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. 2016 Jan 19;8(2):83–90. doi: 10.1177/1756287215626312

An update on the use of transdermal oxybutynin in the management of overactive bladder disorder

Joshua A Cohn 1,✉, Elizabeth T Brown 2, W Stuart Reynolds 3, Melissa R Kaufman 4, Douglas F Milam 5, Roger R Dmochowski 6
PMCID: PMC4772360  PMID: 27034721

Abstract

Antimuscarinic medications are used to treat nonneurogenic overactive bladder refractory to nonpharmacologic therapy. Side effects such as dry mouth, constipation, blurred vision, dizziness, and impaired cognition limit the tolerability of therapy and are largely responsible for high discontinuation rates. Oxybutynin is a potent muscarinic receptor antagonist whose primary metabolite after first-pass hepatic metabolism is considered largely responsible for its associated anticholinergic side effects. Transdermal administration of medications bypasses hepatic processing. Specifically with oxybutynin, whose low molecular weight permits transdermal administration, bioavailability of the parent drug with oral administration is less than 10%, whereas with transdermal delivery is a minimum of 80%. The result has been an improved side effect profile in multiple clinical trials with maintained efficacy relative to placebo; however, the drug may still be discontinued by patients due to anticholinergic side effects and application site reactions. Transdermal oxybutynin is available as a patch that is changed every 3–4 days, a gel available in individual sachets, or via a metered-dose pump that is applied daily. The transdermal patch was briefly available as an over-the-counter medication for adult women, although at this time all transdermal formulations are available by prescription only.

Keywords: overactive bladder, oxybutynin, transdermal, cost, efficacy, pharmacology

Introduction

Idiopathic, nonneurogenic overactive bladder (OAB) represents a significant public health burden, affecting 1 out of 7 US women [Hartmann et al. 2009]. OAB accounts for US$66 billion in total annual US societal costs [Ganz et al. 2010] and can be difficult to treat effectively [Reynolds et al. 2015]. Both American Urological Association and European Association of Urology guidelines recommend behavioral intervention as initial therapy for OAB with or without urge urinary incontinence (UUI) [Gormley et al. 2015; Lucas et al. 2012]. When behavioral therapy fails or is likely to fail, pharmacologic therapy is recommended.

Antimuscarinic drugs are the mainstay of initial pharmacologic management of OAB. Since oxybutynin was introduced in the early 1970s [Diokno and Lapides, 1972], antimuscarinic medications have been extensively studied in patients with OAB with encouraging results. Relative to placebo, anticholinergic drugs are associated with a 40% increased likelihood of cure or improvement and a significantly decreased number of leakage and voiding episodes [Nabi et al. 2006]. Nevertheless, over 60% of patients discontinue antimuscarinic medications within 6 months of initiating therapy [Ivanova et al. 2014], undoubtedly due, at least in part, to a high risk of side effects such as dry mouth and constipation [Meek et al. 2011; Nabi et al. 2006; Novara et al. 2008; Starkman and Dmochowski, 2006]. Therefore, much of the effort in OAB drug development has been focused on improving tolerability of these medications.

Transdermal delivery of oxybutynin was developed in an effort to limit plasma metabolites primarily responsible for anticholinergic side effects that are produced during first-pass metabolism with oral pharmacotherapy [Appell et al. 2003; Nitti et al. 2006]. In addition, transdermal delivery may limit pill burden, memory lapses, and drug–drug interactions, particularly desirable advantages in the aging population – those most likely to suffer from OAB. Herein we provide a review of the pharmacologic benefits of transdermal delivery of oxybutynin, administration, efficacy, and side effect profile, as well as the availability and cost of transdermal formulations of oxybutynin.

