EMSELEX 15mg prolonged-release tablets medication leaflet

Emselex 15 mg prolonged-release tablets

Each tablet contains 15 mg of darifenacin (as hydrobromide)

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Light peach round, convex tablet debossed with “DF” on one side and “15” on the reverse.

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as mayoccur in adult patients with overactive bladder syndrome.

The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients should bereassessed. For those patients requiring greater symptom relief, the dose may be increased to 15 mgdaily, based on individual response.

Elderly patients (≥ 65 years)

The recommended starting dose for the elderly is 7.5 mg daily. After 2 weeks of starting therapy,patients should be reassessed for efficacy and safety. For those patients who have an acceptabletolerability profile but require greater symptom relief, the dose may be increased to 15 mg daily, basedon individual response (see section 5.2).

Emselex is not recommended for use in children below 18 years of age due to a lack of data on safetyand efficacy.

No dose adjustment is required in patients with impaired renal function. However, caution should beexercised when treating this population (see section 5.2).

No dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). However,there is a risk of increased exposure in this population (see section 5.2).

Patients with moderate hepatic impairment (Child Pugh B) should only be treated if the benefitoutweighs the risk, and the dose should be restricted to 7.5 mg daily (see section 5.2). Emselex iscontraindicated in patients with severe hepatic impairment (Child Pugh C) (see section 4.3).

Patients receiving concomitant treatment with substances that are potent inhibitors of CYP2D6 ormoderate inhibitors of CYP3A4

In patients receiving substances that are potent CYP2D6 inhibitors, such as paroxetine, terbinafine,quinidine and cimetidine, treatment should start with the 7.5 mg dose. The dose may be titrated to15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However,caution should be exercised.

In patients receiving substances that are moderate CYP3A4 inhibitors, such as fluconazole, grapefruitjuice and erythromycin, the recommended starting dose is 7.5 mg daily. The dose may be titrated to15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However,caution should be exercised.

Emselex is for oral use. The tablets should be taken once daily with liquid. They can be taken with orwithout food, and must be swallowed whole and not chewed, divided or crushed.

Emselex is contraindicated in patients with:

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Urinary retention.

- Gastric retention.

- Uncontrolled narrow-angle glaucoma.

- Myasthenia gravis.

- Severe hepatic impairment (Child Pugh C).

- Severe ulcerative colitis.

- Toxic megacolon.

- Concomitant treatment with potent CYP3A4 inhibitors (see section 4.5).

Emselex should be administered with caution to patients with autonomic neuropathy, hiatus hernia,clinically significant bladder outflow obstruction, risk for urinary retention, severe constipation orgastrointestinal obstructive disorders, such as pyloric stenosis.

Emselex should be used with caution in patients being treated for narrow-angle glaucoma (seesection 4.3).

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatmentwith Emselex. If urinary tract infection is present, an appropriate antibacterial therapy should bestarted.

Emselex should be used with caution in patients with risk of decreased gastrointestinal motility,gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as oralbisphosphonates) that can cause or exacerbate oesophagitis.

Safety and efficacy have not yet been established in patients with a neurogenic cause for detrusor overactivity.

Caution should be used when prescribing antimuscarinics to patients with pre-existing cardiacdiseases.

As with other antimuscarinics, patients should be instructed to discontinue Emselex and seekimmediate medical attention if they experience oedema of the tongue or laropharynx, or difficultybreathing (see section 4.8).

Effects of other medicinal products on darifenacin

Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and

CYP3A4. Therefore, inhibitors of these enzymes may increase darifenacin exposure.

In patients receiving substances that are potent CYP2D6 inhibitors (e.g. paroxetine, terbinafine,cimetidine and quinidine) the recommended starting dose should be 7.5 mg daily. The dose may betitrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated.

Concomitant treatment with potent CYP2D6 inhibitors results in an increase in exposure (e.g. of 33%with 20 mg paroxetine at the 30 mg dose of darifenacin).

