Fesoterodine

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). This especially holds true when taking potent CYP3A4 inhibitors.

The interaction with CYP2D6 inhibitors was not tested clinically. Mean C_max 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.

Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, C_max 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.

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.

¹ Mild GFR = 50-80 ml/min; Moderate GFR = 30-50 ml/min; Severe GFR = <30 ml/min
² Cautious dose increase
³ Moderate CYP3A4 inhibitors
⁴ Potent CYP3A4 inhibitors

In subjects with normal renal and hepatic function receiving concomitant administration of potent CYP3A4 inhibitors, the maximum daily dose of fesoterodine should be 4 mg once daily.

Following inhibition of CYP3A4 by co-administration of ketoconazole 200 mg twice daily, C_max 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.

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)
• 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

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. The potential risk for humans is unknown. Fesoterodine is not recommended during pregnancy.

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. Women of child bearing 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.

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.

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.

Tabulated list of adverse reactions

The table below gives the frequency of treatment emergent adverse reactions from placebocontrolled 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.

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.

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.