- darifenacin hydrobromide
POM: Prescription only medicine
This information is intended for use by health professionals
Prolonged-release tabletLight peach round, convex tablet debossed with DF on one side and 15 on the reverse.
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 acceptable tolerability profile but require greater symptom relief, the dose may be increased to 15 mg daily, based on individual response (see section 5.2).Paediatric populationEmselex is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
Renal impairmentNo dose adjustment is required in patients with impaired renal function. However, caution should be exercised when treating this population (see section 5.2).
Hepatic impairmentNo 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 benefit outweighs the risk, and the dose should be restricted to 7.5 mg daily (see section 5.2). Emselex is contraindicated 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 or moderate inhibitors of CYP3A4In 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 to 15 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, grapefruit juice and erythromycin, the recommended starting dose is 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However, caution should be exercised.
Method of administrationEmselex is for oral use. The tablets should be taken once daily with liquid. They can be taken with or without food, and must be swallowed whole and not chewed, divided or crushed.
Effects of other medicinal products on darifenacinDarifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inhibitors of these enzymes may increase darifenacin exposure.CYP2D6 inhibitorsIn 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 be titrated 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).CYP3A4 inhibitorsDarifenacin should not be used together with potent CYP3A4 inhibitors (see section 4.3) such as protease inhibitors (e.g. ritonavir), ketoconazole and itraconazole. Potent P-glycoprotein inhibitors such as ciclosporin and verapamil should also be avoided. Co-administration of darifenacin 7.5 mg with the potent CYP3A4 inhibitor ketoconazole 400 mg resulted in a 5-fold increase in steady-state darifenacin AUC. In subjects who are poor metabolisers, darifenacin exposure increased approximately 10-fold. Due to a greater contribution of CYP3A4 after higher darifenacin doses, the magnitude of the effect is expected to be even more pronounced when combining ketoconazole with darifenacin 15 mg.When co-administered with moderate CYP3A4 inhibitors such as erythromycin, clarithromycin, telithromycin, fluconazole and grapefruit juice, the recommended starting dose of darifenacin should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. Darifenacin AUC24 and Cmax from 30 mg once-daily dosing in subjects 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 inducersSubstances 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 productsCYP2D6 substratesDarifenacin is a moderate inhibitor of the enzyme CYP2D6. Caution should be exercised when darifenacin is used concomitantly with medicinal products that are predominantly metabolised by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine, or tricyclic antidepressants such as imipramine. The effects of darifenacin on the metabolism of CYP2D6 substrates are mainly clinically relevant for CYP2D6 substrates which are individually dose titrated.CYP3A4 substratesDarifenacin treatment resulted in a modest increase in the exposure of the CYP3A4 substrate midazolam. However the data available do not indicate that darifenacin changes either midazolam clearance or bioavailability. It can therefore be concluded that darifenacin administration does not alter the pharmacokinetics of CYP3A4 substrates in vivo. The interaction with midazolam lacks clinical relevance, and therefore no dose adjustment is needed for CYP3A4 substrates.
WarfarinStandard therapeutic prothrombin time monitoring for warfarin should be continued. The effect of warfarin on prothrombin time was not altered when co-administered with darifenacin.
DigoxinTherapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacin treatment as well as changing the darifenacin dose. Darifenacin 30 mg once daily (two times greater than the recommended daily dose) co-administered with digoxin at steady state resulted in a small increase in digoxin exposure (AUC: 16% and Cmax: 20%). The increase in digoxin exposure could be caused by competition between darifenacin and digoxin for P-glycoprotein. Other transporter-related interactions cannot be excluded.
Antimuscarinic agentsAs with any other antimuscarinic agents, concomitant use of medicinal products that possess antimuscarinic properties, such as oxybutynin, tolterodine and flavoxate, may result in more pronounced therapeutic and side effects. The potentiation of anticholinergic effects with anti-parkinson agents and tricyclic antidepressants may also occur if antimuscarinic agents are used concurrently with such medicinal products. However, no studies involving the interaction with anti-parkinson agents and tricyclic antidepressants have been performed.
FertilityThere are no human fertility data for darifenacin. Darifenacin had no effect on male or female fertility in rats or any effect in the reproductive organs of either sex in rats and dogs (for details, see section 5.3). Women of child bearing potential should be made aware of the lack of fertility data, and Emselex should only be given after consideration of individual risks and benefits.
PregnancyThere are limited amount of data from the use of darifenacin in pregnant women. Studies in animals have shown toxicity to parturition (for details, see section 5.3). Emselex is not recommended during pregnancy.