Darifenacin should not be used together with potent CYP3A4 inhibitors (see section 4.3) such asprotease inhibitors (e.g. ritonavir), ketoconazole and itraconazole. Potent P-glycoprotein inhibitorssuch as ciclosporin and verapamil should also be avoided. Co-administration of darifenacin 7.5 mgwith the potent CYP3A4 inhibitor ketoconazole 400 mg resulted in a 5-fold increase in steady-statedarifenacin AUC. In subjects who are poor metabolisers, darifenacin exposure increasedapproximately 10-fold. Due to a greater contribution of CYP3A4 after higher darifenacin doses, themagnitude of the effect is expected to be even more pronounced when combining ketoconazole withdarifenacin 15 mg.

When co-administered with moderate CYP3A4 inhibitors such as erythromycin, clarithromycin,telithromycin, fluconazole and grapefruit juice, the recommended starting dose of darifenacin shouldbe 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical responseprovided the dose is well tolerated. Darifenacin AUC24 and Cmax from 30 mg once-daily dosing insubjects who are extensive metabolisers were 95% and 128% higher when erythromycin (moderate

CYP3A4 inhibitor) was co-administered with darifenacin than when darifenacin was taken alone.

Enzyme inducers

Substances that are inducers of CYP3A4, such as rifampicin, carbamazepine, barbiturates and St

John´s wort (Hypericum perforatum) are likely to decrease the plasma concentrations of darifenacin.

Effects of darifenacin on other medicinal products

Darifenacin is a moderate inhibitor of the enzyme CYP2D6. Caution should be exercised whendarifenacin is used concomitantly with medicinal products that are predominantly metabolised by

CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine, or tricyclicantidepressants such as imipramine. The effects of darifenacin on the metabolism of CYP2D6substrates are mainly clinically relevant for CYP2D6 substrates which are individually dose titrated.

Darifenacin treatment resulted in a modest increase in the exposure of the CYP3A4 substratemidazolam. However the data available do not indicate that darifenacin changes either midazolamclearance or bioavailability. It can therefore be concluded that darifenacin administration does not alterthe pharmacokinetics of CYP3A4 substrates in vivo. The interaction with midazolam lacks clinicalrelevance, and therefore no dose adjustment is needed for CYP3A4 substrates.

Standard therapeutic prothrombin time monitoring for warfarin should be continued. The effect ofwarfarin on prothrombin time was not altered when co-administered with darifenacin.

Therapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacintreatment as well as changing the darifenacin dose. Darifenacin 30 mg once daily (two times greaterthan the recommended daily dose) co-administered with digoxin at steady state resulted in a smallincrease in digoxin exposure (AUC: 16% and Cmax: 20%). The increase in digoxin exposure could becaused by competition between darifenacin and digoxin for P-glycoprotein. Other transporter-relatedinteractions cannot be excluded.

Antimuscarinic agents

As with any other antimuscarinic agents, concomitant use of medicinal products that possessantimuscarinic properties, such as oxybutynin, tolterodine and flavoxate, may result in morepronounced therapeutic and side effects. The potentiation of anticholinergic effects with anti-parkinson agents and tricyclic antidepressants may also occur if antimuscarinic agents are usedconcurrently with such medicinal products. However, no studies involving the interaction with anti-parkinson agents and tricyclic antidepressants have been performed.

There are limited amount of data from the use of darifenacin in pregnant women. Studies in animalshave shown toxicity to parturition (for details, see section 5.3). Emselex is not recommended duringpregnancy.

Darifenacin is excreted in the milk of rats. It is not known whether darifenacin is excreted in humanmilk. A risk to the nursing child cannot be excluded. A decision whether to avoid breast-feeding or toabstain from Emselex therapy during lactation should be based on a benefit and risk comparison.

There are no human fertility data for darifenacin. Darifenacin had no effect on male or female fertilityin rats or any effect in the reproductive organs of either sex in rats and dogs (for details, see section5.3). Women of child bearing potential should be made aware of the lack of fertility data, and Emselexshould only be given after consideration of individual risks and benefits.