Pharmacology and drug delivery

Oxybutynin mechanism of action

Muscarinic receptors, stimulated by the acetylcholine neurotransmitter, are located throughout the body. Five subtypes (M1–M5) have been characterized, and more than one may be present in a particular organ [Caulfield and Birdsall, 1998]. The muscarinic receptors in the urinary bladder are predominantly M2 (80%) and M3 (20%), with both receptor types playing important roles in bladder contractility [Hegde and Eglen, 1999; Wang et al. 1995]. Oxybutynin is a tertiary amine (Figure 1) muscarinic receptor antagonist with relative selectivity for M1 and M3 receptors [Nilvebrant et al. 1997]. Oxybutynin has a greater affinity for inhibition of receptors in the parotid gland than the urinary bladder and therefore is a potent inhibitor of salivary secretion [Waldeck et al. 1997].

Figure 1.

Figure 1.

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Molecular structure of oxybutynin.

Immediate-release oxybutynin (OXY-IR) has a bioavailability of approximately 6% following first-pass liver metabolism [MacDiarmid, 2009]. The primary metabolite resulting from cytochrome P-450 metabolism in the liver is N-desethyloxybutynin (N-DEO) (Figure 2), which is thought to be largely responsible for the dry mouth experienced by 17–93% of patients taking this formulation, as well as multiple other undesired anticholinergic side effects [Thüroff et al. 1998]. Indeed, dry mouth has been associated with higher concentrations of N-DEO but not of the parent drug [Sathyan et al. 2001].

Figure 2.

Figure 2.

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Molecular structure of N-desethyloxybutynin.

Benefits of transdermal delivery

Transdermal delivery of medications has multiple purported advantages. First, transdermal delivery avoids first-pass liver metabolism, which can significantly impact the bioavailability of the active drug, lead to undesired metabolites, and impact metabolism of other medications metabolized via the same cytochrome P-450 enzyme subtype [Hall et al. 1999]. Furthermore, transdermal administration permits delivery of a constant amount of drug per unit time and therefore facilitates stable plasma levels (i.e. ‘zero-order kinetics’) [Nitti et al. 2006]. This is in contrast to orally delivered medications, which typically exhibit serum peaks and troughs associated with first-order kinetics. Side effects may be exacerbated during peaks and inefficacy apparent during troughs. Lastly, compliance may be improved by eliminating the need for a pill or daily dosing. Therefore, transdermal administration of oxybutynin could be especially beneficial: first-pass metabolism produces high levels of an undesired and less efficacious metabolite (N-DEO), there is a relatively narrow window between efficacy and intolerability, and the drug is administered in an aging population impacted by polypharmacy [Hajjar et al. 2007; MacDiarmid, 2009; Nitti et al. 2006].

Mechanism of transdermal delivery

The skin is made up of the epidermis, dermis, and subcutaneous tissue. A molecular structure that is moderately lipophilic and of low molecular weight (i.e. <500 Da) is required for drug penetration through the stratum corneum, the keratinized, avascular layer on the skin surface [Paudel et al. 2010]. This represents a considerable challenge and in large part explains why despite the theoretical benefits, relatively few medications are available for transdermal administration.

Oxybutynin chloride is well suited for transdermal delivery because it is lipophilic and has a molecular weight of 393.95 Da [Gomelsky and Dmochowski, 2012; Wiedersberg and Guy, 2014]. Transdermal oxybutynin is available for administration via a patch transdermal system (OXY-TDS; Oxytrol®; Allergan, Parsippany, NJ, US), and a topical gel (OXY-OTG; Gelnique™, Gelnique 3%™; Allergan). Similar to other transdermal medications, consistent drug delivery can be impacted by skin changes secondary to radiation, solvents, exfoliative skin conditions, and blood flow [Paudel et al. 2010]. Absorption may also be impacted by cytochrome P-450 enzymes within the skin that metabolize as much as 10–20% of the delivered drug [Guy et al. 1987].