Breast-feedingDarifenacin is excreted in the milk of rats. It is not known whether darifenacin is excreted in human milk. A risk to the nursing child cannot be excluded. A decision whether to avoid breast-feeding or to abstain from Emselex therapy during lactation should be based on a benefit and risk comparison.
|Infections and infestations|
|Uncommon||Urinary tract infection|
|Uncommon||Insomnia, thinking abnormal|
|Nervous system disorders|
|Uncommon||Dizziness, dysgeusia, somnolence|
|Uncommon||Visual disturbance, including vision blurred|
|Respiratory, thoracic and mediastinal disorders|
|Uncommon||Dyspnoea, cough, rhinitis|
|Very common||Constipation, dry mouth|
|Common||Abdominal pain, nausea, dyspepsia|
|Uncommon||Flatulence, diarrhoea, mouth ulceration|
|Skin and subcutaneous tissue disorders|
|Uncommon||Rash, dry skin, pruritus, hyperhidrosis|
|Renal and urinary disorders|
|Uncommon||Urinary retention, urinary tract disorder, bladder pain|
|Reproductive system and breast disorders|
|Uncommon||Erectile dysfunction, vaginitis|
|General disorders and administration site conditions|
|Uncommon||Oedema peripheral, asthenia, face oedema, oedema|
|Uncommon||Aspartate aminotransferase increased, alanine aminotransferase increased|
|Injury, poisoning, and procedural complications|
Post-marketing experienceThe following events have been reported in association with darifenacin use in worldwide post-marketing experience: generalised hypersensitivity reactions including angioedema, depressed mood/mood alterations, hallucination. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events cannot be estimated from the available data.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard
|Dose||N||Incontinence episodes per week||95% CI||P value2|
|Baseline (median)||Week 12 (median)||Change from baseline (median)||Differences from placebo1 (median)|
|Emselex 7.5 mg once daily||335||16.0||4.9||-8.8 (-68%)||-2.0||(-3.6, -0.7)||0.004|
|Emselex 15 mg once daily||330||16.9||4.1||-10.6 (-77%)||-3.2||(-4.5, -2.0)||<0.001|
AbsorptionDue to extensive first-pass metabolism darifenacin has a bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma levels are reached approximately 7 hours after administration of the prolonged-release tablets and steady-state plasma levels are achieved by the sixth day of administration. At steady state, peak-to-trough fluctuations in darifenacin concentrations are small (PTF: 0.87 for 7.5 mg and 0.76 for 15 mg), thereby maintaining therapeutic plasma levels over the dosing interval. Food had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged-release tablets.
DistributionDarifenacin 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.
MetabolismDarifenacin is extensively metabolised by the liver following oral administration.Darifenacin undergoes significant metabolism by cytochrome CYP3A4 and CYP2D6 in the liver and by CYP3A4 in the gut wall. The three main metabolic routes are as follows:monohydroxylation in the dihydrobenzofuran ring;dihydrobenzofuran ring opening andN-dealkylation of the pyrrolidine nitrogen.The initial products of the hydroxylation and N-dealkylation pathways are major circulating metabolites 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-state exposure. This dose-dependency is probably caused by saturation of the CYP2D6 catalysed metabolism possibly together with some saturation of CYP3A4-mediated gut wall metabolism.
ExcretionFollowing 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 small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 litres/hour. The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.
Special patient population
GenderA population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females (see section 5.1).
Elderly patientsA population pharmacokinetic analysis of patient data indicated a trend for clearance to decrease with age (19% per decade based on Phase III population pharmacokinetic analysis of patients aged 6089 years), see section 4.2.
Paediatric patientsThe pharmacokinetics of darifenacin have not been established in the paediatric population.
CYP2D6 poor metabolisersThe metabolism of darifenacin in CYP2D6 poor metabolisers is principally mediated by CYP3A4. In one pharmacokinetic study the steady-state exposure in poor metabolisers was 164% and 99% higher during treatment with 7.5 mg and 15 mg once daily, respectively. However, a population pharmacokinetic 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 between the ranges of exposures seen in these two populations (see section 4.2).
Renal insufficiencyA small study of subjects (n=24) with varying degrees of renal impairment (creatinine clearance between 10 ml/min and 136 ml/min) given darifenacin 15 mg once daily to steady state demonstrated no relationship between renal function and darifenacin clearance (see section 4.2).
Hepatic insufficiencyDarifenacin 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, protein binding of darifenacin was affected by moderate hepatic impairment. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function (see section 4.2).
Tablet core:Calcium hydrogen phosphate, anhydrousHypromelloseMagnesium stearate
Film coat:Polyethylene glycolHypromelloseTalcTitanium dioxide (E171)Yellow iron oxide (E172)Red iron oxide (E172)