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Oxybutynin Extended-Release

A Review of its Use in the Management of Overactive Bladder

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Summary

Abstract

The OROS®-based oxybutynin extended-release (ER) formulation (Lyrinel XL™; Ditropan XL®) represents a new form of oral delivery for oxybutynin, a muscarinic receptor antagonist used in the treatment of overactive bladder (OAB). The release of oxybutynin from oxybutynin ER occurs in a sustained manner, resulting in a smoother plasma concentration-time profile and a lower maximum plasma concentration than those seen with oxybutynin immediate-release (IR).

The ER formulation has been developed with the aim of improving the tolerability of oxybutynin therapy and facilitating once-daily administration. Moreover, oxybutynin ER offers greater flexibility in dosage (5–30 mg/day) than the other available treatment options.

At dosages of 5–30mg once daily, oxybutynin ER produced significant decreases from baseline in weekly urinary urge incontinence in patients with OAB. In addition, there were significant decreases in weekly total incontinence episodes and micturition frequency. In two randomised, double-blind studies in patients with OAB, the improvement in all the symptoms with once-daily oxybutynin ER 5–30 mg/day was similar to that produced by oxybutynin IR 5–20 mg/day given one to four times daily. Once-daily oxybutynin ER 10mg was superior to tolterodine IR 4 mg/day given as two daily doses and as effective as once-daily tolterodine ER 4 mg/day in decreasing urinary incontinence; the decreases in micturition frequency with oxybutynin ER were significantly greater than those seen with either of tolterodine formulations.

Oxybutynin ER was well tolerated in all the trials, with adverse events usually being mild to moderate and transient. In direct comparisons, the overall tolerability profile of oxybutynin ER was better than that of oxybutynin IR. Oxybutynin ER was similar to tolterodine (IR and ER) with respect to the incidence of clinically important dry mouth. A large 12-month tolerability study demonstrated no significant risks associated with the long-term use of oxybutynin ER.

A few noncomparative studies have shown promising results with oxybutynin ER in the treatment of adult and paediatric patients with neurogenic bladder dysfunction secondary to neuronal injury. Long- and short-term studies have reported significant improvements in health-related quality of life with oxybutynin ER therapy. In addition, pharmacoeconomic studies have suggested that oxybutynin ER is more cost effective than oxybutynin IR and at least as cost effective as tolterodine IR.

In conclusion, oxybutynin ER shows excellent efficacy in the treatment of symptoms associated with OAB in adults and the elderly with a good tolerability profile over a prolonged period of use (12 months). The ER formulation of oxybutynin provides a smooth plasma concentration profile over the 24-hour dosage interval, facilitating once-daily administration. Hence, given its overall efficacy/tolerability profile and dosage flexibility, oxybutynin ER provides an excellent treatment option in the first-line pharmacotherapy of OAB.

Pharmacodynamic Properties

Oxybutynin is an antimuscarinic drug with a high affinity for the muscarinic receptors in the bladder and the parotid gland. The active metabolite of oxybutynin, N-desethyloxybutynin (NDO) shares the pharmacological actions of the parent drug. Both oxybutynin and NDO exhibit stereoisomerism and experimental studies have shown that their antimuscarinic activity mainly resides in the (R)- isomers.

The antimuscarinic properties of oxybutynin result in several beneficial urodynamic effects, such as increases in bladder capacity and micturition threshold pressure, prolongation of micturition interval and reduction in maximum intravesical pressure during the collecting phase.

There are few clinical data available on the urodynamic effects of OROS®-based oxybutynin extended-release (ER). Oxybutynin ER increases the void volume and total bladder capacity; clinically insignificant increases in post-void residual volume have also been observed. In clinical studies, the inhibition of saliva production with oxybutynin ER was similar to that produced by tolterodine immediate-release (IR), but was significantly less pronounced than with oxybutynin IR. These studies also suggest that NDO, especially the (R)-isomer, may be primarily responsible for the inhibitory effects on salivary production, thus producing dry mouth with oxybutynin therapy.

Pharmacokinetic Properties

OROS®-based oxybutynin ER provides sustained drug delivery, facilitating a 24-hour dosage interval. The fluctuations in plasma oxybutynin concentrations seen with 2- to 4-times-daily administration of the IR formulation are minimised with the once-daily oxybutynin ER. Maximum plasma concentrations (Cmax) of oxybutynin and its active metabolite were lower and time to Cmax was longer with oxybutynin ER than with oxybutynin IR. In addition, the bioavailability of oxybutynin is increased and that of its metabolite is decreased with oxybutynin ER, compared with oxybutynin IR, thereby shifting the ratio of the oxybutynin and NDO in plasma towards the parent compound. Concomitant administration of food with oxybutynin ER does not affect the Cmax or area under concentration-time curve of oxybutynin.