As with other antimuscarinic agents, Emselex may produce effects such as dizziness, blurred vision,insomnia and somnolence. Patients experiencing these side effects should not drive or use machines.

For Emselex, these side effects have been reported to be uncommon.

Consistent with the pharmacological profile, the most commonly reported adverse reactions were drymouth (20.2% and 35% for the 7.5 mg and 15 mg dose, respectively, 18.7% after flexible dosetitration, and 8% - 9% for placebo) and constipation (14.8% and 21% for the 7.5 mg and 15 mg dose,respectively, 20.9% after flexible dose titration, and 5.4% - 7.9% for placebo). Anticholinergic effects,in general, are dose-dependent.

However, the patient discontinuation rates due to these adverse reactions were low (dry mouth: 0% -0.9% and constipation: 0.6% - 2.2% for darifenacin, depending on the dose; and 0% and 0.3% forplacebo, for dry mouth and constipation, respectively).

The adverse reactions are ranked under heading of frequency using the following convention: verycommon (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to<1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions with Emselex 7.5 mg and 15 mg prolonged-release tablets

Uncommon Urinary tract infection

Uncommon Insomnia, thinking abnormal

Common Headache

Uncommon Dizziness, dysgeusia, somnolence

Common Dry eye

Uncommon Visual disturbance, including vision blurred

Uncommon Hypertension

Common Nasal dryness

Uncommon Dyspnoea, cough, rhinitis

Very common Constipation, dry mouth

Common Abdominal pain, nausea, dyspepsia

Uncommon Flatulence, diarrhoea, mouth ulceration

Uncommon Rash, dry skin, pruritus, hyperhidrosis

Not known Angioedema

Uncommon Urinary retention, urinary tract disorder, bladder pain

Uncommon Erectile dysfunction, vaginitis

Uncommon Oedema peripheral, asthenia, face oedema, oedema

Uncommon Aspartate aminotransferase increased, alanineaminotransferase increased

Injury, poisoning, and procedural complications

Uncommon Injury

In the pivotal clinical trials with doses of Emselex 7.5 mg and 15 mg, adverse reactions were reportedas presented in the table above. Most of the adverse reactions were of mild or moderate intensity anddid not result in discontinuation in the majority of the patients.

Treatment with Emselex may possibly mask symptoms associated with gallbladder disease. However,there was no association between the occurrence of adverse events related to the biliary system indarifenacin-treated patients and increasing age.

The incidence of adverse reactions with the doses of Emselex 7.5 mg and 15 mg decreased during thetreatment period up to 6 months. A similar trend is also seen for the discontinuation rates.

The following events have been reported in association with darifenacin use in worldwide post-marketing experience: generalised hypersensitivity reactions including angioedema, depressedmood/mood alterations, hallucination. Because these spontaneously reported events are from theworldwide post-marketing experience, the frequency of events cannot be estimated from the availabledata.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Emselex has been administered in clinical trials at doses up to 75 mg (five times maximum therapeuticdose). The most common adverse reactions seen were dry mouth, constipation, headache, dyspepsiaand nasal dryness. However, overdose with darifenacin can potentially lead to severe anticholinergiceffects and should be treated accordingly. Therapy should be aimed at reversing the anticholinergicsymptoms under careful medical supervision. The use of agents such as physostigmine can assist inreversing such symptoms.

Pharmacotherapeutic group: Urologicals, drugs for urinary frequency and incontinence; ATC code:

G04BD10.

Darifenacin is a selective muscarinic M3 receptor antagonist (M3 SRA) in vitro. The M3 receptor isthe major subtype that controls urinary bladder muscle contraction. It is not known whether thisselectivity for the M3 receptor translates into any clinical advantage when treating symptoms ofoveractive bladder syndrome.

Cystometric studies performed with darifenacin in patients with involuntary bladder contractionsshowed increased bladder capacity, increased volume threshold for unstable contractions anddiminished frequency of unstable detrusor contractions.

