Emselex · 4.1 Therapeutic indications · 2

HOS-093842 · has-adverse-reaction-information · PDF-Seite 5

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. 5 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 Not known Confusional state* Not known Depressed mood/mood altered* Not known Hallucination* 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 di

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HOS-093848 · has-adverse-reaction-information · PDF-Seite 15

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. 15 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 Not known Confusional state* Not known Depressed mood/mood altered* Not known Hallucination* 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 d

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HOS-093838 · has-contraindication-information · PDF-Seite 3

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).

HOS-093844 · has-contraindication-information · PDF-Seite 13

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).

HOS-093837 · has-indication-information · PDF-Seite 2

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

HOS-093843 · has-indication-information · PDF-Seite 12

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

HOS-093846 · has-interaction-information · PDF-Seite 14

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, s

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HOS-093840 · has-interaction-information · PDF-Seite 4

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, s

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HOS-093847 · has-pregnancy-information · PDF-Seite 15

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.

HOS-093841 · has-pregnancy-information · PDF-Seite 5

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.

HOS-093845 · has-warning-information · PDF-Seite 13

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). 13

HOS-093839 · has-warning-information · PDF-Seite 3

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). 3