4.1. Therapeutic indications

Fesoterodine fumarate 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.

4.2. Posology and method of administration

Posology

Adults (including elderly)

The recommended starting dose is 4 mg once daily. Based upon individual response, the dose may be increased to 8 mg once daily. The maximum daily dose is 8 mg.

Full treatment effect was observed between 2 and 8 weeks. Hence, it is recommended to re-evaluate the efficacy for the individual patient after 8 weeks of treatment.

In subjects with normal renal and hepatic function receiving concomitant administration of potent CYP3A4 inhibitors, the maximum daily dose of Fesoterodine fumarate should be 4 mg once daily (see section 4.5).

Special population

Renal and hepatic impairment

The following table provides the daily dosing recommendations for subjects with renal or hepatic impairment in the absence and presence of moderate and potent CYP3A4 inhibitors (see sections 4.3, 4.4, 4.5 and 5.2).

Moderate (3) or potent (4) CYP3A4 inhibitors

None

Moderate

Potent

Renal impairment (1)

Mild

4→8 mg (2)

4 mg

Should be avoided

Moderate

4→8 mg (2)

4 mg

Contraindicated

Severe

4 mg

Should be avoided

Contraindicated

Hepatic impairment

Mild

4→8 mg (2)

4 mg

Should be avoided

Moderate

4 mg

Should be avoided

Contraindicated

(1) Mild GFR = 50-80 ml/min; Moderate GFR = 30-50 ml/min; Severe GFR = < 30 ml/min

(2) Cautious dose increase. See sections 4.4, 4.5 and 5.2

(3) Moderate CYP3A4 inhibitors. See section 4.5

(4) Potent CYP3A4 inhibitors. See sections 4.3, 4.4 and 4.5

Fesoterodine fumarate is contraindicated in subjects with severe hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of fesoteradine in children below 18 years of age have not yet been established. No data are available.

Method of administration

Oral Use.

Tablets are to be taken once daily with liquid and swallowed whole. Fesoterodine fumarate can be administered with or without food.

4.3. Contraindications

• 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)

• Concomitant use of potent CYP3A4 inhibitors in subjects with moderate to severe hepatic or renal impairment

• Severe ulcerative colitis

• Toxic megacolon

4.4. Special warnings and precautions for use

Fesoterodine 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. 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

Fesoterodine should be used with caution in patients with risk for QT prolongation (e.g., hypokalaemia, bradycardia and concomitant administration of medicines known to prolong QT interval) and relevant pre-existing cardiac diseases (e.g. myocardial ischaemia, arrhythmia, congestive heart failure), (see section 4.8). This especially holds true when taking potent CYP3A4 inhibitors (see sections 4.2, 4.5 and 5.1).

Excipients

Fesoterodine fumarate prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

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 2.3fold 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, phenobarbital, phenytoin, St John's Wort) is not recommended (see section 4.4).

CYP2D6 inhibitors

The interaction with CYP2D6 inhibitors was not tested clinically. Mean Cmax and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolisers as compared to extensive metabolisers. Co-administration of a potent CYP2D6 inhibitor may result in increased exposure and adverse events. A dose reduction to 4 mg may be needed (see section 4.4).

Oral contraceptives

Fesoterodine does not impair the suppression of ovulation by oral hormonal contraception. In the presence of fesoterodine there are no changes in the plasma concentrations of combined oral contraceptives containing ethinylestradiol and levonorgestrel.

Warfarin

A clinical study in healthy volunteers has shown that fesoterodine 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity of a single dose of warfarin.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

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. Fesoterodine 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 fesoterodine.

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 childbearing potential should be made aware of the lack of human fertility data, and fesoterodine should only be given after consideration of individual risks and benefits.

4.7. Effects on ability to drive and use machines

Fesoterodine has minor influence on the ability to drive and use machines.

Caution should be exercised when driving or using machines due to possible occurrence of side effects such as blurred vision, dizziness, and somnolence (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety of fesoterodine was evaluated in placebo-controlled clinical studies in a total of 2,859 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.

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 infestations

Urinary tract infection

Psychiatric disorders

Insomnia

Confusional state

Nervous system disorders

Dizziness, headache

Dysgeusia, somnolence

Eye disorders

Dry eye

Blurred vision

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Tachycardia, palpitations

Respiratory, thoracic and mediastinal disorders

Dry throat

Pharyngolaryngeal pain, cough, nasal dryness

Gastrointestinal disorders

Dry mouth

Abdominal pain, diarrhoea, dyspepsia, constipation, nausea

Abdominal discomfort, flatulence, gastroesophageal reflux

Hepatobiliary disorders

ALT increased, GGT increased

Skin and subcutaneous tissue disorders

Rash, dry skin, pruritus

Angioedema, urticaria

Renal and urinary disorders

Dysuria

Urinary retention (including feeling of residual urine, micturition disorder), urinary hesitation

General disorders and administration site conditions

Fatigue

Description of selected adverse reactions

In clinical trials of fesoterodine, cases of markedly elevated liver enzymes were reported with the occurrence frequency no different from the placebo group. The relation to fesoterodine treatment is unclear.

Electrocardiograms were obtained from 782 patients treated with 4 mg, 785 treated with 8 mg, 222 treated with 12 mg fesoterodine and 780 with placebo. The heart rate corrected QT interval in fesoterodine treated patients did not differ from that seen in placebo treated patients. The incidence rates of QTc ≥ 500 ms post baseline or QTc increase of ≥ 60 ms is 1.9 %, 1.3 %, 1.4 % and 1.5 %, for fesoterodine 4 mg, 8 mg, 12 mg and placebo, respectively. The clinical relevance of these findings will depend on individual patient risk factors and susceptibilities present (see section 4.4).

Post-marketing cases of urinary retention requiring catheterisation have been described, generally within the first week of treatment with fesoterodine. They have mainly involved elderly (≥ 65 years) male patients with a history consistent with benign prostatic hyperplasia (see section 4.4).

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

4.9. Overdose

Overdose with antimuscarinics, including fesoterodine can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdose, ECG monitoring is recommended; standard supportive measures for managing QT prolongation should be adopted. Fesoterodine has been safely administered in clinical studies at doses up to 28 mg/day.

In the event of fesoterodine overdose, treat with gastric lavage and give activated charcoal. Treat symptoms as follows:

• Severe central anticholinergic effects (e.g., hallucinations, severe excitation): treat with physostigmine

• Convulsions or pronounced excitation: treat with benzodiazepines

• Respiratory insufficiency: treat with artificial respiration

• Tachycardia: treat with beta-blockers

• Urinary retention: treat with catheterisation

• Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room