Transdermal oxybutynin: a new treatment for overactive bladder

Overactive bladder has been successfully treated with oral anticholinergic drugs such as oxybutynin chloride. Although oral oxybutynin has been effective in controlling urinary urge incontinence and in decreasing incontinence episodes, adverse events, particularly dry mouth, often cause patients to discontinue oral therapy and to endure incontinence. Transdermal oxybutynin (Oxytrol, Watson Pharmaceuticals) is applied twice-weekly to maintain the efficacy of oral oxybutynin while significantly minimising side effects (e.g., dry mouth) that complicate therapy. By avoiding hepatic and gastrointestinal metabolism of oxybutynin, less N-desethyloxybutynin (N-DEO), the compound thought to be responsible for anticholinergic side effects, such as dry mouth, is produced. The new transdermal oxybutynin formulation offers patients with urinary incontinence an effective, safe and well-tolerated option for managing the symptoms of overactive bladder.     

Transdermal oxybutynin: a review

Overactive bladder is a common and disabling problem. The mainstay of pharmacological treatment is with oral anticholinergic drugs. Anticholinergic side effects are common and include dry mouth and constipation. Compliance is limited by these side effects. Transdermal administration of oxybutynin has been shown to be as effective as oral treatment while minimising the anticholinergic side effects. Skin reactions occur frequently, necessitating changes of application site. Despite this, the preparation is a useful element in the armamentarium to treat overactive bladder. It is likely to be particularly useful in those in whom side effects of oral medication are intolerable or in whom oral administration of drug is not possible. Here, the pharmacokinetics, pharmacodynamics, efficacy and safety of transdermal oxybutynin are reviewed.     

Current concepts in the treatment of disorders of micturition

Disorders of micturition may be divided into disturbances of the storage function of the bladder, and disturbances of the emptying function. The main symptoms of disturbances of storage function are frequency, urgency and incontinence. Hyperactivity of the bladder may lead to urge incontinence, and incompetence of the urethral closure mechanism to stress incontinence. There are many drugs available for treating bladder hyperactivity, but their efficacy as judged from controlled clinical trials (when available) is often limited. Bladder contraction in man is mediated by stimulation of muscarinic receptors, and when given parenterally anticholinergic drugs have been shown to depress bladder hyperactivity irrespective of the underlying cause. Clinically, however, treatment of urge incontinence with anticholinergic drugs is often unsatisfactory. Lack of effect of oral treatment and systemic side effects limit the use of available agents. Drugs with "mixed" actions (anticholinergic and 'direct' muscle effects), for example oxybutynin and terodiline, have well-documented efficacy in bladder hyperactivity. Side effects are common with oxybutynin; terodiline seems to be well tolerated. The aim of drug treatment of stress incontinence is to increase outflow resistance. Although there is only limited possibility of improving the condition with drugs, beneficial effects can be obtained in some patients by use of orally active alpha-adrenoceptor agonists (e.g. phenylpropanolamine) and/or oestrogens. The main symptom of disturbed bladder emptying is urinary retention. Drug therapy is aimed at improving the contractile activity of the detrusor or reducing urethral outflow resistance. Drugs used for improving bladder contractility include parasympathomimetic agents, e.g. bethanechol or carbachol, and intravesical instillation of prostaglandins. Although the efficacy of both types of treatment is open to question, bethanechol seems to be widely used. Increased outflow resistance may be seen in patients with parasympathetic decentralization of the lower urinary tract or in patients with benign prostatic hypertrophy. These patients may respond favourably to alpha-adrenoceptor blockers such as phenoxybenzamine or prazosin.     

