Oxybutynin Extended-Release

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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. 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. 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, 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. 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 (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.