Suffolk PCT Drug & Therapeutics Committee New Medicine Report This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Fesoterodine (Toviaz, Pfizer) Document status Agreed by Suffolk D&T Date of last revision 7 May 2008 Traffic light decision Blue GP Prescribed Prescribers rating Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products Mechanism of action Indication Usual dosage Treatment alternatives Place in therapy Future alternatives A competitive specific muscarinic receptor antagonist. It is rapidly and extensively hydrolysed by non-specific plasma esterases to the 5- hydroxymethyl derivative, its primary active metabolite, which is the main active pharmacological principal of fesoterodine. Treatment of the symptoms (increased urinary frequency and/or urgency and/or urgency incontinence) that may occur in adults with overactive bladder syndrome. The recommended starting dose is 4mg once daily. Based on individual response, the dose may be increased to 8mg once daily. The maximum daily dose is 8mg. Both the 4 and 8mg tablets are prolonged release (PR). Non-drug treatments such as behavioural therapy. Drug therapy; oxybutynin / oxybutynin MR, tolterodine / tolterodine MR, solifenacin, darifenacin, propantheline, propiverine / propiverine MR and tospium. Relief of symptoms of over active bladder (OAB) in male and female patients who have not responded to behavioural therapy. None known This is an NHS Suffolk document that has been adopted by the WSCCG.
Evidence for use Fesoterodine has been studied in two phase 3 randomised, double blind, placebo controlled, 12 week multicentre trials. One study also included tolterodine 4mg ER. Fesoterodine 4 and 8mg prolonged release tablets were studied. Chapple An international multicentre, randomised, double-blind, placebo and active comparator- controlled trial with extended release (ER) tolterodine in 1135 subjects. The primary outcome was a change from baseline to week 12 in micturitions per 24 hours. Co-primary endpoints included change from baseline to week 12 in urge urinary incontinence episodes per 24 hours and treatment response. Fesoterodine prolonged release 4 and 8 mg was shown to be statistically superior to placebo (p<0.05) and equivalent in efficacy to tolterodine ER. Nitti A randomised double blind, placebo controlled multicentre trial performed in the United States. 836 subjects were randomised to placebo (274), fesoterodine 4mg (283) or fesoterodine 8mg (279) daily for 12 weeks. The primary end point was change in the number of urinary micturitions per 24 hours. Co-primary end points included the change in number of urge urinary incontinent episodes per 24 hours and the treatment response.
Cautions / side effects Cost for 28 days Costs of alternatives for 28 days Treatment with 4 or 8 mg fesoterodine PR resulted in statistically significant improvements from baseline to end of treatment compared with placebo (p<0.05). Contraindications Severe hepatic impairment, concomitant CYP3A4 inhibitors in subjects with moderate to severe hepatic or renal impairment, urinary retention, gastric retention, uncontrolled narrow angle glaucoma, myasthenia gravis, severe hepatic impairment, severe ulcerative colitis, toxic megacolon. Cautions Patients at risk of urinary retention, gastrointestinal obstructive disorders, gastro-oesophageal reflux, reduced gastrointestinal motility, autonomic neuropathy, controlled narrow-angle glaucoma, hepatic and renal impairment, concomitant administration of CYP3A4 and CYP2D6 inhibitors, patients at risk of QT prolongation Side Effects The safety of fesoterodine has been evaluated in placebo controlled studies in a total of 2859 patients of which 780 received placebo. Due to the pharmacologial properties of fesoterodine, treatment may cause mild to moderate antimuscarinic effects. Dry mouth was very commonly reported in 28.8% vs 8.5% treated with placebo. Other adverse effects included dizziness, headache, dry eye, dry throat, abdominal pain, diarrhoea, dyspepsia, constipation, nausea, dysuria and insomnia. Further information available via www.emc.medicines.org.uk (Toviaz). 