Current pharmacotherapeutic strategies for overactive bladder

Overactive bladder (OAB) is a chronic, distressing condition characterised by symptoms of urgency (sudden overwhelming urge to urinate) and frequency (urinating more than eight times daily), with or without urge urinary incontinence (sudden involuntary loss of urine). It affects millions of people of all ages and both sexes world wide, with greater prevalence in women and the elderly. The treatment of OAB is aimed at reducing debilitating symptoms, which have a significant effect on all aspects of an individual's quality of life, including social, domestic, psychological, occupational, physical and sexual functioning. Anticholinergic agents are currently recommended as first-line therapy for OAB. Their use results in significant clinical improvement in patients, although a lack of selectivity for receptors in the bladder may lead to troublesome side effects, including dry mouth, blurred vision, somnolence, dizziness and constipation. Recent research efforts have focused on developing drugs with a reduced propensity for causing these problems. Of the available anticholinergic agents, oxybutynin and tolterodine are the most widely used to treat OAB. Studies directly comparing tolterodine immediate-release (IR) with oxybutynin IR have shown that the two agents have similar efficacy. However, tolterodine IR is significantly better tolerated, particularly with respect to the incidence and severity of dry mouth. An extended-release formulation of tolterodine (4 mg capsules) has recently been developed to allow for once-daily dosing. In addition to greater convenience, tolterodine extended-release has shown enhanced efficacy and tolerability compared with tolterodine IR.     

Transdermal oxybutynin: for overactive bladder

Oxybutynin binds to the M(3) muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. The transdermal system delivers oxybutynin over a 3- to 4-day period after application to intact skin. Peak plasma concentrations of oxybutynin and the major active metabolite, N-desethyloxybutynin, are reached 24 - 48 hours after a single application and therapeutic concentrations are maintained throughout the dosage interval. In a large, randomised, double-blind trial, transdermal oxybutynin 3.9 mg/day significantly decreased the median number of incontinence episodes per week compared with placebo (-19 vs -15, p = 0.0165) in patients with overactive bladder. In addition, the micturition frequency was reduced and average voided volume was increased by transdermal oxybutynin treatment. Significant reductions in incontinence episodes following transdermal oxybutynin treatment were also observed in two further studies and the clinical efficacy was similar to that of oral tolterodine or oral oxybutynin. Transdermal oxybutynin was well tolerated in clinical trials. Application site reactions were the most common adverse effect; however, the majority were mild to moderate in severity. Adverse events associated with anticholinergic drugs (e.g. dry mouth) were less frequently reported in patients treated with transdermal oxybutynin than in those receiving orally administered oxybutynin or tolterodine.     

Tolterodine, a new antimuscarinic drug for treatment of bladder overactivity

Tolterodine is a nonsubtype selective antimuscarinic agent recently approved as therapy in patients with overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence. It acts by muscarinic receptor blockade in the bladder wall and detrusor muscle. Despite short terminal disposition half-lives of 2-3 and 3-4 hours for tolterodine and its active 5-hydroxy metabolite, respectively, twice/day dosing is effective due to the drug's prolonged pharmacodynamic effects. Dosage adjustment is recommended in the presence of hepatic impairment and during concurrent therapy with drugs that inhibit cytochrome P450 2D6 and 3A4 isozymes. Tolterodine significantly reduces clinically relevant end points such as number of micturitions and number of incontinence episodes/day. In general, it is superior to placebo and equivalent to oxybutynin in this regard. As might be expected from its pharmacologic profile, the principal adverse effects of the drug are anticholinergic. In clinical trials, tolterodine was tolerated significantly better than oxybutynin. Its relative merits as a first- or second-line agent for patients intolerant of oxybutynin are unclear. Until pharmacoeconomic analyses are conducted that clearly justify use of this more expensive agent, tolterodine is perhaps best reserved for patients who are intolerant of or fail oxybutynin therapy.     

Improving the tolerability of anticholinergic agents in the treatment of overactive bladder.

Pharmacological treatment for overactive bladder has centred around the interruption of the detrusor activity that is central to urge and incontinence symptoms. The majority of patients with this disorder are treated with antimuscarinic agents. These drugs have been demonstrated to improve urgency, frequency of micturition and urge incontinence, all of which are primary symptoms of overactive bladder; however, they are also commonly associated with anticholinergic adverse effects, most notably dry mouth. Attempts to increase tolerability have included the development of advanced formulations that regulate release of the active ingredient and the development of pharmacological agents that target the desired bladder receptors more specifically and accurately. Although all agents provide good efficacy, tolerability is greatly affected by the formulation used to deliver the active pharmacological agent, as well as the specificity of the targeted receptors. Clinical trials involving a transdermal formulation of oxybutynin have shown that this delivery method may be associated with a lower incidence of anticholinergic adverse events compared with both the immediate-release and the extended-release oral formulations of traditional agents, as well as the most recently approved agents - trospium chloride, solifenacin and darifenacin. Much is still being learned about the function and specificity of muscarinic receptors, which will support the development of agents with sustained efficacy and enhanced tolerability compared with the available formulations to date. These include the S-isomer of oxybutynin, as well as selective muscarinic M2 receptor antagonists.     

