Toviaz · 4.8 Undesirable effects · 1

HOS-094568 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The safety of fesoterodine was evaluated in placebo-controlled clinical studies in a total of 2859 patients with overactive bladder, of which 780 received placebo. Due to the pharmacological properties of fesoterodine, treatment may cause mild to moderate antimuscarinic effects like dry mouth, dry eye, dyspepsia and constipation. Urinary retention may occur uncommonly. Dry mouth, the only very common adverse reactions, occurred with a frequency of 28.8% in the fesoterodine group compared to 8.5% in the placebo group. The majority of adverse reactions occurred during the first month of treatment with the exception of cases classified as urinary retention or post void residual urine greater than 200 ml, which could occur after long term treatment and was more common in male than female subjects. 6 Tabulated list of adverse reactions The table below gives the frequency of treatment emergent adverse reactions from placebo-controlled clinical trials and from post-marketing experience. The adverse reactions are reported in this table with the following frequency 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. System organ class Very common Common Uncommon Rare Infections and Urinary tract infestations infection Psychiatric disorders Insomnia Confusional state Nervous system Dizziness; Dysgeusia; disorders Headache Somnolence Eye disorders Dry eye Blurred vision Ear and labyrinth Vertigo disorders Cardiac disorders Tachycardia; Palpitations Respiratory, thoracic Dry throat Pharyngolaryng and mediastinal eal pain; Cough; disorders

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HOS-094564 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substance or to peanut or soya 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) • Concomitant use of potent CYP3A4 inhibitors in subjects with moderate to severe hepatic or renal impairment • Severe ulcerative colitis • Toxic megacolon. 3

HOS-094563 · has-indication-information · PDF-Seite 2

TOVIAZ is indicated in adults for treatment of the symptoms (increased urinary frequency and/or urgency and/or urgency incontinence) that may occur with overactive bladder syndrome.

HOS-094566 · has-interaction-information · PDF-Seite 5

Pharmacological interactions Caution should be exercised in coadministration of fesoterodine with other antimuscarinics and medicinal products with anticholinergic properties (e.g. amantadine, tri-cyclic antidepressants, certain neuroleptics) as this may lead to more pronounced therapeutic- and side-effects (e.g. constipation, dry mouth, drowsiness, urinary retention). Fesoterodine may reduce the effect of medicinal products that stimulate the motility of the gastro-intestinal tract, such as metoclopramide. Pharmacokinetic interactions In vitro data demonstrate that the active metabolite of fesoterodine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant plasma concentrations. Thus fesoterodine is unlikely to alter the clearance of medicinal products that are metabolised by these enzymes. CYP3A4 inhibitors Potent CYP3A4 inhibitors Following inhibition of CYP3A4 by co-administration of ketoconazole 200 mg twice daily, Cmax and AUC of the active metabolite of fesoterodine increased 2.0 and 2.3-fold in CYP2D6 extensive metabolisers and 2.1 and 2.5-fold in CYP2D6 poor metabolisers, respectively. Therefore, the maximum dose of fesoterodine should be restricted to 4 mg when used concomitantly with potent CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir (and all ritonavir boosted PI-regimens), saquinavir and telithromycin (see sections 4.2 and 4.4). Moderate CYP3A4 inhibitors Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, Cmax and AUC of the active metabolite of fesoterodine increased approximately 19% and 27%, respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). Weak CYP3A4 inhibitors The effect of weak CYP3A4 inhibitors (e.g. cimetidine), was not examined; it is not expected to be in excess of the effect of moderate inhibitor. CYP3A4 inducers Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, Cmax and AUC of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine 8 mg. Induction of CYP3A4 may lead to subtherapeutic plasma levels. Concomitant use with CYP3A4 inducers (e.g. carbamazepine, rifampicin,

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HOS-094567 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no adequate data from the use of fesoterodine in pregnant women. Reproductive toxicity studies with fesoterodine in animals show minor embryotoxicity. In animal reproduction studies, oral administration of fesoterodine to pregnant mice and rabbits during organogenesis resulted in fetotoxicity at maternal exposures that were 6 and 3 times the maximum recommended human dose (MRHD), respectively, based on AUC (see section 5.3). The potential risk for humans is unknown. TOVIAZ is not recommended during pregnancy. Breast-feeding It is unknown whether fesoterodine/metabolites are excreted into human milk; therefore, breast-feeding is not recommended during treatment with TOVIAZ. Fertility No clinical trials have been conducted to assess the effect of fesoterodine on human fertility. Findings in mice at exposures approximately 5 to 19 times those at the MRHD show an effect on female fertility, however, the clinical implications of these animal findings are not known (see section 5.3). Women of child bearing potential should be made aware of the lack of human fertility data, and TOVIAZ should only be given after consideration of individual risks and benefits.

HOS-094565 · has-warning-information · PDF-Seite 4

TOVIAZ should be used with caution in patients with: - Clinically significant bladder outflow obstruction at risk of urinary retention (e.g. clinically significant prostate enlargement due to benign prostatic hyperplasia, see section 4.3) - Gastrointestinal obstructive disorders (e.g. pyloric stenosis) - Gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as oral bisphosphonates) that can cause or exacerbate oesophagitis - Decreased gastrointestinal motility - Autonomic neuropathy - Controlled narrow-angle glaucoma Caution should be exercised when prescribing or uptitrating fesoterodine to patients in whom an increased exposure to the active metabolite (see section 5.1) is expected: - Hepatic impairment (see sections 4.2, 4.3 and 5.2) - Renal impairment (see sections 4.2, 4.3 and 5.2) - Concomitant administration of potent or moderate CYP3A4 inhibitors (see sections 4.2 and 4.5) - Concomitant administration of a potent CYP2D6 inhibitor (see sections 4.5 and 5.2). Dose increases In patients with a combination of these factors, additional exposure increases are expected. Dose dependent antimuscarinic adverse reactions are likely to occur. In populations where the dose may be increased to 8 mg once daily, the dose increase should be preceded by an evaluation of the individual response and tolerability. Organic causes must be excluded before any treatment with antimuscarinics is considered. Safety and efficacy have not yet been established in patients with a neurogenic cause for detrusor overactivity. Other causes of frequent urination (treatment of heart failure or renal disease) should be assessed before treatment with fesoterodine. If urinary tract infection is present, an appropriate medical approach should be taken/antibacterial therapy should be started. Angioedema Angioedema has been reported with fesoterodine and has occurred after the first dose in some cases. Some cases may be associated with upper airway swelling and may be life-threatening. If angioedema occurs, fesoterodine should be discontinued and appropriate therapy should be promptly provided. Potent CYP3A4 inducers The concomitant use of fesoterodine with a potent CYP3A4 inducer (i.e. carbamazepine, rifampicin, phenobarbital, phenytoin, St John’s Wort) is not recommended (see section 4.5). QT prolongation TOVIAZ should be used with caution in patients with risk for QT prolongation (e.g. hypokalaemi

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