Both oxybutynin and NDO are >97% protein bound. Oxybutynin is extensively metabolised mainly by cytochrome P450 3A4, resulting in the formation of the active metabolite, NDO. Metabolism of oxybutynin is stereoselective and results in lower plasma concentration of (R)-oxybutynin than that of (5)-oxybutynin.

Owing to an extensive metabolism, <0.1% of oxybutynin is excreted as unchanged drug in the urine. In healthy volunteers, the plasma elimination half-lives of oxybutynin and NDO were 14 and 8 hours, respectively.

Therapeutic Efficacy

Oxybutynin ER was significantly more effective than placebo in reducing the weekly urinary urge incontinence (UUI) episodes in patients with overactive bladder (OAB) in a randomised, double-blind study. At the end of 6-week dose-escalating treatment with oxybutynin ER 5–15mg once daily, a significantly higher proportion of patients receiving oxybutynin ER were free from incontinence compared with patients receiving the same dosage of oxybutynin IR or those on placebo.

Oxybutynin ER 5–30 mg/day was as effective as oxybutynin IR 5–20 mg/day in relieving UUI and other symptoms of OAB. UUI episodes decreased from baseline by 83–92% in patients receiving oxybutynin ER and by 72–88% in oxybutynin IR recipients. However, the increase in ‘normal’ (voluntary) micturition frequency with oxybutynin ER was significantly greater than with oxybutynin IR in one trial.

In randomised, double-blind, 12-week trials, oxybutynin ER 10mg once daily was significantly more effective than tolterodine IR 2mg twice daily (Overactive Bladder: Judging Effective Control and Treatment [OBJECT] trial) and as effective as tolterodine ER 4mg once daily (Overactive bladder: Performance of Extended Release Agents [OPERA] trial) in relieving weekly UUI episodes in patients with OAB. Oxybutynin ER was more effective than tolterodine IR and similar to tolterodine ER in reducing weekly total incontinence episodes. Patients receiving oxybutynin ER had significantly greater reductions in micturition frequency than either tolterodine IR or tolterodine ER recipients. A significantly higher proportion of patients achieved total continence (relief from both urge and non-urge incontinence) with oxybutynin ER than with tolterodine ER.

The results of the above trials were corroborated in a single-treatment study using the same dose-titration schedule of oxybutynin ER (5-30mg) in a community-dwelling population. Both therapy-naive and previously treated patients had significant reductions in weekly UUI episodes after 12 weeks of maintenance treatment with oxybutynin ER at their optimal doses.

Limited data from two small, noncomparative studies in patients with neurogenic detrusor dysfunction secondary to neuronal injury (one each in multiple sclerosis and spinal cord injury patients) and three nonblind studies in paediatric patients with neurogenic or non-neurogenic detrusor overactivity have shown favourable results on urinary dysfunction in these patient populations.

Health-Related Quality of Life

Oxybutynin ER significantly improves health-related quality of life (HR-QOL) in patients with urinary incontinence. In a large, noncomparative trial in patients with urge or mixed incontinence (including the elderly) in a community-dwelling population, oxybutynin ER (5-30 mg/day) produced significant improvements in all three questionnaires (General Health and Bother Scale, Individual Incontinence Impact Questionnaire and Sleep Impact Questionnaire) used to assess quality of life. These improvements were maintained for up to 12 months of therapy. Results of short-term studies have also shown similar improvements in HR-QOL measures with oxybutynin ER.

Pharmacoeconomic Considerations

Analysis of retrospective clinical trial data using a decision-tree model from a payer perspective showed that oxybutynin ER was a more cost-effective treatment option for patients with OAB than oxybutynin IR or tolterodine IR. A further analysis of this study suggested that oxybutynin ER and tolterodine IR may be similarly cost effective. Pharmacoeconomic analyses in the UK and Canada of data from the OBJECT trial showed that treatment with oxybutynin ER was more cost effective than tolterodine IR therapy. Oxybutynin ER was equivalent to tolterodine ER with respect to the direct health-care cost and medication persistence, although the risk of hospitalisation was lower when treatment was initiated with the latter.