In vivo characterization of muscarinic receptors in peripheral tissues: evaluation of bladder selectivity of anticholinergic agents to treat overactive bladder

The present study was undertaken to characterize in vivo muscarinic receptors in peripheral tissues (urinary bladder, submaxillary gland, colon, stomach, heart) of mice, and further to evaluate bladder-selectivity of anticholinergic agents to treat overactive bladder. Following i.v. injection of [(3)H]QNB in mice, the radioactivity in peripheral tissues was exclusively detected as the unchanged form. The in vivo specific [(3)H]QNB binding in particulate fraction of tissue homogenates of mice showed a pharmacological specificity which characterized muscarinic receptors. Binding parameters (K (d) and B (max)) for in vivo specific [(3)H]QNB binding differed between mouse tissues. Oral administration of oxybutynin attenuated significantly in vivo specific [(3)H]QNB binding in all tissues of mice. From ratios of AUC(urinary bladder)/AUC(other tissues) of time-dependent muscarinic receptor occupancy, oral oxybutynin has been shown to exert little urinary bladder selectivity. Following oral administration of propiverine, there was a significant reduction of in vivo specific [(3)H]QNB binding in the urinary bladder, colon and submaxillary gland, but not in the stomach and heart. From the ratios of AUC(urinary bladder) to AUC(submaxillary gland) or AUC (heart), it has been shown that oral propiverine exerts higher selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland and heart. Similarly, tolterodine displayed high selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland. Thus, the present study has demonstrated that [(3)H]QNB may be a useful ligand for in vivo characterization of muscarinic receptor binding of anticholinergic agents to treat overactive bladder. Propiverine and tolterodine have exhibited in vivo selectivity of muscarinic receptor in the mouse urinary bladder rather than in the submaxillary gland, and such receptor binding specificity may be the reason of lower incidence of dry mouth.     

Contemporary and emerging drug treatments for urinary incontinence in children

Pediatric incontinence is a bothersome symptom for children and their parents. It can have a profound influence on a child's social and psychologic development and well-being. It is important to understand the different disorders that result in incontinence and also to understand the neural influences and development on urinary control. Urinary leakage can be a functional or organic disorder, with many possible etiologies. The most common group of pediatric patients with incontinence are those with overactive bladder disorder. Pharmacologic therapy centers on the blockage of muscarinic receptors by the tertiary amines such as oxybutynin, tolterodine, trospium chloride, and propiverine. Although most novel anticholinergic medications are effective and well tolerated in children, in our experience oxybutynin extended release provides superior relief for urge urinary incontinence in children. Other agents such as alpha-adrenoceptor antagonists have been used with success to improve bladder empyting and decrease outlet resistance. Night-time voiding disorders such as primary monosymptomatic nocturnal enuresis tend to be symptomatically treated. One of the mainstays of pharmacotherapy is desmopressin, an analog to antidiuretic hormone, which decreases night-time urine production. Tricyclic antidepressants such as imipramine have also been used successfully through a combined mechanism of action believed to be the result of anticholinergic, antispasmodic, and sympathomimetic effects. Often the successful treatment of constipation also treats urinary incontinence or at least the symptoms of urinary leakage are improved. The new non-absorbable, tasteless, and odorless PEG-3350 (polyethylene glycol 3350) powder has quickly become a mainstay of the pharmacologic treatment for constipation because of its ease of preparation and favorable adverse effect profile. A better understanding of the physiologic control, cellular interactions, and second messenger signal transduction pathways has led to the development of many new potential target sites for pharmacologic intervention. The advancement of new uroselective muscarinic antagonists is currently under investigation for agents such as darifenacin and temiverine, which have the potential to improve efficacy without increasing unwanted adverse effects. New pharmacologic delivery systems are also being developed ranging from intravesical to transdermal applications to change biodistribution and improve selectivity. Incontinence is a significant problem for children, their parents, and their physicians. The changing and advancing field of pharmacotherapy has made big strides for symptom control in this patient population.     