29.03 price for 28 tablets PR tablets (4mg and 8mg) Antimuscarinic Approx cost / 28 days (see appendix 1) Darifenacin 7.5mg PR Oxybutynin IR Oxybutynin MR Tolterodine IR Tolterodine 4mg MR Solifenacin 5mg and 10mg Tropsium 20mg 26.13 5.88 9.79-39.16 29.03 29.03 27.62-33.52 24.27 Potential number of patients in Suffolk PCT Points for consideration Data provided by Pfizer The prevalence of AOB is 10.4% in the UK. Suffolk PCT population = 595,000. 10.4% = 61,880 people. NICE have issued guidance on urinary incontinence (UI) in women CG 40 available via http://www.nice.org.uk/ Immediate release non-proprietary oxybutynin should be offered to women with OAB or mixed UI as first-line drug treatment if bladder training has been ineffective. If immediate release oxybutynin is not well tolerated, dafenacin, solifenacin, tolterodine, tospium, or an extended release or transdermal formulation of oxybutynin should be considered as alternatives. Women should be counselled about the adverse effects of antimuscarinic drugs. There is no evidence of a clinically important difference in efficacy between antimuscarinic drugs. However, immediate release nonproprietary oxybutynin is the most cost effective of the available options. (See section 4.4.1 of the full guideline.) There are currently 7 antimuscarinic drugs licensed for the treatment
of OAB symptoms in the UK. Published evidence suggests there is little difference between these agents in terms of efficacy; approximately 56% of patients will experience an improvement in symptoms, regardless of which antimuscarinic is taken. National guidelines recommend that patients with OAB should be prescribed antimuscarinic drugs only if lifestyle advice and bladder training fail to control symptoms; non-proprietary immediate-release (IR) oxybutynin is the most cost effective agent. Up to 23% of patients are likely to discontinue oxybutynin IR because of intolerable adverse effects, such as dry mouth and constipation. There are no differences between the adverse effect profiles of the other oral antimuscarinc drugs. Economic considerations should be the main factor guiding choice of an alternative antimuscarinic drug to oxybutynin IR. Fesoterodine may be a suitable alternative in some patients unable to tolerate the currently available pharmacotherapeutic options for the treatment of OAB and in whom non-drug treatments are unsuitable or ineffective. Decisions from other bodies Comments to be sought from - Cambridgeshire not considered Norfolk not considered Ipswich Hospital not considered West Suffolk Hospital not considered Decision review date December 2012 References Chapple C et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 2007; 52: 1204-1212 Nitti V et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urol 2007; 178:2488-2494 McEntree J. Antimuscarinic drugs for overactive bladder syndrome in adults. 22/01/2008 Post-launch review. North West Medicines Information Centre available via www.nelm.nhs.uk Appendix 1 below Doses, licensed indications and 28 day costs of antimuscarinic drugs (taken from McEntree J 2008)
Drug name (Brand) Form Licensed indications Dose Cost14 Patent expiry Darifenacin (Emselex ) 7.5mg and 15mg prolonged-release tablets and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome. 7.5mg once daily. Increase to 15mg once daily if needed. 26.13 2015 Oxybutynin generic (Cystrin ) (Ditropan ) (Lyrinel XL) (Kentera ) Propantheline (Pro-Banthine ) Propiverine (Detrunorm ) (Detrunorm XL)23 2.5mg, 3mg and 5mg tablets 3mg and 5mg tablets 2.5mg and 5mg tablets 2.5mg/5ml elixir 5mg and 10mg prolonged-release tablets 3.9mg/24 hours transdermal patch Urinary incontinence, urgency and frequency in unstable bladder conditions due either to idiopathic detrusor instability or neurogenic bladder disorders (detrusor hyperreflexia) in conditions such as spina bifida and multiple sclerosis. and/or increased urinary frequency associated with urgency as may occur in patients with unstable bladder. 2.5mg to 5mg two or three times daily (2.5mg to 3mg twice daily in elderly patients). Increase to 5mg four times daily if needed (maximum twice daily in elderly patients). 5mg two or three times daily (2.5mg or 3mg twice daily in elderly patients). Increase to 5mg four times daily if needed (maximum twice daily in elderly patients). 5mg once daily. Increase to 20mg daily if needed. One 3.9mg patch applied twice a week. 15mg tablet Adult enuresis. 