New products
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`Fesoterodine (Foviaz): new
`option for overactive bladder
`
`Steve Chaplin MSG, A/lF?PharmS and Adrian Wagg FRCP
`
`KEY POINTS
`
`0 fesoterodine (Toviaz) is a prodrug that is
`rapidly converted to the active metabolite of
`tolterodine, which is an antimuscarinic agent
`
`
`
`' licensed for the treatment of OAB symptoms
`and shares the contraindications of other agents in its class
`
`' available as prolonged-release 4mg and 8mg tablets (28, £29.03)
`
`' dosage 4mg once daily, increasing to max. 8mg once daily if necessary;
`reassess after eight weeks
`
`Fesoterodine, the prodrug of
`
`the active metabolite of
`
`tolterodine, has been
`
`launched in two strengths for
`
`the treatment of overactive
`
`bladder. In our New products
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`review Steve Chaplin pre-
`
`sents the clinical data relat-
`
`' in clinical trials, fesoterodine 4 or 8mg once daily reduced the mean
`number of micturitions per day by about 0.5-1.0 and the mean number
`of urge incontinence episodes by 0.8-1.3 compared with placebo
`
`ing to its efficacy and
`
`adverse effects, and Dr
`
`' an additional 20-30 per cent of patients reported their symptoms
`improvedlvery improved compared with placebo
`
`9 although fesoterodine has not been directly compared with tolterodine,
`its efficacy appears to be similar
`
`° adverse effects are similar to those of other antimuscarinic agents, the
`commonest being dry mouth, headache and constipation
`
`‘ for some outcome measures the 8mg dose appears to be more effec-
`tive than the 4mg dose, offering flexibility in dosing
`
`Adrian Wagg comments on
`
`its place in treatment.
`
`veractive bladder syndrome
`(OAB) is defined as urgency,
`with or without urge urinary incon-
`tinence, usually with frequency and
`nocturia. Current management
`guidelines for OAB in women rec-
`ommend lifestyle change, pelvic
`floor muscle training for three
`months and bladder training for
`six weeks as first-line therapy.l If
`bladder training is ineffective, an
`antimuscarinic agent should be
`added and women should be coun-
`selled about the adverse effects.
`
`The drug of first choice is imme-
`diate-release oxybutynin; if this is
`not tolerated, the alternatives are
`darifenacin (Emselex), solifenacin
`(Vesicare), tolterodine (Detrusitol),
`
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`Prescriber 5 November 2008
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`trospium (Regurin) and modified-
`release (Lyrinel XL) or transdermal
`(Kentera) oxybutynin. These drugs
`improve
`frequency,
`leakage
`episodes and quality oflife with no
`evidence of clinically important dif-
`ferences in efficacy. Antimuscarinic
`adverse-effects are common.2=3
`
`Propiverine (Detrunorm) is a
`further alternative to treat urinary
`frequency but not urge inconti-
`nence; intravaginal oestrogens are
`an option for OAB symptoms in
`postmenopausal wome11 with vagi-
`nal atrophy.1
`
`The technology
`
`Fesoterodine (Toviaz) is a pro-
`drug: it is rapidly and extensively
`
`hydrolysed in plasma to 5-hydroxy-
`methyltolterodine (5-HMT), the
`active metabolite of tolterodine. 5-
`
`HMT is an antagonist at mus-
`carinic
`receptors with
`no
`selectivity for receptor subtypes in
`vit1ra.4
`Fesoterodine is licensed for
`
`the treatment of OAB symptoms
`— increased urinary frequency
`and/or urgency and/or urgency
`incontinence. It is formulated as
`a modified-release tablet for
`
`administration.
`once-daily
`Treatment should be initiated at
`
`a dose of 4mg per day and
`increased to a maximum of 8mg
`per day according to individual
`response. The full therapeutic
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`Patent Owner, UCB Pharma GmbH — Exhibit 2082 - 0001
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`

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`effect is apparent within two to
`eight weeks. Dose adjustment
`may be required in patients with
`impaired renal or hepatic func-
`tion depending on the severity of
`impairment.
`As with all antimuscarinic drugs
`caution must be exercised when
`
`the patient is undergoing concur-
`rent treatment with drugs that
`inhibit hepatic CYP3A4 enzymes,
`eg
`clarithromycin,
`protease
`inhibitors, as this will increase
`
`plasma levels of 5-HMT (see SPC
`for details).
`Fesoterodine has the same cau-
`tions and contraindications as
`other antimuscarinics.
`
`Clinical trials
`
`Two phase III randomised, double-
`blind, 12-week trials provide the
`key clinical data for fesoterodine.
`Both included patients (mean age
`58, 80 per cent of whom were
`women) with OAB and averaging
`12-13 micturitions and four urge
`incontinence episodes per day.
`Seventy-five to eighty per cent of
`patients reported incontinence.
`The mean duration of OAB was 8-
`
`10 years.
