 mg/day of OXY-TDS or placebo, followed by an optional 1-week, open-label, dose titration period. At the completion of the first open-label period, eligible patients could opt to enroll in another fixed-dose, open-label period of 8 weeks duration (results not yet available for publication). The double-blind phase completion rate was high, with 7 patients (8%) remaining on therapy after 1 weeks. Patients receiving OXY-TDS 3.9 mg/day experienced a significantly greater reduction in urinary incontinence episodes than patients receiving placebo at all evaluation time points (Table ) and a greater decrease in mean daily urinary frequency, compared with the rate for placebo patients (.3 ±.5 vs. 1.7 ± 3.; P =.57, respectively). Patients in this OXY-TDS group also experienced greater median increases in average urine volume per void ( ml vs. ml with placebo, P =.3) and reported improved quality of life (Incontinence Vol. 9 No. June P&T 373

5 Impact Questionnaire total score, P =.37 vs. placebo). The incidence of dry mouth was low, and rates for the OXY-TDS users (7%) and the placebo group were similar (8.3%; P =.98). No patients discontinued therapy because of dry mouth. The rates of other reported anticholinergic ADEs, including constipation, dizziness, and nausea, were similar between the groups. Pruritus at the application site was the most common ADE (1.8% 1.8% with OXY-TDS and.1% with placebo) and was mild to moderate in intensity and duration. Of those enrollees who completed the double-blind period, 91.9% (11 patients) entered the open-label phase; 358 patients completed the study. Following dose titration, 51.3% of patients received OXY-TDS 3.9 mg/day (see Table ). With this dose, mild or no erythema was observed in 87.8% of patients. Overall, 15 patients (3.%) in the open-label period withdrew from treatment because of reactions at the application site. Dry mouth, application-site pruritus, and erythema were reported by 3.9%, 5.%, and.7% of patients, respectively. Transdermal Oxybutynin vs. Controlled-Release Tolterodine and Placebo Dmochowski et al. compared the safety and efficacy of OXY-TDS vs. controlled-release (long-acting) tolterodine tartrate capsules (TOL-CR) (Detrol LA, Pharmacia) or placebo in 31 adults with overactive bladder. 18 Previous responders to antimuscarinic therapy (more than six weeks) were randomly selected to receive OXY-TDS (3.9 mg/day applied twice weekly), TOL-CR ( mg daily), or matching placebo during 1 weeks of blinded treatment. Following the prestudy treatment washout period, participants had to have four or more episodes of urge urinary incontinence, voids or more, and an average urinary voiding volume of 35 ml or more in a three-day period. Patients were predominantly white women (93%) with an average age of years. The double-blind period of the trial was completed by 3 patients. The median duration of prior treatment with antimuscarinic therapy was greater than one year (range, six weeks to years). Recipients of OXY-TDS and TOL-CR Table Incontinence Episodes per Week at the Baseline Evaluation and Change from Baseline to Endpoint (Updated Report) Twice Weekly Transdermal Oxybutinin (OXY-TDS) Study Period 1.3 mg/day. mg/day 3.9 mg/day Placebo Double-Blind No. of patients Baseline (mean ± (SD) 38. ± ± ± ±. Baseline (median) Change (mean ± SD) 18. ± ± ± ± 1. Change (median) * 15. Open Label No. of patients NA Baseline (mean ± SD) 3.7 ± ± ±. NA Baseline (median) NA Change (mean ± SD). ±.5.9 ± ± 1.9 NA Change (median) NA 95% CI 31.5, , , 19. NA * Transdermal oxybutynin compared with placebo, P =.15. CI = confidence interval; NA = not applicable; SD = standard deviation. Total Saliva Weight (g) * 15.7 OXY-TDS 1. OXY-ER *P =.1 vs OXY-ER Figure 5 Total saliva weight (over 9 hours) following administration of transdermal oxybutynin (OXY-TDS) or oral oxybutynin. (OXY-TDS) = 3.9 mg/day; OXY-ER = extended-release oxybutynin chloride tablets (Ditropan XL ) 1 mg/day. (Courtesy of Rodney Appell, MD, et al. 3nd annual meeting of the International Continence Society, August 8 3,. 1 ) showed significant reductions over those receiving placebo in terms of incontinence episodes and urine voiding volumes (Table 5), with no differences noted between the two active treatment groups (P >.5). Reductions in voiding frequency were similar between both active arms of the trial. In addition, the most severely affected patients (with 1 or more micturitions daily) in each treatment group experienced a statistically significant reduction in voiding frequency (with OXY-TDS,.9/day, P =.3). Of the patients who were receiving OXY-TDS, 39% achieved complete continence; of the TOL-CR users, 38% did (in both groups, P =.1 vs. placebo, %). Patients Global Assessment of Disease State scores reflected overall improve- 37 P&T June Vol. 9 No.