15mg three times daily before meals and 30mg at bedtime, adjusted to a maximum daily dose of 120mg. 15mg coated tablet 30mg modified-release capsule The treatment of urinary incontinence, as well as urgency and frequency in patients who have either idiopathic detrusor overactivity (overactive bladder) or neurogenic detrusor overactivity (detrusor hyperreflexia) from spinal cord injuries. The treatment of urinary incontinence, as well as urgency and frequency in patients who have idiopathic detrusor overactivity (overactive 15mg twice daily. Increase to 15mg three times daily if needed. 5.88 to 5.37 9.15 to 30.51 4.57 to 42.86 9.79 to 39.16 27.20 19.15 to 30.64 24.45 to 36.67 30mg once daily. 24.45 2004
Solifenacin (Vesicare ) Tolterodine (Detrusitol ) (Detrusitol XL)26 Trospium (Regurin ) 5mg and 10mg filmcoated tablet 1mg and 2mg filmcoated tablet 4mg prolonged-release capsule 20mg coated tablet bladder). and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome. and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome. and/or increased urinary frequency and urgency as may occur in patients with overactive bladder (e.g. idiopathic or neurogenic detrusor overactivity). 5mg once daily. Increase to 10mg once daily if needed. 2mg twice daily. Decrease to 1mg twice daily if needed. 4mg once daily. (Note: manufacturer advises decrease to 2mg once daily if needed but 2mg capsule not yet available in UK.) 20mg twice daily before meals. 25.78 to 33.52 30.56 ( 29.03) 29.03 24.27 2018 2012
Charts to be used in the decision making process in Suffolk PCT Quality of Evidence categories I Strong evidence from at least 1 RCT II-1 Evidence from a well designed CT without randomisation II-2 Evidence from well designed cohort or case controlled study II-3 Evidence from multiple time series or dramatic results III Opinions of respected clinicians or expert committees IV Evidence inadequate Cost utility categories Per life year gained A Less than 3,000 B 3,000 to 20,000 C > 20,000 D Negative life years Recommendations informed by cost utility and quality of evidence Quality of evidence A B C D I ++ (high) ++ - X II ++ + - X III + - - X IV 0 0 0 0 (low) Key to table above ++ Strongly recommended + Recommended - Beneficial but high cost X Not recommended 0 Not proven Adapted from: Quick and Clean : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay. Health Trends Vol 27 No 2 1995 Prescriber s Rating Definitions [With acknowledgement to Prescrire] Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages To decide if a medication is to be used in Suffolk PCT
Criterion Tends to poor 2 Medium 4 Tends to good Quality of evidence in the IV III II-2 II-1 I papers reviewed Magnitude of effect inferred Low xxxx Medium xxxx High from the trials reviewed Clinical trial end points Surrogate markers Clinical outcomes Clinical usefulness of trial x endpoints Known side effect profile High xxxx Medium xxxx Low Known interactions High xxxx Medium xxxx Low Concern re: possible side High xxxx Medium xxxx Low effects not yet uncovered Balance of benefit to harm Poor xxxx Medium xxxx Good (side effects, toxicity, interactions etc) NNT High xxxx Medium xxxx Low Comparison of effectiveness Poor xxxx Medium xxxx Good with other medicines in use for the same condition Severity of condition to be Trivial xxxx Medium xxxx Severe treated Uptake estimated proportion of people with the condition likely to be prescribed the medicine Prevalence 10% = 62000 people Of these 5% might be given this medicine for a while Cost utility score D C B?A A Recommendations informed by cost utility and quality of evidence 0 X - + ++ Is the medicine to be used in Suffolk PCT? YES SEE BELOW NO = DOUBLE RED To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Blue Experience of the condition Specific Specific Specific Genera Diagnosis Specific Specific Specific Genera Monitoring progress of Difficult Specific Genera Genera treatment Therapy Patient selection Difficult Specific Specific Easy Initiation of treatment Difficult Difficult Easy Easy Dose titration Difficult Specific Easy Easy Monitoring of side effects Complex Easy Easy Easy Method of administration Complex Normal Normal Normal Discontinuation of treatment Complex Complex Easy Easy