Comparative evaluation of exocrine muscarinic receptor binding characteristics and inhibition of salivation of solifenacin in mice

Anticholinergic agents such as oxybutynin are clinically useful in the treatment of overactive bladder. However, oral administration of oxybutynin is frequently accompanied by side effects such as dry mouth, and novel bladder-selective anticholinergic agents such as solifenacin and tolterodine are now under development. The aim of the present study was to characterize the suppression of cholinergic salivation and exocrine muscarinic receptor binding of solifenacin on oral administration to mice in comparison with those of oxybutynin. Results showed that both drugs produced a significant increase in K(d) values for specific [N-Methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) binding in the mouse submaxillary gland, compared with control values. However, this enhancement in K(d) values was significantly smaller with solifenacin than with oxybutynin. Moreover, the inhibitory effect of solifenacin on pilocarpine-induced salivary secretion was significantly weaker than that of oxybutynin. Solifenacin dissociated more readily from muscarinic receptors in the mouse submaxillary gland than oxybutynin. In conclusion, the present study indicates that the weak suppression of cholinergic salivation by solifenacin compared with oxybutynin may be partially attributed to its relatively fast dissociation kinetics from exocrine muscarinic receptors.     

Oxybutynin extended-release: a review of its use in the management of overactive bladder

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 5-30 mg 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 10 mg 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.     

Muscarinic receptor binding characteristics in rat tissues after oral administration of oxybutynin and propiverine

Ex vivo muscarinic receptor binding of oxybutynin and propiverine, the most commonly used anticholinergic agents for the treatment in patients with urinary incontinence, was investigated in rat tissues. The oral administration of oxybutynin (50.8 and 127 micromol/kg) caused a significant increase in the apparent dissociation constant (Kd) for specific (-)-[3H]QNB binding in the rat bladder, prostate, submaxillary gland, heart and cerebral cortex, compared with each of the control values. Also, in the submaxillary gland of these rats, there was a reduction in the maximal number of binding sites (Bmax) for (-)-[3H]QNB binding. Similarly, oral administration of propiverine at doses of 74.3-297 micromol/kg brought about a significant increase in the Kd values for (-)-[3H]QNB binding in rat tissues including the bladder, and greater increase in Kd values was seen in the rat prostate, heart and submaxillary gland. On the other hand, oral administration of propiverine, unlike oxybutynin, resulted in very little reduction in the Bmax valules for (-)-[3H]QNB binding in the submaxillary gland. In conclusion, the present study has shown that oxybutynin and propiverine, after oral administration, bind significantly to muscarinic receptors in tissues such as the bladder, which is the target organ for the treatment of urinary incontinence, and that oxybutynin appears to exhibit long-term binding to muscarinic receptors in the salivary gland.     

曲司氯铵——治疗伴有急迫性尿失禁症状的膀胱过度活动症的新药

曲司氯铵为新近上市的用于治疗伴有急迫性尿失禁症状的膀胱过度活动症的抗胆碱药物,具有抗胆碱能神经末梢M_1,M_2,M_3受体的作用,从而拮抗乙酰胆碱对人膀胱平滑肌的收缩效应。可有效降低膀胱平滑肌的紧张度、解除痉挛状态,显著增加最大膀胱容量、第1次逼尿肌收缩时膀胱容量,提高膀胱顺应性,降低最大逼尿肌压力,有效减轻尿频、尿急以及尿失禁症状。临床效能与奥昔布宁相当,而优于托特罗定。本品起效快、长期疗效优良,此外,本品仅具有抗胆碱药物的外周常见不良反应,如口干、便秘等,但不进入中枢神经系统,没有中枢神经系统毒性。本文对其药理学及临床研究进行综述。     

Preliminary evaluation of a new controlled-release oxybutynin in urinary incontinence

