4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

Adults

The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed. For those patients requiring greater symptom relief, the dose may be increased to 15 mg daily, 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 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 population

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

Renal impairment

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

Hepatic impairment

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 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 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 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 administration

Emselex 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.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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

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

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

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 oral bisphosphonates) that can cause or exacerbate oesophagitis.

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

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

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

4.5. Interaction with other medicinal products and other forms of interaction

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.

CYP2D6 inhibitors

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 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 inhibitors

Darifenacin 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 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

CYP2D6 substrates

Darifenacin 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 substrates

Darifenacin 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.

Warfarin

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

Digoxin

Therapeutic 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 agents

As 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There 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-feeding

Darifenacin 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.

Fertility

There 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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

Consistent with the pharmacological profile, the most commonly reported adverse reactions were dry mouth (20.2% and 35% for the 7.5 mg and 15 mg dose, respectively, 18.7% after flexible dose titration, 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% for placebo, for dry mouth and constipation, respectively).

Tabulated list of adverse reactions

The adverse reactions are ranked under heading of frequency using the following convention: very common (≥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). Within each 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

Infections and infestations

Uncommon

Urinary tract infection

Psychiatric disorders

Uncommon

Insomnia, thinking abnormal

Nervous system disorders

Common

Headache

Uncommon

Dizziness, dysgeusia, somnolence

Eye disorders

Common

Dry eye

Uncommon

Visual disturbance, including vision blurred

Vascular disorders

Uncommon

Hypertension

Respiratory, thoracic and mediastinal disorders

Common

Nasal dryness

Uncommon

Dyspnoea, cough, rhinitis

Gastrointestinal disorders

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

Not known

Angioedema

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

Investigations

Uncommon

Aspartate aminotransferase increased, alanine aminotransferase increased

Injury, poisoning, and procedural complications

Uncommon

Injury

Description of selected adverse reactions

In the pivotal clinical trials with doses of Emselex 7.5 mg and 15 mg, adverse reactions were reported as presented in the table above. Most of the adverse reactions were of mild or moderate intensity and did 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 in darifenacin-treated patients and increasing age.

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

Post-marketing experience

The 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 reactions

Reporting 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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