The Role of Transdermal Oxybutynin in the Treatment of Urinary Incontinence

Antimuscarinic therapy remains the mainstay of pharmacological management for overactive bladder (OAB), complementing the improvements achieved by bladder retraining and lifestyle measures.^1–3 Antimuscarinic drugs are effective at controlling the symptoms caused by this highly prevalent and distressing condition, which affects more people in later life. However, adherence to antimuscarinic therapy in the long term is not good. The primary cause for withdrawal from medication is the relatively high incidence of unwanted side effects, predominantly dry mouth but also including constipation, heartburn, blurred vision, dizziness and drowsiness. Alternative routes of administration of antimuscarinic therapy have been shown to reduce the occurrence of side effects while retaining efficacy in symptom control. Oxybutynin, the oldest antimuscarinic drug, has predominantly been used in this fashion both rectally and intravesically with published reports supporting its efficacy.^4,5 The use of oxybutynin in a transdermal preparation is relatively new. This article will consider the pharmacology, pharmacokinetics, clinical trial data and practical use of transdermal oxybutyinin in the management of urinary incontinence and OAB.

Pharmacology
Oxybutynin is a partially selective antagonist of M₁, M₂and M₃ receptors, and at high concentrations has local anaesthetic and antispasmodic actions. In the transdermal formulation, it is transported across intact skin and absorbed into the circulation by passive diffusion across the stratum corneum. The release of oxybutynin in the transdermal patch is directly related to its cross-sectional area; the average dose of 0.1mg oxybutynin per cm² of patch was obtained from an analysis of the residual content of patches worn during a four-day period over 303 applications in 76 healthy volunteers.⁶ Following an initial application, the plasma concentration of oxybutynin increases for 24–48 hours, reaching average maximal concentrations of 3–4ng/ml; following this, steady-state concentrations are maintained for up to 96 hours. Therefore, the patch is changed every four days or twice weekly. Absorption is equivalent whether the patch is applied to the abdomen, buttocks or thighs, where the patch has been tested in vivo in randomised clinical studies. There appears to be no alteration in drug delivery with age or heating, so changes in surrounding temperature will not alter the rate of drug delivery.^7,8

Oxybutynin is metabolised by the P450 cytochrome enzyme systems found in the liver and gut wall. Its metabolites include phenylcyclohexylglycolic acid, which is inactive, and N-desethyloxybutynin (N-DEO), which is pharmacologically active. Following oral administration, pre-systemic metabolism results in oral bioavailability of approximately 6% and a higher plasma concentration of N-DEO than the parent compound. The first-pass metabolism is avoided by transdermal application, reducing the formation of N-DEO. Only small amounts of CYP3A4, the predominant enzyme, are found in the skin, limiting presystemic metabolism during transdermal application. A lowering of the N-DEO concentration is the likely reason for a reduction in dry mouth in clinical trials.⁹ The pharmacokinetics and effect on salivation have been assessed in a small cross-over study against extended-release oxybutynin in 13 healthy subjects. Steady-state concentrations of oxybutynin were reached after one oral administration and two transdermal applications of the patch. Concentrations of N-DEO were statistically significantly lower with the transdermal application and mean saliva output was greater and associated with lower N-DEO concentrations.¹⁰

The 3.9mg/day licensed dose was assessed in a randomised, controlled, double-blind study of different doses of the transdermal formulation against immediate-release oxybutynin in a group of prior oxybutynin responders who had at least three incontinence episodes daily and who had deteriorated in a two-week wash-out period. The dose was given at a comparable level to that taken by the subjects prior to the trial. Bladder diaries and visual analogue scales were used as outcome measures for the study. Of the 74 subjects who enrolled for at least four weeks of therapy, daily incontinence episodes decreased equally in each group – from 7.3 to 2.4 (66%) transdermal and from 7.4 to 2.6 (72%) oral – as did urinary leakage. Statistically significant dry mouth occurred in fewer of the subjects using the transdermal than the oral application, and compared with their previous oral medication 67% of the subjects using the transdermal application noticed a reduction in the severity of their dry mouth. The 3.9mg/day dose was selected on the basis of its tolerability and efficacy.¹¹