- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal category
Excipients with known effect:Each 4 mg prolonged-release tablet contains 0.525 mg of soya lecithin and 91.125 mg of lactose.Each 8 mg prolonged-release tablet contains 0.525 mg of soya lecithin and 58.125 mg of lactose.For the full list of excipients, see section 6.1.
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 TOVIAZ should be 4 mg once daily (see section 4.5).
Renal and hepatic impairmentThe 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|
|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|
Paediatric populationThe safety and efficacy of TOVIAZ in children below 18 years of age have not yet been established. No data are available.
Method of administrationTablets are to be taken once daily with liquid and swallowed whole. TOVIAZ can be administered with or without food.
Dose increasesIn 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.
AngioedemaAngioedema 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 inducersThe 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 prolongationTOVIAZ 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).
LactoseTOVIAZ prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Pharmacological interactionsCaution 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 interactionsIn 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.
Potent CYP3A4 inhibitorsFollowing 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), saquinovir and telithromycin (see sections 4.2 and 4.4)).
Moderate CYP3A4 inhibitorsFollowing 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 inhibitorsThe 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 inducersFollowing 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 inhibitorsThe 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 contraceptivesFesoterodine 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.
WarfarinA 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.
PregnancyThere are no adequate data from the use of fesoterodine in pregnant women. Reproductive toxicity studies with fesoterodine in animals show minor embryotoxicity (see section 5.3). The potential risk for humans is unknown. TOVIAZ is not recommended during pregnancy.
Breast-feedingIt is not known whether fesoterodine is excreted into human milk; therefore, breast-feeding is not recommended during treatment with TOVIAZ.
FertilityNo clinical trials have been conducted to assess the effect of fesoterodine on human fertility. Fesoterodine fumarate had no effect on male or female fertility in mice or any effects on reproductive function, or early embryonic development of the fetus in mice (for details see section 5.3). Women of child bearing potential should be made aware of the lack of fertility data, and TOVIAZ should only be given after consideration of individual risks and benefits.
Summary of the safety profileThe 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 reactionsThe 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 reactionsIn 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).
Mechanism of actionFesoterodine is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolysed by non-specific plasma esterases to the 5-hydroxymethyl derivative, its primary active metabolite, which is the main active pharmacological principle of fesoterodine.
Clinical efficacy and safetyThe efficacy of fixed doses of fesoterodine 4 mg and 8 mg was evaluated in two Phase 3 randomised, double-blind, placebo-controlled, 12-week studies. Female (79%) and male (21%) patients with a mean age of 58 years (range 19-91 years) were included. A total of 33% of patients were ≥65 years of age and 11% were ≥75 years of age.Fesoterodine treated patients had statistically significant mean reductions in the number of micturitions per 24 hours and in the number of urge incontinence episodes per 24 hours at the end of treatment compared to placebo. Likewise, the response rate (% of patients reporting that their condition has been greatly improved or improved using a 4-point Treatment Benefit Scale) was significantly greater with fesoterodine compared to placebo. Furthermore, fesoterodine improved the mean change in the voided volume per micturition, and the mean change in the number of continent days per week (see Table 1 below).
Table 1: Mean changes from Baseline to end of treatment for primary and selected secondary endpoints
|Study 1||Study 2|
|Parameter||Placebo||Fesoterodine4 mg||Fesoterodine 8 mg||Active comparator||Placebo||Fesoterodine 4 mg||Fesoterodine 8 mg|
|Number of micturitions per 24 hours#|
|Change from baseline||-1.02||-1.74||-1.94||-1.69||-1.02||-1.86||-1.94|
|Responder rate (treatment response)#|
|Number of urge incontinence episodes per 24 hours|
|Change from baseline||-1.20||-2.06||-2.27||-1.83||-1.00||-1.77||-2.42|
|Number of continent days per week|
|Change from baseline||2.1||2.8||3.4||2.5||1.4||2.4||2.8|
|Voided volume per micturition (ml)|
|Change from baseline||10||27||33||24||8||17||33|
Cardiac electrophysiologyThe effect of fesoterodine 4 mg and 8 mg on the QT interval was thoroughly evaluated in a double-blind, randomised, placebo- and positive-controlled (moxifloxacin 400 mg) parallel group study with once-daily treatment over a period of 3 days in 261 male and female subjects aged 45 to 65 years. Change from baseline in QTc based on the Fridericia correction method did not show any differences between the active treatment and placebo group.
AbsorptionAfter oral administration, due to rapid and extensive hydrolysis by non-specific plasma esterases, fesoterodine was not detected in plasma. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. Therapeutic plasma levels are achieved after the first administration of fesoterodine. No accumulation occurs after multiple-dose administration.
DistributionPlasma protein binding of the active metabolite is low with approximately 50% bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 l.
BiotransformationAfter oral administration, fesoterodine is rapidly and extensively hydrolysed to its active metabolite. The active metabolite is further metabolised in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolite with involvement of CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine. 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.
EliminationHepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in faeces. The terminal half-life of the active metabolite following oral administration is approximately 7 hours and is absorption rate-limited.
Age and genderNo dose adjustment is recommended in these subpopulations. The pharmacokinetics of fesoterodine are not significantly influenced by age and gender.
Paediatric populationThe pharmacokinetics of fesoterodine have not been evaluated in paediatric patients.
Renal impairmentIn patients with mild or moderate renal impairment (GFR 30 80 ml/min), Cmax and AUC of the active metabolite increased up to 1.5 and 1.8-fold, respectively, as compared to healthy subjects. In patients with severe renal impairment (GFR < 30 ml/min), Cmax and AUC are increased 2.0 and 2.3-fold, respectively.
Hepatic impairmentIn patients with moderate hepatic impairment (Child Pugh B), Cmax and AUC of the active metabolite increased 1.4 and 2.1-fold, respectively, as compared to healthy subjects. Pharmacokinetics of fesoterodine in patients with severe hepatic impairment have not been studied.
Tablet coreXylitolLactose monohydrateMicrocrystalline celluloseHypromelloseGlycerol dibehenateTalc
Film-coatingPolyvinyl alcoholTitanium dioxide (E171)Macrogol (3350)TalcSoya lecithinIndigo carmine aluminium lake (E132)
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