Toviaz Information
Toviaz () Indications And Usage
Toviaz () is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
Toviaz () Dosage And Administration
The recommended starting dose of Toviaz () is 4 mg once daily. Based upon individual response and tolerability, the dose may be increased to 8 mg once daily.
The daily dose of Toviaz () should exceed 4 mg in the following populations:
Toviaz () is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [].
Toviaz () should be taken with liquid and swallowed whole. Toviaz () can be administered with or without food, and should not be chewed, divided, or crushed.
Toviaz () Dosage Forms And Strengths
Toviaz () (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated, and engraved with "FS" on one side.
Toviaz () (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-coated, and engraved with "FT" on one side.
Toviaz () Contraindications
Toviaz () is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Toviaz () is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to tolterodine tartrate tablets or tolterodine tartrate extended-release capsules [ ].
Toviaz () Warnings And Precautions
Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. 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, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.
Doses of Toviaz () greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin).
In patients taking weak or moderate CYP3A4 inhibitors (e.g., erythromycin), careful assessment of tolerability at the 4 mg daily dose is advised prior to increasing the daily dose to 8 mg. While this specific interaction potential was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors [].
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 fesoterodine. 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 two 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.
Table 1 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.
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 fesoterodine use in worldwide post-marketing experience: Blurred vision; Palpitations; Hypersensitivity reactions, including angioedema with airway obstruction, face edema; Urticaria, pruritus.
Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.
Toviaz () Drug Interactions
Doses of Toviaz () greater than 4 mg are not recommended in patients taking potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin. Coadministration of the potent CYP3A4 inhibitor ketoconazole with fesoterodine led to approximately a doubling of the maximum concentration (C) and area under the concentration versus time curve (AUC) of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. Compared with CYP2D6 extensive metabolizers not taking ketoconazole, further increases in the exposure to 5-HMT were observed in subjects who were CYP2D6 poor metabolizers taking ketoconazole [].
The effects of weak or moderate CYP3A4 inhibitors were not examined.
The interaction with CYP2D6 inhibitors was not tested clinically. In poor metabolizers for CYP2D6, representing a maximum CYP2D6 inhibition, C 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.
In vitro
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Toviaz () Use In Specific Populations
The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
The safety and effectiveness of Toviaz () in pediatric patients have not been established.
No dose adjustment is recommended for the elderly. The pharmacokinetics of fesoterodine are not significantly influenced by age.
Of 1567 patients who received Toviaz () 4 mg/day or 8 mg/day in the Phase 2 and 3, placebo-controlled, efficacy and safety studies, 515 (33%) were 65 years of age or older, and 140 (9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies; however, the incidence of antimuscarinic adverse events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (at 8 mg only) and urinary tract infection, was higher in patients 75 years of age and older as compared to younger patients [].
Toviaz () 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.
Toviaz () Description
Toviaz () contains fesoterodine fumarate and is an extended-release tablet. Fesoterodine is rapidly de-esterified to its active metabolite (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxymethyl tolterodine, which is a muscarinic receptor antagonist.
Chemically, fesoterodine fumarate is designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is CHNO and its molecular weight is 527.66. The structural formula is:
The asterisk (*) indicates the chiral carbon.
Fesoterodine fumarate is a white to off-white powder, which is freely soluble in water. Each Toviaz () extended-release tablet contains either 4 mg or 8 mg of fesoterodine fumarate and the following inactive ingredients: glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
Toviaz () Clinical Pharmacology
Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine and is also one of the active moieties of tolterodine tartrate tablets and tolterodine tartrate extended-release capsules.
Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.
Toviaz () Clinical Studies
Toviaz () extended-release tablets were evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥ 6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period. Patients were randomized to a fixed dose of Toviaz () 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received Toviaz () 4 mg/day, and 566 patients received Toviaz () 8 mg/day. The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19–91 years).
The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.
Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of Toviaz () are reported in Table 3.
Figures 1–4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies.
A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting Toviaz () therapy.
Toviaz () How Supplied/storage And Handling
Toviaz () (fesoterodine fumarate) extended-release tablets 4 mg are light blue, oval, biconvex, film-coated, and engraved with "FS" on one side. They are supplied as follows:
Toviaz () (fesoterodine fumarate) extended-release tablets 8 mg are blue, oval, biconvex, film-coated, and engraved with "FT" on one side. They are supplied as follows:
Toviaz () Patient Counseling Information
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Patients should be informed that fesoterodine may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue fesoterodine therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficult breathing.
Patients should be informed that Toviaz () , like other antimuscarinic agents, may produce clinically significant adverse effects related to antimuscarinic pharmacological activity including constipation and urinary retention. Toviaz () , like other antimuscarinics, may be associated with blurred vision, therefore, patients should be advised to exercise caution until the drug's effects on the patient have been determined. Heat prostration (due to decreased sweating) can occur when Toviaz () , like other antimuscarinic drugs, is used in a hot environment.
Patients should also be informed that alcohol may enhance the drowsiness caused by Toviaz () , like other anticholinergic agents. Patients should read the patient leaflet entitled "Patient Information Toviaz () " before starting therapy with Toviaz () .
Manufactured by:Aesica Pharmaceuticals GmbHGalileistraße 608056 Zwickau, Germany
LAB-0381-9.0June 2011
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