Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Merus Labs Luxco II S.à R.L., 26-28, rue Edward Steichen, L-2540 Luxembourg
Emselex is contraindicated in patients with:
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).
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 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).
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.
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.
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.
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.
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.
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.
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 antiparkinson agents and tricyclic antidepressants may also occur if antimuscarinic agents are used concurrently with such medicinal products. However, no studies involving the interaction with antiparkinson agents and tricyclic antidepressants have been performed.
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.
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.
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.
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 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).
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:
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, alanine aminotransferase increased
Uncommon: Injury
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.
The following events have been reported in association with darifenacin use in worldwide postmarketing 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 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 national reporting system listed in Appendix V.
Not applicable.
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