Toviaz

Toviaz

fesoterodine

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Fesoterodine fumarate.
Description
4 mg: Each tablet contains fesoterodine fumarate equivalent to 3.1 mg fesoterodine.
8 mg: Each tablet contains fesoterodine fumarate equivalent to 6.2 mg fesoterodine.
Excipients/Inactive Ingredients: Tablet Core: Xylitol, Lactose monohydrate, Microcrystalline cellulose, Hypromellose, Glycerol dibehenate, Talc.
Film-Coating: Poly(vinyl alcohol), Titanium dioxide (E171), Macrogol (3350), Talc, Soya lecithin, Indigo carmine aluminium lake (E132).
Action
Pharmacology: Pharmacodynamics: Toviaz is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolyzed by non-specific esterases to the 5-hydroxymethyl derivative, its primary active metabolite, which is the active pharmacological principle of Toviaz.
The efficacy of fixed doses of Toviaz 4 mg and 8 mg was evaluated in two Phase 3 randomized, 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.
Toviaz 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 with placebo treated patients. 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 Toviaz compared with placebo. Furthermore, Toviaz 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).

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Cardiac Electrophysiology: The effect of Toviaz 4 mg and 28 mg on the QT interval was thoroughly evaluated in a double-blind, randomized, 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 Toviaz 4 mg and 28 mg treatment and the placebo group.
Pharmacokinetics: Absorption: After oral administration, Toviaz was well-absorbed and was not detected in plasma due to rapid and extensive hydrolysis by non-specific esterases. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of Toviaz 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 Toviaz. No accumulation occurs after multiple-dose administration.
Distribution: Plasma 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.
Metabolism: After oral administration, Toviaz is rapidly and extensively hydrolysed to its active metabolite. The active metabolite is further metabolized 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 Toviaz. Mean Cmax and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolizers as compared with extensive metabolizers.
Elimination: Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of Toviaz, 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 feces. The terminal half-life of the active metabolite following oral administration is approximately 7 hours.
Pharmacokinetics in special patient groups: Age and Gender: The pharmacokinetics of Toviaz is not significantly influenced by age and gender. No dose adjustment is recommended for the elderly.
Pediatric Patients: The pharmacokinetics of Toviaz has not been evaluated in pediatric patients.
Renal Impairment: In patients with mild or moderate renal impairment (CrCl 30-80 mL/min), Cmax and AUC of the active metabolite increased up to 1.5 and 1.8-fold, respectively, as compared with healthy subjects. In patients with severe renal impairment (CrCl <30 mL/min), Cmax and AUC are increased 2.0 and 2.3-fold, respectively, as compared with healthy subjects (see Dosage & Administration and Precautions).
Hepatic Impairment: In 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 with healthy subjects. Pharmacokinetics of Toviaz in patients with severe hepatic impairment have not been studied (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: In non-clinical safety pharmacology, general toxicity, genotoxicity and carcinogenicity studies no clinically relevant effects have been observed, except those related to the pharmacological effect of the active substance. Fesoterodine had no effect on male reproductive function or fertility in mice at doses up to 45 mg/kg/day. At doses of 45 mg/kg/day, resulting in exposures approximately 5 to 19 times those at the MRHD, a lower number of corpora lutea, implantation sites and viable fetuses was observed in female mice administered fesoterodine for 2 weeks prior to mating and continuing through day 7 of gestation. Reproduction studies have shown minor embryotoxicity (increased number of resorptions, pre-implantation and post-implantation losses). The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day.
Indications/Uses
Toviaz is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
Dosage/Direction for Use
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.
Tablets are to be taken once daily with liquid and swallowed whole. Toviaz can be administered with or without food and should not be chewed, divided, or crushed.
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 Interactions).
Special Populations: 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 Contraindications, Precautions, Interactions and Pharmacology: Pharmacokinetics under Actions). (See Table 2.)