6 Table 5 Changes in Urinary Incontinence Episodes, Frequency, Voiding Volume, and Quality of Life with Transdermal Oxybutynin and Oral Tolterodine Change from Baseline* Placebo TOL-CR OXY-TDS OXY-TDS vs. TOL-CR Daily incontinence episodes (.1 ± 3.) 3 ( 3. ±.8) 3 (.9 ± 3.) P =.11 P =.137 NS Daily frequency 1 ( 1. ±.7) (. ±.) ( 1.9 ±.7) P =.5 P =.11 NS Average voiding volume 5.5 (9.3 ± 3) 9 (9 ± 57) (3 ± 55) P =.17 P =.1 NS Incontinence Impact Questionnaire: 9 ( 3 ± 9) 57 ( 7 ± 8) 55 ( 8 ± 85) total score P =.193 P =.71 NS * Change from baseline = median (mean + SD). P values vs. placebo. TOL-CR = controlled-release (long-acting) tolterodine tartrate (Detrol LA) mg orally daily. OXY-TDS = transdermal oxybutynin 3.9 mg/day twice weekly. NS = not significant. Data from Dmochowski RR, Sand PK, Zinner NR, et al. Urology 3;:37. Copyright 3. With permission from Elsevier. 18 C ave (ng/ml) Figure Mean oxybutynin (OXY) and N-desethyl oxybutynin () plasma concentrations in patients with overactive bladder who are receiving transdermal oxybutynin (OXY-TDS) therapy over six, 1, and weeks. Cave = average concentration. (Courtesy of David Guay, PharmD, and K. New, PharmD. 37th midyear clinical meeting of the American Society of Health-System Pharmacists,. 15 ) 3.9 OXY 1 Duration of Treatment (weeks) ments during OXY-TDS (P =.5) and TOL-CR (P =.5) treatments, and no differences between the groups were observed (P =.181). Because of the study design (with 1% of the patients having used antimuscarinic therapy along with their protracted use prior to enrollment), the incidence of dry mouth was lower than expected for all treatment arms. Dry mouth occurred in.1% of the transdermal recipients and in 7.3% of the TOL-CR recipients (1.7% with placebo; P =.78 and.379, respectively). Erythema (8.3% vs. 1.7% with placebo) and pruritus (1.% vs..3% with placebo) were among the most common treatment-related ADEs observed in the transdermal group. DOSAGE AND ADMINISTRATION The recommended dose of Oxytrol is one transdermal application, 3.9 mg/ day, twice weekly. 9 The patch should be applied to dry, intact skin on the abdomen, buttock, or hip. To minimize irritation, patients should choose a different site with each new transdermal system to avoid re-applying the patch to the same site within seven days. CONCLUSION Oxybutynin is widely used for the management of patients with overactive bladder (urgency frequency syndrome). Oral oxybutynin undergoes extensive first-pass metabolism, resulting in high plasma concentrations of its active metabolite,, which is thought to contribute to anticholinergic side effects. The transdermal system has the following advantages: First-pass metabolism is avoided, and plasma concentrations are decreased. Stereoselectivity of OXY metabolism is diminished (compared with oral dosing). R-OXY retention is facilitated. R- formation is reduced. Twice-weekly application of OXY-TDS results in consistent plasma levels of OXY and, without peak-and-trough fluctuations, and offers the prospect of improved compliance over that of daily regimens. Clinical trials of OXY-TDS have demonstrated comparable efficacy of oral Vol. 9 No. June P&T 375

7 oxybutynin and tolterodine, with fewer anticholinergic side effects. In placebocontrolled trials, the incidence of dry mouth was similar in both OXY-TDS and placebo patients, with no patients discontinuing therapy because of dry mouth. Application site reactions, such as erythema and pruritus, were among the most commonly reported side effects in patients using OXY-TDS and were mild to moderate in duration and intensity. In summary, this innovative therapeutic medication system holds promise for patients with overactive bladder. REFERENCES 1. Abrams P, Cardozo L, Fall M, et al. The standardization of terminology of lower urinary tract function: Report from the Standardization Subcommittee of the International Continence Society. Neurourol Urodyn ;1: Stewart K, McGhan WF, Offerdahl T, Corey R. Overactive bladder patients and the role of the pharmacist. J Am Pharm Assoc ;: Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 3;: Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 1;87: Dmochowski R. Interventions for detrusor overactivity: The case for multimodal therapy. Rev Urol ;(Suppl ):S19 S7.. Haeusler G, Leitich H, van Trotsenburg M, et al. Drug therapy of urinary urge incontinence: A systematic review. Obstet Gynecol ;1: Lai HH, Boone TB, Appell RA. Selecting a medical therapy for overactive bladder. Rev Urol ;(Suppl ):S8 S Wein AJ, Rovner ES. Pharmacologic management of urinary incontinence in women. Urol Clin North Am ;9: Oxytrol prescribing information. Watson Pharmaceuticals, Inc., Corona, CA. February 3. Available at com. Accessed August 1, Zobrist RH, Schmidt B, Feick A, et al. Pharmacokinetics of the R- and S-enantiomers of oxybutynin and N-desethyl oxybutynin following oral and transdermal administration of the racemate in healthy volunteers. Pharm Res 1;18: Davila GW, Dmochowski RR, Sanders SW. Transdermal and oral oxybutynin: Comparison of anticholinergic side effects. Poster presented at the 3rd annual meeting of the American Urogynecologic Society, San Francisco, October 17 19,. 1. Zobrist RH, Quan D, Thomas HM, et al. Pharmacokinetics and metabolism of transdermally administered oxybutynin: In vitro and in vivo performance of a novel delivery system. Pharm Res 3;: Appell RA, Chancellor MB, Zobrist RH, et al. Pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy volunteers. Mayo Clin Proc 3;78: Appell R, Zobrist RH, Thomas HM, Sanders SW. Pharmacokinetic profile of oxybutynin and its active metabolite N-desethyl oxybutynin in relation to salivary production in healthy volunteers. Poster presented at the 3nd annual meeting of the International Continence Society, Heidelberg, Germany, August 8 3,. 15. Guay D, New K. Pharmacokinetics of oxybutynin transdermal delivery in healthy volunteers and patients with overactive bladder. Poster presented at the 37th midyear clinical meeting of the American Society of Health-System Pharmacists, Atlanta, December 8 1,. 1. Davila GW, Daugherty CA, Sanders SW. A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol 1;1: Dmochowski RR, Davila GW, Zinner NR, et al. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. J Urol ; 18: Dmochowski RR, Sand PK, Zinner NR, et al. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 3;: P&T June Vol. 9 No.