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PROPANTHELINE IS "EFFECTIVE AND RECOMMENDED" FOR URGE URINARY INCONTINENCE, NEW AHCPR GUIDELINE SAYS; BENEFIT OF FLAVOXATE, OTHER DRUGS QUESTIONED

Executive Summary

The anticholinergic agent propantheline is an "effective and recommended treatment" for urge incontinence, according to a new guideline for the treatment of urinary incontinence released March 23 by HHS' Agency for Health Care Policy and Research. As a class, "anticholinergic agents block contraction of the normal bladder and probably the unstable bladder as well," the guideline states. "The prototype of anticholinergic agents used for urologic conditions is propantheline." The guideline defines urge incontinence as involuntary loss of urine associated with an abrupt and strong desire to void. The recommendations also address stress incontinence and combinations of the two conditions. Treatment of UI with propantheline is an off-label indication; the drug currently is approved for treatment of peptic ulcer. However, at least one source (USP DI) lists propantheline as being used for urinary incontinence. Propantheline is manufactured under the brandname Pro-Banthine by Schiapparelli Searle and is also widely available as a generic. The guideline acknowledges that there are only five "adequately controlled trials" of propantheline for treatment of UI in the literature. Nonetheless, "despite the lack of adequate trials, there appears to be a consensus among experts that at least for less impaired patients who can tolerate full doses, propantheline is effective and recommended," the guideline states. The guide recommends 7.5-30 mg administered three to five times daily. The reimbursement implications of recommending off-label use as a first-line drug therapy for a widespread health problem are unclear. AHCPR estimates that 10 mil. Americans suffer from some form of urinary incontinence. Asked in general terms how the recommendations may affect health care costs, AHCPR Administrator Jarrett Clinton, MD, told a press briefing on the guideline that the primary focus of the AHCPR guidelines is "to improve the quality of medical care" rather than provide a cost-containment service. "Certainly the focus first of all [is] on what works best, what improves the quality of medical care, and thereby contribute a value for the dollar spent," Clinton stated. "But to point out each dollar expended or saved is premature at this time." Entitled "Urinary Incontinence in Adults," the guideline is the second clinical practice guideline released by AHCPR. A package on the management of acute post-operative pain was released earlier this month ("The Pink Sheet" March 9, p. 3). Expected to be widely disseminated and highly influential, the guidelines distill an intensive review of medical literature into recommendations for the most effective treatment options. So far, the AHCPR panels have turned to older drugs with a lot of clinical use behind them as lead recommendations: the guideline on pain strongly recommended use of morphine as the primary drug therapy. For urinary incontinence, in addition to propantheline, the guideline recommends Marion Merrell Dow's Ditropan (oxybutynin) and the generic drug dicyclomine as acceptable anticholinergic agents. Oxybutynin has been approved by FDA specifically for the treatment of urinary incontinence. The clinical literature on dicyclomine is very limited, but "clinical experience suggests that it is as effective as other anticholinergic agents in controlling detrusor overactivity," the guideline says. In other drug classes, Ciba-Geigy's tricyclic agent Tofranil (imipramine) is recommended as "beneficial" for urge incontinence, as is doxepin. Imipramine is approved for treatment of enuresis in children but not adults. "To date, no agent recommended [by the guideline] has proved better than another," the guideline adds. "[S]election must be individualized and based on the side effects most desired or unwanted, as well as the impact of the drug's half-life and onset of action." The guideline, however, mentions propantheline most frequently and highlights the drug in a quick reference guide. The guideline also identifies several drugs that currently are used to treat urinary incontinence but that may, in fact, be ineffective. For example, while calcium channel blockers have been "often advocated for bladder storage disorders," the case literature does not support general use for treatment of detrusor overactivity, the guideline states. "No controlled studies could be found for nifedipine, diltiazem or verapamil," the AHCPR panel said. "A positive placebo-controlled study of flunarizine was identified, but in a subsequent one-month controlled trial by the same investigators, its efficacy diminished and the high (but unreported) rate of side effects led the investigators to temper their original enthusiasm," the panel noted. AHPCR also recommends against use of flavoxate, a tertiary amine with smooth muscle relaxant properties. Flavoxate is marketed by SmithKline Beecham under the brandname Uripas with indications for symptomatic relief of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence associated with cystitis, prostatitis, urethritis and urethrocystitis/urethrotrigonitis. "Although flavoxate is widely used for incontinence," the guideline states, the limited number of controlled randomized trials performed for that indication have not demonstrated any "significant benefit." AHCPR notes in the guideline that pharmacotherapy should be regarded as an adjunct to, rather than replacement for, other approaches such as behavioral modification. "Regardless of the agent chosen, involuntary bladder contractions are usually not abolished, the 'warning time' between appreciation of the need to void and the onset of bladder contraction is usually not affected, the degree of improvement is modest, and 'cure' is uncommon," the guideline states. For stress incontinence, which is caused by urethral sphincter insufficiency, drug treatment is based on "the high concentration of alpha-adrenergic receptors in the bladder neck, bladder base and proximal urethra," the guideline explains. Options include drugs with direct alpha-adrenergic activity, estrogen supplements and beta-adrenergic blockers. Of the alpha-adrenergic agonist drugs, phenylpropanolamine appears to be the most effective, according to the guideline. While the cure rate is low, 30% to 60% of patients in the literature experienced improvement when treated with phenylpropanolamine, the guide says. A common ingredient in weight-loss aids, phenylpropanolamine is often used off-label to treat mild to moderate stress incontinence. Among other drugs, "clinical experience suggests that imipramine is beneficial in the treatment of mixed stress and urge UI," the guide says. The beta-adrenergic blocking drug propranolol (Wyeth-Ayerst's Inderal) "has been reported in one uncontrolled study to improve symptoms of stress UI"; however, the AHCPR panel concluded that "it cannot be recommended for treatment of incontinence at this time." Overall, pharmacological intervention should be the second- line therapy for UI, the guide suggests. At a March 23 press conference announcing the guide, speakers repeatedly advised that practitioners should begin with the least invasive intervention -- behavioral therapy -- before trying pharmacotherapy or surgery. According to HHS Assistant Secretary for Health James Mason, MD, more than 25% of women aged 30 to 59 have incontinent episodes; overall, the problem affects 10 mil. Americans, about three quarters of whom are women. Mason said that at least 80% of those patients can be cured or have their condition significantly improved (a 50% or greater reduction of incontinent episodes).

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