OBJECTIVE: To conduct a preliminary evaluation of a new oral formulation of controlled-release (CR) oxybutynin tablet taken once-daily in patients with urinary urge incontinence. RESEARCH DESIGN AND METHODS: A single-centre, open-label, 8-week study was conducted. Patients with urodynamically-confirmed detrusor instability, micturition frequency (>/= 8 voids/day) and/or urinary incontinence (>/= 2 incontinence periods/day) were enrolled. The study duration was 8 weeks: patients received IR oxybutynin (2.5-5 mg bid) for 2 weeks, followed by a 2-week washout/baseline period to avoid carryover effects, and oral CR oxybutynin (15 mg OD) for 4 weeks. Daily void frequency, fluid intake, urinary incontinence episodes, and spontaneously reported adverse events were recorded in a daily diary for five consecutive days in each treatment period. RESULTS: Of 12 enrolled patients, 9 patients efficacy; all patients were evaluable for safety. completed the study and were evaluable for Compared to baseline/washout, CR oxybutynin reduced UI episodes/day by 45% (p = 0.13) and micturitions/day by 15% (p = 0.07). Treatment with IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day) reduced UI episodes/day from baseline by 7% (p = 0.58) and voids/day by 6% (p = 0.29). Fluid intake remained consistent at approximately 2 litres/day during all study periods. The most common adverse event was dry mouth. CONCLUSIONS: Based on the reductions in daily frequency of incontinence and micturition following 4-weeks treatment, CR oxybutynin (15 mg OD) was at least as effective as the patients' previous dose of IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day). These improvements were achieved without restriction of fluid intake. Initial 15 mg doses of CR oxybutynin appear to be well tolerated.     

Extended-release oxybutynin

Extended-release oxybutynin (Ditropan XL) uses an osmotic system (OROS) to deliver a controlled amount of oxybutynin chloride into the gastrointestinal tract over a 24-hour period when taken once daily. Oxybutynin binds to M3 muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. Mean peak plasma concentrations are lower with extended-release oxybutynin 15mg once daily than with conventional immediate-release oxybutynin 5mg taken 3 times daily. Relative bioavailabilities of parent drug and metabolite N-desethoxybutynin are 153 and 69%, respectively, for extended-release oxybutynin when compared with immediate-release oxybutynin. In short (< or =6 weeks) randomised, double-blind clinical trials of patients with detrusor instability, extended-release oxybutynin 5 to 30mg once daily significantly reduced the mean weekly number of urge incontinence episodes by 84 to 90%. Extended-release oxybutynin had similar efficacy to immediate-release oxybutynin. Adverse events reported by patients taking extended-release oxybutynin were dose-related anticholinergic effects, most frequently dry mouth, somnolence, constipation, blurred vision and dizziness. A large noncomparative study demonstrated that approximately two thirds of the patients prescribed extended-release oxybutynin for detrusor instability were still taking the medication 6 months later.     

Trospium chloride: the European experience

The primary pharmacological therapy for overactive bladder syndrome is muscarinic receptor antagonists. Muscarinic receptor blockade is effective in decreasing the symptoms of urinary urgency and urgency incontinence, but can be associated with troublesome complications, such as dry mouth, blurred vision, constipation and CNS side effects. Trospium chloride, an antimuscarinic medication, has been available in Europe for > 20 years and has recently been approved by the FDA for the treatment of overactive bladder. Trospium chloride is a quaternary amine that is minimally metabolised, not highly protein bound and, importantly, has not been demonstrated to cross the unaltered blood–brain barrier in healthy volunteers. Some characteristics of this unique antimuscarinic agent and the European experience with trospium chloride are reviewed in this article.     

A benefit-risk assessment of extended-release oxybutynin.

Oxybutynin is a muscarinic receptor antagonist, which has been available for a number of years in its original immediate-release (IR) formulation. While oxybutynin IR has proven effective for the treatment of overactive bladder, its extended use can be limited by adverse effects, particularly dry mouth. An extended-release (ER) formulation of oxybutynin based on the OROS system has recently become available, which allows once daily administration. In direct comparison to oxybutynin IR, oxybutynin ER has an increased oral bioavailability for the parent compound oxybutynin which is accompanied by a reduced bioavailability for the active metabolite N-desethyl-oxybutynin. The latter has been implicated in mediating a major part of the adverse effects of oxybutynin treatment. Two double-blind, placebo-controlled, randomised studies in patients with overactive bladder have demonstrated that oxybutynin ER has a similar efficacy as oxybutynin IR but with improved tolerability. This is in line with clinical pharmacological studies demonstrating a smaller impairment of saliva production with oxybutynin ER than with oxybutynin IR. Thus, the ER formulation of oxybutynin maintains the therapeutic benefits and concomitantly improves tolerability.     