`The primary end-points were
`the change, after 12 weeks’ treat-
`ment, in the mean number of mic-
`
`turitions per 24 hours, mean
`number ()f episodes of urge incon-
`tinence per 24 hours and the treat-
`ment response, defined as the
`proportion of patients reporting
`their condition as improved or
`greatly improved.4
`In a US study in 836 patients,
`fesoterodine significantly reduced
`the mean number of micturitions
`
`per 24 hours compared with
`placebo (by 1.61 at 4mg per day
`and 2.09 at 8mg per day US 1.08
`with placebo) .5 It also significantly
`reduced the mean number ofurge
`incontinence episodes in 24 hours
`(by 1.65 and 2.28 vs 0.96 with
`placebo) and was associated with a
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`New products
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`significantly greater treatment
`response (64 and 74 vs 45 per cent
`with placebo).
`Treatment with fesoterodine
`also increased the number of con-
`
`tinent days per week (from a base-
`line of 0.6-0.7) by 1.3 with placebo
`and 2.3 and 2.8 with 4 and 8mg per
`day. The two doses of fesoterodine
`were not compared. Nineteen per
`
`cent of patients did not complete
`the trial, of whom one-third (of all
`treatment arms) withdrew due to
`adverse events.
`
`A European study involving
`1135 patients compared fesotero-
`dine 4 or 8mg per day with placebo
`and included modified—release
`
`tolterodine 4mg per day as an
`active control to validate the study
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`design.6 The principal results are
`summarised in Table 1.
`Both doses offesoterodine and
`
`to
`tolterodine were superior
`placebo; fesoterodine was not com-
`pared with tolterodine. All active
`treatments reduced the frequency
`of nocturia and overall urgency
`severity. Thirteen per cent of
`patients withdrew from the trial, of
`whom 24 per cent (from all treat-
`ment arms) did so due to adverse
`effects.
`
`Adverse effects
`
`In data pooled from clinical trials,
`adverse effects were reported by 50
`per cent of patients assigned to
`placebo or tolterodine 4mg per
`day, and by 60 and 64 per cent of
`patients taking fesoterodine 4 or
`8mg per day.4 Discontinuation due
`to adverse effects occurred in 3 per
`cent of patients taking placebo, 5-6
`per cent with fesoterodine and 3
`per cent with tolterodine. In long-
`term nonblinded studies, the dose
`of fesoterodine was reduced from
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`New products
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`Placebo
`
`Fesoterodine
`
`Fesoterodine
`
`Tolterodine
`
`4mg/day
`
`8mg/day
`
`4mg/day
`
`reduction in
`micturitions/24h
`
`0.95
`
`reduction in urge
`incontinence/24h
`
`increase in number
`
`of continent days
`per week
`
`Table 1. Efficacy of fesoterodine 4 and 8mg daily compared with placebo and tolterodines
`
`8 to 4mg per day due to adverse
`effects in 12 per cent of patients.
`The adverse effects associated
`
`with fesoterodine are typical of an
`antimuscarinic agent (see Table 2)
`and include dry mouth (placebo 8
`per cent, fesoterodine 4mg per day
`22 per cent, Srng per day 35 per
`cent, tolterodine 17 per cent),
`headache (8, 8, 6 and 5 per cent
`respectively) and constipation (2,
`4, 5 and 3 per cent) .4
`
`Data from ongoing long-term
`nonblinded studies suggest that
`most adverse effects occurred early
`during treatment with the excep-
`tion of urinary retention, which
`occurred in 2-3 per cent of patients
`and was more common in men and
`
`older patients.
`
`RBf6I'BI'IGBS
`1. National Institute for Health and
`
`Clinical Excellence. Urinary inconti-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2082 - 0003
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`

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`New products
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`Placebo (°/a)
`{n=780 )
`
`Feso 4mg/day (°/a)
`(n=782}
`
`Feso 8mg/day (%) Tolt 4mg/day (“/o)
`(n=785)
`(n=290)
`
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`—l—lI\3l\3l\J|\JI\3l\JbDU3-l!hUJU5a
`
`‘E.
`
`1 1 3 1 2 2 2 2 2 2
`
`Adverse event
`
`dry mouth
`headache
`
`constipation
`urinary tract infection
`dyspepsia
`Iacrimal disorder (dry eye)
`nausea
`
`dry throat
`dysuna
`abdominal pain, upper
`nasopharyngitis
`back pain
`diarrhoea
`
`upper respiratory tract infection
`influenza
`dizziness
`
`abdominal pain
`cough
`
`feso = fesoterodine; tolt = tolterodine
`
`nence. Clinical Guideline No. 40.
`
`October 2006. www.nice.org.uk/nice-
`media/pdf/CG40NICEgL1ideline.pdf;
`accessed 17.7.08
`
`2. National Collaborating Centre for
`Women's and Children's Health.
`
`Urinary inrantmenre. RCOG Press:
`London, October
`2006
`www.