Tolerability

Oxybutynin ER 5–30mg once daily has been well tolerated for up to 23 weeks in clinical trials assessing its therapeutic efficacy in patients with OAB including the elderly. In a pooled analysis of four clinical trials, approximately 7% of patients treated with oxybutynin ER discontinued treatment because of adverse events. The adverse events reported in >5% of patients included dry mouth, constipation, somnolence, diarrhoea, nausea, headache, dizziness, blurred vision and dry eyes. Oxybutynin does not appear to produce any significant adverse cardiac effects. A dose-related incidence of dry mouth was noted in clinical trials; however, most of the dry mouth events with oxybutynin ER were of mild intensity.

In direct comparisons, the tolerability profile of oxybutynin ER 5–30 mg/day was at least as good as that of oxybutynin IR 5–20 mg/day, and similar to that of tolterodine IR or ER 4 mg/day, except for the incidence of dry mouth. The incidence of dry mouth events of any severity in patients receiving oxybutynin ER was at least similar or similar, respectively, to that in recipients of oxybutynin IR or tolterodine IR; these events were more frequent in oxybutynin ER than in tolterodine ER recipients. However, the propensity of oxybutynin ER to produce clinically bothersome dry mouth was lower than that of oxybutynin IR and similar to that of tolterodine (IR or ER). The nature and frequency of all other adverse events with oxybutynin ER were generally similar to those reported with oxybutynin IR, tolterodine IR or tolterodine ER.

In long-term treatment (for up to 1 year), oxybutynin ER was well tolerated in patients with OAB, including the elderly, with no serious adverse effect reported.

Dosage and Administration

Adverse CNS events were uncommon during oxybutynin ER therapy, and only headache and dizziness occurred in ≥5% of patients in the long-term study. The incidence of CNS adverse events with oxybutynin ER was similar between the elderly (>65 years) and the younger (<65 years) patients. Oxybutynin ER is indicated for the treatment of urinary incontinence, urgency and frequency in patients with idiopathic detrusor overactivity. The drug is also indicated for the treatment of adult and paediatric (aged >6 years; approved only in the US) patients with symptoms of detrusor overactivity secondary to neurogenic disease (e.g. spina bifida).

The recommended dosage range for oxybutynin ER is 5–30mg once daily. Treatment is generally started at 5 mg/day and titrated by 5 mg/day every week until a balance of efficacy and tolerability is achieved. The dosage may be increased up to a maximum of 30 mg/day if the desired efficacy is not achieved. In the US, the maximum recommended dosage in paediatric patients (≥6 years) with detrusor overactivity secondary to neurological injury is 20mg once daily. For patients switching from oxybutynin IR, clinical judgement should be exercised in selecting the appropriate initial dose of oxybutynin ER, with subsequent titration according to the response. Oxybutynin ER may be administered with or without food.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, 41, Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    M. Asif A. Siddiqui, Caroline M. Perry & Lesley J. Scott

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  1. M. Asif A. Siddiqui
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  2. Caroline M. Perry
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  3. Lesley J. Scott
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Correspondence to M. Asif A. Siddiqui.

Additional information

Various sections of the manuscript reviewed by: G. Amarenco, Department of Neurologic Rehabilitation, Hospital Rothschild, Paris, France; K.-E. Andersson, Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden; R.A. Appell, Department of Urology, Baylor College of Medicine, Houston, Texas, USA; C.J. Fowler, Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, London, UK; D. Getsios, Caro Research, Concord, MA, USA; S.K. Gupta, Alza Corporation, Mountain View, California, USA; D. Staskin, Department of Urology, New York Presbyterian Hospital, New York, New York, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on oxybutynin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘oxybutynin’ and (‘controlled release’ or ‘extended release’). EMBASE search terms were ‘oxybutynin’ and (‘extended release’ or ‘controlled release’). AdisBase search terms were ‘oxybutynin’ and (‘controlled release’ or ‘extended release’). Searches were last updated 2 March 2004.

Selection: Studies in patients with overactive bladder who received oxybutynin extended-release. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Oxybutynin, extended-release, pharmacodynamics, pharmacokinetics, therapeutic use, overactive bladder.

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Siddiqui, M.A.A., Perry, C.M. & Scott, L.J. Oxybutynin Extended-Release. Drugs 64, 885–912 (2004). https://doi.org/10.2165/00003495-200464080-00011

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