Trospium chloride: the European experience

The primary pharmacological therapy for overactive bladder syndrome is muscarinic receptor antagonists. Muscarinic receptor blockade is effective in decreasing the symptoms of urinary urgency and urgency incontinence, but can be associated with troublesome complications, such as dry mouth, blurred vision, constipation and CNS side effects. Trospium chloride, an antimuscarinic medication, has been available in Europe for > 20 years and has recently been approved by the FDA for the treatment of overactive bladder. Trospium chloride is a quaternary amine that is minimally metabolised, not highly protein bound and, importantly, has not been demonstrated to cross the unaltered blood-brain barrier in healthy volunteers. Some characteristics of this unique antimuscarinic agent and the European experience with trospium chloride are reviewed in this article.     

Trospium chloride in the management of overactive bladder

Trospium chloride is an orally active, quaternary ammonium compound with antimuscarinic activity. It binds specifically and with high affinity to muscarinic receptors M(1), M(2) and M(3), but not nicotinic, cholinergic receptors. It is hydrophilic and does not cross the normal blood-brain barrier in significant amounts and, therefore, has minimal central anticholinergic activity. Peak plasma trospium chloride concentrations are attained approximately 5-6 hours after oral administration, which should occur before meals as concurrent food ingestion significantly reduces trospium bioavailability. Trospium chloride undergoes negligible metabolism by the hepatic cytochrome P450 system; few metabolic drug interactions are known. While trospium chloride dosage adjustments based on age or sex appear unwarranted, such adjustments may be needed in patients with severe renal impairment. Direct comparative studies in patients with overactive bladder indicate that trospium chloride is at least as effective as oxybutynin and tolterodine. Placebo-controlled studies have also confirmed the efficacy of trospium chloride in terms of improved urodynamic parameters; small-scale, noncomparative studies have documented significant trospium chloride-induced improvements in patients with reflex neurogenic bladder, postoperative bladder irritation and radiation-induced cystitis; and observational studies including >10,000 patients have also revealed favourable findings for trospium chloride, including a marked decrease in incontinence episodes and substantial improvement in health-related quality of life.Trospium chloride is generally well tolerated, and significantly more so than immediate-release oxybutynin. The most frequent adverse events, occurring in >1% of trospium chloride-treated patients, are dry mouth, dyspepsia, constipation, abdominal pain and nausea.Available for many years in several countries outside North America, trospium chloride is likely to develop an important role in the management of overactive bladder following its approval in the US on 28 May 2004.     

Oxybutynin gel for the treatment of overactive bladder

INTRODUCTION: Overactive bladder (OAB) is a common condition that has a profound impact on an individual's overall health and quality of life. Muscarinic receptor antagonists are the mainstay of oral pharmacotherapy for OAB. While all of the medications in this class are significantly more effective than placebo, they are also associated with more adverse events that may limit their overall use. Transdermal application of oxybutynin has been shown to avoid first-pass metabolism and, thus, may be associated with fewer antimuscarinic side effects. AREAS COVERED: This paper reviews the pharmacology of transdermal oxybutynin gel and summarizes the available data regarding this product in the treatment of OAB. It also discusses the role of this product in the OAB treatment armamentarium. EXPERT OPINION: Oxybutynin transdermal gel has been shown to have significant advantages over placebo, in terms of urgency incontinence episodes, urinary frequency and voided volume in a Phase III study. Application site effects were higher in the gel group, but the incidence of antimuscarinic side effects were lower than those seen with oral preparations. The lower incidence of skin side effects, as compared with the transdermal patch, may confer a theoretical advantage toward the gel product. While promising, unanswered questions remain regarding persistence with treatment after this mode of therapy, and head-to-head comparisons with other antimuscarinics are absent.