`nice.nrg.uk/nicemedia/pdf/CG40full
`guidelinepdf; accessed 17.7.08.
`elf ml.
`3. Nabi G, Cody JD, Ellis G,
`Anticholinergic drugs versus placebo
`
`for overactive bladder syndrome in
`adults. Cochrane Database of Systematic
`Reviews 2006,
`Issue 4. Art. No.:
`CD00378l. DOI: 10.1002/14651858.
`CDOO3781.pub2.
`4. European Medicines Agency. Tlruiaz
`European public a.rses.smmt ref1ort._]une
`2008. www.emea.europa.eu/human-
`Cl(}CS/PDFS/EPAR/[()VlaZ/H-723-
`en6.pdf; accessed 18.7.08.
`5. Nitti VW, Dmochowski R, Sand PK,
`et al. Efficacy, safety and tolerability
`
`of fesoterodine for overactive blad-
`
`der syndrome. _] Ural.‘ 2007;l78:
`2488-94.
`
`6. Chapple C, Van Kerrebroeck P,
`Tubaro A, et al. Clinical efficacy,
`safety, and tolerability of once-daily
`fesoterodine in subjects with overac-
`tive bladder. Eur Urol 2007;52:
`1204-12.
`
`By Steve (Jhaplirr, at pharmacist who
`spec2'a!z‘ses in writing on therapeutics
`
`Place in therapy
`OAB is a common condition that
`
`has a significant negative impact
`upon quality of life for many peo-
`ple.1 Treatment, according to pub-
`lished guidelines,2'4 consists of
`lifestyle and behavioural
`tech-
`niques, adding in antimuscarinic
`therapy should these measures not
`achieve symptom improvement.
`Fesoterodine is the prodrug of
`5-HMT, the active metabolite of
`tolterodine. Unlike tolterodine,
`
`conversion to 5—HMT is by non-
`specific esterases rather than the
`cytochrome
`P450
`system
`although its elimination is still
`dependent upon this system. This
`may be clinically relevant — patients
`who do not respond to the licensed
`dose of tolterodine (4mg) or expe-
`rience intolerable side-effects may
`have either had subtherapeutic or
`toxic doses of 5-HMT. This may be
`due to the variability in serum con-
`centration of 5-HMT associated
`
`with the given 4mg dose.
`
`www.prescriber.co.uk
`
`Fesoterodine is also available as
`
`an 8mg dose, and for some out-
`come measures appears to be
`more effective than the 4mg dose.5
`Additionally, secondary analyses of
`available data show a favourable
`
`and clinically meaningful improve-
`ment on quality of life,5 though
`the available data are limited and
`
`much evidence relies upon post-hoe
`analyses of clinical
`trials per-
`formed by the previous owner of
`the compound. More data are
`awaited.
`
`Prescriber 5 November 2008
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`17
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`Patent Owner, UCB Pharma GmbH — Exhibit 2082 - 0004
`
`

`
` New products
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`Fesoterodine’s side-effect pro-
`file appears much the same as
`other available antimuscarinics
`
`with the exception of a lower inci-
`dence of reported constipation;
`whether this is borne out in cur-
`rent trials and clinical use remains
`to be seen.
`
`References
`
`1. Coyne KS, Sexton CC, Irwin DE, et
`ml. The impact of overactive bladder,
`incontinence and other lower urinary
`tract synlptoms on quality of life, work
`productivity, sexuality and emotional
`
`well—bcing in men and women: results
`from the EPIC study. BJU Int 2008;
`101 (11):1?a88-95.
`2. European Association of Urology.
`C‘ttideli?tt:.s'
`in urinary incrintinerice.
`www.uroweb.org/fileadmin/tx_eau-
`guidelines/l6%20Urinary% 20Inconti
`ncnce.pdf (accessed 18.8.08) .
`3. 3rd International Consultation on
`
`Incontinence. 2005. www.congress-
`urology.org/publishing/page.accueil.
`pub.html (accessed 18.8.08).
`4.National Institute for Health and
`
`Clinical Excellence. Urinary inconti-
`'l'lf,‘T1(",K.’.
`Clinical Guideline No. 40.
`
`October 2006. www.nice.org.uk/nice-
`
`media/pdf/ CG40NICEguideline.pdf.
`5. Khullar V, Rovner ES, Dmo-
`chowski R, elf (ll. Fesoterodine dose
`response in subjects with overactive
`bladder syndrome. Urology 2008;7I
`(5):839-43.
`6. Kcllchcr C}, Tubaro A, WangJT, et
`ril. Impact of fcsolerocline on quality of
`life: pooled data from two randomized
`trials. BJU Int 2008;102(1) :56-61.
`
`By Dr Wszgg, senior lecturer and
`consultant in geriatric medicine at
`University College London H0.€}l)ll(£l.§
`and Camden PCT
`
`www.prescriber.co.uk
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`Prescriber 5 November 2008
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`Patent Owner, UCB Pharma GmbH — Exhibit 2082 - 0005