Treatment with Emselex administered at dosages of 7.5 mg and 15 mg daily has been investigated infour double-blind, Phase III, randomised, controlled clinical studies in male and female patients withsymptoms of overactive bladder. As seen in Table 2 below, a pooled analysis of 3 of the studies for thetreatment with both Emselex 7.5 mg and 15 mg provided a statistically significant improvement in theprimary endpoint, reduction in incontinence episodes, versus placebo.

Table 2: Pooled analysis of data from three Phase III clinical studies assessing fixed doses of 7.5 mgand 15 mg Emselex

Dose N Incontinence episodes per week 95% CI P value2

Baseline Week 12 Change from Differences(median) (median) baseline from placebo1(median) (median)

Emselex 335 16.0 4.9 -8.8 (-68%) -2.0 (-3.6, -0.7) 0.0047.5 mgonce daily

Placebo 271 16.6 7.9 -7.0 (-54%) -- -- --

Emselex 330 16.9 4.1 -10.6 (-77%) -3.2 (-4.5, -2.0) <0.00115 mgonce daily

Placebo 384 16.6 6.4 -7.5 (-58%) -- -- --1 Hodges Lehmann estimate: median difference from placebo in change from baseline2 Stratified Wilcoxon test for difference from placebo.

Emselex 7.5 mg and 15 mg doses significantly reduced both the severity and number of urinaryurgency episodes and the number of micturitions, while significantly increasing the mean volumevoided from baseline.

Emselex 7.5 mg and 15 mg were associated with statistically significant improvements over placebo insome aspects of quality of life as measured by the Kings Health Questionnaire including incontinenceimpact, role limitations, social limitations and severity measures.

For both doses of 7.5 mg and 15 mg, the percentage median reduction from baseline in the number ofincontinence episodes per week was similar between males and females. The observed differencesfrom placebo for males in terms of percentage and absolute reductions in incontinence episodes waslower than for females.

The effect of treatment with 15 mg and 75 mg of darifenacin on QT/QTc interval was evaluated in astudy in 179 healthy adults (44% male: 56% females) aged 18 to 65 for 6 days (to steady state).

Therapeutic and supra-therapeutic doses of darifenacin resulted in no increase in QT/QTc intervalprolongation from baseline compared to placebo at maximum darifenacin exposure.

Darifenacin is metabolised by CYP3A4 and CYP2D6. Due to genetic differences, about 7% of the

Caucasians lack the CYP2D6 enzyme and are said to be poor metabolisers. A few percent of thepopulation have increased CYP2D6 enzyme levels (ultrafast metabolisers). The information belowapplies to subjects who have normal CYP2D6 activity (extensive metabolisers) unless otherwisestated.

Due to extensive first-pass metabolism darifenacin has a bioavailability of approximately 15% and19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma levels are reachedapproximately 7 hours after administration of the prolonged-release tablets and steady-state plasmalevels are achieved by the sixth day of administration. At steady state, peak-to-trough fluctuations indarifenacin concentrations are small (PTF: 0.87 for 7.5 mg and 0.76 for 15 mg), thereby maintainingtherapeutic plasma levels over the dosing interval. Food had no effect on darifenacin pharmacokineticsduring multiple-dose administration of prolonged-release tablets.

Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 litres.

Darifenacin is extensively metabolised by the liver following oral administration.

Darifenacin undergoes significant metabolism by cytochrome CYP3A4 and CYP2D6 in the liver andby CYP3A4 in the gut wall. The three main metabolic routes are as follows:monohydroxylation in the dihydrobenzofuran ring;dihydrobenzofuran ring opening and

N-dealkylation of the pyrrolidine nitrogen.

The initial products of the hydroxylation and N-dealkylation pathways are major circulatingmetabolites but none contribute significantly to the overall clinical effect of darifenacin.

The pharmacokinetics of darifenacin at steady state are dose-dependent, due to saturation of the

CYP2D6 enzyme.