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Toviaz is contraindicated in subjects with severe hepatic impairment (see Contraindications).
Paediatric population: The safety and efficacy of Toviaz in children below 18 years of age have not yet been established. No data are available.
Overdosage
Overdosage with Toviaz can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.
Contraindications
Hypersensitivity to the active substance or to peanut or soya or to any of the excipients listed in Description,
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.
Special Precautions
Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with Toviaz. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, Toviaz should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.
Bladder Outlet Obstruction: Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention (see Contraindications).
Decreased Gastrointestinal Motility: Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.
Controlled Narrow-Angle Glaucoma: Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks (see Contraindications).
Central Nervous System Effects: Toviaz is associated with anticholinergic central nervous sytem (CNS) effects (see Adverse Reactions). A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
Hepatic Impairment: Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population (see Contraindications, Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Myasthenia Gravis: Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
Renal Impairment: Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Autonomic Neuropathy: Toviaz should be used with caution in patients with autonomic neuropathy.
Gastrointestinal Obstructive Disorders: Toviaz should be used with caution in patients with gastrointestinal obstructive disorders (e.g., pyloric stenosis).
Gastro-oesophageal Reflux: Toviaz should be used with caution in patients with gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as oral bisphosphanates) that can cause or exacerbate oesophagitis.
Concomitant Administration with CYP3A4 Inhibitors: Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).
No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil and grapefruit juice). While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors [see Interactions and Dosage & Administration].
Concomitant Use of Potent CYP3A4 Inducers: Concomitant use of Toviaz with a potent CYP3A4 inducer (i.e., carbamazepine, rifampicin, phenobarbital, phenytoin, St John's wort) is not recommended.
Lactose: Toviaz 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 medicine.
Concomitant Administration in Factors Contributing to Increased Exposure to Active Metabolite: Caution should be exercised when prescribing or uptitrating Toviaz to patients in whom an increased exposure to the active metabolite is expected.
Hepatic impairment [see Dosage & Administration and Contraindications].
Renal impairment [see Dosage & Administration and Contraindications].
Concomitant administration of potent or moderate CYP3A4 inhibitors [see Dosage & Administration and Interactions].
Concomitant administration of a potent CYP2D6 inhibitor [see Interactions and Pharmacology: Pharmacokinetics under Actions].
In patients with a combination of these factors, additional exposure increases are expected. Dose dependent antimuscarinic side effects 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.
Others: As with all medicinal products indicated for the treatment of overactive bladder, 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 Toviaz. If urinary tract infection is present, an appropriate medical approach should be taken/antibacterial therapy should be started.
As with other antimuscarinics, Toviaz 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 [see Dosage & Administration, Interactions and Pharmacology: Pharmacodynamics under Actions].
Effects on Activities Requiring Concentration and Performance: The ability to drive and use machinery may be negatively affected. Patients should be advised to exercise caution [see Adverse Reactions].
Use In Pregnancy & Lactation
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 Maximum Recommended Human Dose (MRHD) show an effect on female fertility, however, the clinical implications of these animal findings are not known (see Pharmacology: Toxicology: Preclinical Safety Data).
Pregnancy: There are no adequate data from the use of Toviaz in pregnant women. The potential risk for humans is unknown. Therefore, Toviaz should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. 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 MRHD, respectively, based on AUC (see Pharmacology: Toxicology: Preclinical Safety Data).
Lactation: It is not known whether Toviaz is excreted into human milk; therefore, breast-feeding is not recommended during treatment with Toviaz.
Adverse Reactions
The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder of which 2288 were treated with Toviaz. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.
A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these 2 studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.
In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.
The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.
The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.
The following table lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks. (See Table 3).

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Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator, and reported more than once during the open-label treatment period of up to 3 years included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).
The following events have been reported in association with Toviaz use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and subcutaneous tissue disorders: Urticaria, pruritus.
Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of Toviaz in their causation cannot be reliably determined.
Drug Interactions
Antimuscarinic Drugs: Co-administration of Toviaz with other antimuscarinic agents that produce dry mouth, constipation, urinary retention, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
In vitro studies: Drugs Metabolized by Cytochrome P450: At therapeutic concentrations, the active metabolite of Toviaz does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, 2C19 or 3A4 in vitro.
In vivo studies: CYP3A4 Inhibitors: Following blockade of CYP3A4 by co-administration of the potent CYP3A4 inhibitor ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite of Toviaz increased 2.0- and 2.3-fold, respectively, after oral administration of Toviaz 8 mg to CYP2D6 extensive metabolizers. In CYP2D6 poor metabolizers, Cmax and AUC of the active metabolite of Toviaz increased 2.1- and 2.5-fold, respectively, following co-administration of ketoconazole 200 mg twice a day for 5 days. In a separate study co-administering Toviaz with ketoconazole 200 mg once a day for 5 days, the Cmax and AUC values of the active metabolite of Toviaz were increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers.
Therefore, doses of Toviaz greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, miconazole and clarithromycin (see Precautions and Dosage & Administration).
There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of Toviaz. Following blockade of CYP3A4 by co-administration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, Cmax and AUC of the active metabolite of Toviaz 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).
The effects of weak or moderate CYP3A4 inhibitors were not examined; it is not expected to be in excess of the effect of moderate inhibitors.
CYP3A4 Inducers: Following induction of CYP3A4 by rifampicin 600 mg once a day, Cmax and AUC of the active metabolite of Toviaz decreased by approximately 70% and 75%, respectively, after oral administration of Toviaz 8 mg. The terminal half-life of the active metabolite was not changed.
Induction of CYP3A4 may lead to reduced plasma levels. No dosing adjustments are recommended in the presence of CYP3A4 inducers.
CYP2D6 Inhibitors: The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, Cmax and AUC of the active metabolite are increased 1.7 and 2-fold, respectively. No dosing adjustments are recommended in the presence of CYP2D6 inhibitors.
Oral Contraceptives: In the presence of Toviaz, there are no changes in the plasma concentrations of combined oral contraceptives containing ethinyl estradiol and levonorgestrel.
Warfarin: A clinical study has shown that Toviaz 8 mg once daily has no significant effect on the pharmacokinetics or the anticoagulant activity of warfarin.
Drug-Laboratory Test Interactions: Interactions between Toviaz and laboratory tests have not been studied.
Caution For Usage
Special Precautions for Disposal and Other Handling: Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: None.
Storage
Bottles: Do not store above 30oC.
Blister: Do not store above 25oC. Store in the original package to protect from moisture.
ATC Classification
G04BD11 - fesoterodine ; Belongs to the class of urinary antispasmodics.
Presentation/Packing
PR tab 4 mg (light blue, oval, biconvex, film-coated and engraved with "FS" on one side) x 28's. 8 mg (blue, oval, biconvex, film-coated and engraved with "FT" on one side) x 28's.
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