OXY-TDS is a matrix diffusion-controlled system consisting of three layers: (1) backing, (2) drug, polymer, and adhesive polymeric matrix, and (3) a release liner [Nitti et al. 2006]. Prior to placement of the patch on the skin, the release liner is removed to expose the adhesive polymeric matrix. It is essential that the release liner be easy to remove and resistant to moisture. The drug diffuses through the polymeric matrix to the skin, with drug closer to the skin released prior to medication deeper within the patch. In addition to oxybutynin, the OXY-TDS polymeric matrix layer contains a permeation enhancer called triacetin that controls the rate of drug delivery through the stratum corneum via its interaction with lipids in the skin [MacDiarmid, 2009]. With OXY-TDS, steady-state plasma concentrations persist at 96 hours [Actavis Pharma, Inc., 2015].

In addition to oxybutynin, OXY-OTG contains ethanol to facilitate skin permeation and glycerin, which functions as a skin emollient [Staskin and Robinson, 2009]. It is transported through the skin by passive diffusion. Following cutaneous and peripheral metabolism, plasma ratios of N-DEO:oxybutynin have been found to be approximately 0.8:1, in contrast to the 5.5:1 ratio observed with OXY-IR [Alberti et al. 2005; Rovner and Wein, 2002]. OXY-OTG has a half-life of 62 to 84 hours and therefore does not require daily dosing to maintain steady-state concentrations [Watson Pharma, Inc., 2015a, 2015b].

Administration, efficacy and tolerability

Oxybutynin transdermal system (Oxytrol®)

OXY-TDS is a 39 cm2 patch containing a total of 36 mg of oxybutynin; 3.9 mg are delivered daily [MacDiarmid, 2009]. The patch should be applied to dry, intact skin on the abdomen, hip, or buttocks and changed every 3 to 4 days, and the same site should be avoided for reapplication within 1 week [Actavis Pharma, Inc., 2015].

Dmochowski and colleagues evaluated the safety and efficacy of OXY-TDS in a combined analysis of two randomized clinical trials [Dmochowski et al. 2005]. Primary outcomes in both studies were changes from baseline to end of treatment in UUI episodes, frequency, and voided volume. The first of the two trials [Dmochowski et al. 2002] compared OXY-TDS with placebo over 12 weeks with a 28-week open-label extension. In the second trial [Dmochowski et al. 2003], OXY-TDS was compared with long-acting tolterodine and placebo in a 12-week randomized period followed by a 52-week open-label extension. OXY-TDS was found to be more effective than placebo in reducing median episodes of daily incontinence (−3.0 versus −2.0, p = 0.0004), of daily urinary frequency (−2.0 versus −1.0, p = 0.0023) and increasing voided volume (25 versus 5.5 ml, p < 0.00001). As a follow up to these two RCTs, the Multicenter Assessment of Transdermal Therapy in Overactive Bladder With Oxybutynin (MATRIX) study group evaluated changes from baseline in healthcare-related quality of life (HRQoL) in nearly 3000 patients taking OXY-TDS for as long as 6 months [Sand et al. 2007]. The authors reported significant improvement in 9/10 domains of the King’s Health Questionnaire, suggesting OXY-TDS improved HRQoL, and a subsequent analysis of the MATRIX data demonstrated significant improvements in labor productivity and fatigue [Pizzi et al. 2009].

Anticholinergic-related adverse effects are not eliminated with OXY-TDS, however, these effects appear to be mitigated by transdermal administration. Specifically, although dry mouth with OXY-TDS was reported to be as high as 7.0%, this rate did not differ significantly from placebo [Dmochowski et al. 2005]. Unfortunately, application site adverse reactions such as erythema or pruritus are common, reported at as high as 31.8% in a trial in which patches were changed daily [Yamaguchi et al. 2014]. Both dry mouth and application-site adverse events have been responsible for discontinuation of the drug in all studies involving OXY-TDS, even though most reactions are reported as ‘minor’. To this end, in the MATRIX study, only half of patients completed a full 6 months of therapy [Sand et al. 2007]. In addition, a more recent study reported no significant difference for OXY-TDS relative to placebo in achieving pretreatment patient-selected goals of therapy despite a significant decrease in urgency episodes similar to those experienced by patients in other trials [Cartwright et al. 2011]. This underscores the ongoing challenges in treatment of OAB not unique to transdermal oxybutynin: improvements in objective measures across a study population may not translate to adequate clinical benefit to an individual patient.

Nevertheless, in certain individuals and select populations transdermal delivery of oxybutynin may be of particular benefit. For example, children requiring anticholinergic therapy may be more likely to struggle with oral formulations and thus could particularly benefit from transdermal formulations. Gleason and colleagues evaluated 35 children (mean age 8 years, range 4–16 years) with nonneurogenic DO and found that 97% reported good symptom response with OXY-TDS. Objectively, mean bladder capacity increased on average from 104 to 148 ml at follow up. Skin irritation at the application site was experienced by 35% of subjects, leading to discontinuation in 20% of patients [Gleason et al. 2014]. OXY-TDS has also been reported as an effective medication-delivery option in children with neurogenic bladder [Cartwright et al. 2009], however, caution is advised with use of transdermal oxybutynin in children, as the safety and efficacy of OXY-TDS and OXY-OTG have not been established in the pediatric population.

Oxybutynin gel (Gelnique 3%™ and Gelnique™)

OXY-OTG 10% was approved by the Food and Drug Administration in 2009. It is packaged in daily-dose sachets containing 1 g of OXY-OTG to be applied once daily to the abdomen, upper arms, shoulders, or thighs. OXY-OTG 3% was launched in 2012 and is an odorless gel delivered via a metered-dose pump. Three pumps (3 ml) provides the recommended 84 mg dose. Drug delivery is consistent over 24 hours following application, which should similarly be applied to the thigh, abdomen, upper arm, or shoulder.

Staskin and colleagues randomized 789 patients with UUI to OXY-OTG 10% or placebo for 12 weeks [Staskin et al. 2009]. Relative to placebo, OXY-OTG 10% was associated with a significant decrease in mean UUI episodes (−3.0 versus −2.5 per day, p < 0.0001) and micturitions (−2.7 versus −2.0 per day, p = 0.0017) as well as significantly increased voided volume (21.0 versus 3.8 ml, p = 0.0018). Dry mouth and application site reactions were experienced by 6.9% and 5.4%, respectively, in the treatment group versus 2.8% and 1.0%, respectively, in the placebo group, suggesting relatively limited risk of anticholinergic side effects with treatment. To this end, a more recent study found that in contrast to OXY-IR, OXY-OTG 10% was not associated with any cognitive changes in elderly patients taking the medication relative to baseline over the course of 1 week [Kay et al. 2012].

Goldfischer and colleagues randomized 626 patients with UUI 1:1:1 to 12 weeks of OXY-OTG 3% 84 mg, 56 mg, or placebo applied once daily [Goldfischer et al. 2015]. Treatment with OXY-OTG 3% was associated with improvement relative to placebo in weekly UUI episodes (−20.4 versus −18.1, p < 0.05), number of daily micturitions (−2.6 versus −1.9, p = 0.001), and mean voided volume (32.7 versus 9.8 ml, p < 0.0001). It is notable that in this particular study, in contrast to those of OXY-TDS and OXY-OTG 10%, patients on active therapy were significantly more likely to report dry mouth (OXY-OTG 3% 84 mg versus placebo, 12.1% versus 5.0%, p = 0.028). Application site erythema was experienced by 3.7% of patients receiving the 84 mg dose. The 56 mg dose did not appear to differ significantly in terms of efficacy, suggesting a potential role for dose reduction in patients experiencing side effects with the standard 84 mg dosage.

Theoretical concerns with transdermal therapy exist regarding its efficacy under certain conditions as well as the potential for transference of the medication to others after application, particularly with gel formulations. Dmochowski and colleagues evaluated four phase I open-label studies to assess the impact of site of application, post-application showering, and sunscreen application on oxybutynin pharmacokinetics and bioavailability, and person-to-person transfer through skin-to-skin contact at the application site [Dmochowski et al. 2011]. All four studies were conducted with the 10% formulation of OXY-OTG. The respective studies concluded that choice of application site, showering 1–6 hours after application, and sunscreen application had relatively minor effects on oxybutynin plasma concentrations. Vigorous skin-to-skin contact following application did result in plasma levels in the untreated subjects of about 25% of those experienced with a single dose of OXY-OTG. Patients should be advised to wash their hands thoroughly after application to avoid transferring the drug to others and to avoid showering within 1 hour of application [Watson Pharma, Inc., 2015a, 2015b].

Availability and cost

Even when a medication is effective and well tolerated, its cost and availability can have a significant impact on medication compliance. In January 2013 the FDA approved OXY-TDS for over-the-counter (OTC) use in women over the age of 18; it was launched in September of that year under the name Oxytrol® for Women [FDA, 2013]. The oxybutynin transdermal patch remained prescription only for children and men. The retail cost of the OTC product was US$29.99 for 8 patches, versus a US$320 wholesale price for the same quantity of the prescription version [The Medical Letter, Inc., 2013]. Reportedly, due to disappointing sales results, distribution of the OTC version of OXY-TDS was discontinued by Bayer AG in early 2015 following their acquisition of Merck & Co [Wilkes, 2015].

OXY-TDS continues to be available but via prescription only. Costco Pharmacy reports the cost of an 8-patch supply of prescription Oxytrol® at US$527 [Costco Pharmacy, 2015b], and the Medicare-negotiated price is approximately US$480 with the cost to the beneficiary of approximately US$220 per month [Q1 Group LLC, 2015]. OXY-OTG is similarly available only by prescription. The Medicare negotiated price for OXY-OTG 3% is approximately US$256 for a 30-day supply with a cost to the patient of US$47–115 depending on phase of coverage. A 30-day supply of OXY-OTG 10% has a Medicare-negotiated price of approximately US$279 with the cost to the patient of US$47 per month. The prices and costs to the patient for all three forms of transdermal oxybutynin are comparable with those of other nongeneric antimuscarinics [Consumer Reports, 2012]. In comparison, the cost of a 30-day supply of generic oxybutynin is listed by Costco pharmacy at between US$18 and US$48 depending on the dosage and formulation chosen [Costco Pharmacy, 2015a], with a Medicare beneficiary cost of US$20 per month for the generic 5 mg immediate-release tablet [Q1 Group LLC, 2015]. It is worth noting that many individual pharmacies do not carry any of the transdermal formulations in stock, although most will be able to order them in within 24–72 hours. It may be beneficial to check with the patient’s pharmacy to determine availability of a specific transdermal formulation prior to prescribing these medications.

Conclusions

Transdermal delivery of oxybutynin has the purported advantages of decreased anticholinergic side effects relative to oral administration. This is primarily related to avoidance of first-pass metabolism and therefore significantly reduced production of the N-DEO metabolite. Transdermal administration appears to translate into a decreased risk of dry mouth and possibly other untoward anticholinergic side effects; however, application site reactions are common and have been responsible for drug discontinuation in adult and pediatric populations. The increased cost of the transdermal formulations remains a consideration and a potential barrier to long-term compliance with therapy.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare that there is no conflict of interest.

Contributor Information

Joshua A. Cohn, Department of Urologic Surgery, Vanderbilt University Medical School, 1302A Medical Center North, Nashville, TN 37232-2765, USA.

Elizabeth T. Brown, Department of Urologic Surgery, Vanderbilt University Medical School, Nashville, TN, USA

W. Stuart Reynolds, Department of Urologic Surgery, Vanderbilt University Medical School, Nashville, TN, USA.

Melissa R. Kaufman, Department of Urologic Surgery, Vanderbilt University Medical School, Nashville, TN, USA

Douglas F. Milam, Department of Urologic Surgery, Vanderbilt University Medical School, Nashville, TN, USA

Roger R. Dmochowski, Department of Urologic Surgery, Vanderbilt University Medical School, Nashville, TN, USA

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