Doubling the darifenacin dose from 7.5 mg to 15 mg result in a 150% increase in steady-stateexposure. This dose-dependency is probably caused by saturation of the CYP2D6 catalysedmetabolism possibly together with some saturation of CYP3A4-mediated gut wall metabolism.

Excretion

Following administration of an oral dose of 14C-darifenacin solution to healthy volunteers,approximately 60% of the radioactivity was recovered in the urine and 40% in the faeces. Only a smallpercentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is40 litres/hour. The elimination half-life of darifenacin following chronic dosing is approximately13-19 hours.

Special patient population

A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23%lower in males than females (see section 5.1).

A population pharmacokinetic analysis of patient data indicated a trend for clearance to decrease withage (19% per decade based on Phase III population pharmacokinetic analysis of patients aged 60-89 years), see section 4.2.

The pharmacokinetics of darifenacin have not been established in the paediatric population.

CYP2D6 poor metabolisers

The metabolism of darifenacin in CYP2D6 poor metabolisers is principally mediated by CYP3A4. Inone pharmacokinetic study the steady-state exposure in poor metabolisers was 164% and 99% higherduring treatment with 7.5 mg and 15 mg once daily, respectively. However, a populationpharmacokinetic analyses of Phase III data indicated that on average steady-state exposure is 66%higher in poor metabolisers than in extensive metabolisers. There was considerable overlap betweenthe ranges of exposures seen in these two populations (see section 4.2).

A small study of subjects (n=24) with varying degrees of renal impairment (creatinine clearancebetween 10 ml/min and 136 ml/min) given darifenacin 15 mg once daily to steady state demonstratedno relationship between renal function and darifenacin clearance (see section 4.2).

Darifenacin pharmacokinetics were investigated in subjects with mild (Child Pugh A) or moderate(Child Pugh B) impairment of hepatic function given darifenacin 15 mg once daily to steady state.

Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, proteinbinding of darifenacin was affected by moderate hepatic impairment. Unbound darifenacin exposurewas estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects withnormal hepatic function (see section 4.2).

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. There were no effectson fertility in male and female rats treated at oral doses up to 50 mg/kg/day (78 times the AUC0-24h offree plasma concentration at maximum recommended human dose [MRHD]). There were no effectson reproductive organs in either sex in dogs treated for 1 year at oral doses up to 6 mg/kg/day(82 times the AUC0-24h of free plasma concentration at MRHD). Darifenacin was not teratogenic inrats and rabbits at doses up to 50 and 30 mg/kg/day, respectively. At the dose of 50 mg/kg/day in rats(59 times the AUC0-24h of free plasma concentration at MRHD), delay in the ossification of the sacraland caudal vertebrae was observed. At the dose of 30 mg/kg/day in rabbits (28 times the AUC0-24h offree plasma concentration at MRHD), maternal toxicity and foetotoxicity (increased post implantationloss and decreased number of viable foetuses per litter) were observed. In peri and post-natal studies inrats, dystocia, increased foetal deaths in utero and toxicity to post-natal development (pup body weightand development land marks) were observed at systemic exposure levels up to 11 times the AUC0-24hof free plasma concentration at MRHD.

Calcium hydrogen phosphate, anhydrous

Hypromellose

Magnesium stearate

Polyethylene glycol

Hypromellose

Talc

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Not applicable

3 years

Keep the blister packs in the outer carton in order to protect from light.

Clear PVC/CTFE/aluminium or PVC/PVDC/aluminium blisters in cartons containing 7, 14, 28, 49, 56or 98 tablets as unit pack or in multipacks containing 140 (10x14) tablets.

Not all pack sizes may be marketed.

No special requirements.

pharmaand GmbH

Taborstrasse 11020 Vienna

Austria

EU/1/04/294/007-012

EU/1/04/294/014

EU/1/04/294/021-026

EU/1/04/294/028

Date of first authorisation: 22 October 2004

Date of latest renewal: 24 September 2009

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu