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What other information should I know?
Keep all appointments with your doctor.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Toviaz is a prescription medication used to treat symptoms of overactive bladder in adults. Toviaz belongs to a group of drugs called antimuscarinics, which help the bladder muscles to relax.
This medication comes in tablet form and is taken once a day, with or without food. It should be taken with liquid and swallowed whole.
Common side effects include dry mouth and constipation. Toviaz can cause blurred vision, dizziness, and drowsiness. Do not drive or operate machinery until you know how it will affect you.
Pfizer Laboratories Div Pfizer Inc.
Do not take Toviaz if you:
- Are not able to empty your bladder (urinary retention).
- Have delayed or slow emptying of your stomach (gastric retention).
- Have an eye problem called "uncontrolled narrow-angle glaucoma".
- Are allergic to Toviaz or any of its ingredients.
- Are allergic to Detrol or Detrol LA, which contains tolterodine.
- Do not drive, operate machinery, or do other dangerous activities until you know how Toviaz affects you. Blurred vision, dizziness, and drowsiness are possible side effects of medicines such as Toviaz.
- Use caution in hot environments. Decreased sweating and severe heat illness can occur when medicines such as Toviaz are used in a hot environment.
- Drinking alcohol while taking medicines such as Toviaz may cause increased drowsiness.
What is fesoterodine?
Fesoterodine reduces spasms of the bladder muscles.
Fesoterodine is used to treat overactive bladder with symptoms of urinary frequency, urgency, and incontinence.
Fesoterodine may also be used for purposes not listed in this medication guide.
Interactions for Toviaz
Rapidly metabolized to active metabolite, 5-hydroxymethyl tolterodine (5-HMT), by nonspecific esterases; active metabolite is further metabolized, principally via CYP2D6 and CYP3A4.1 2 10 5-HMT does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4.1
Drugs Affecting Hepatic Microsomal Enzymes
Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma 5-HMT concentrations).1 Do not exceed 4 mg daily when used concomitantly with potent CYP3A4 inhibitors.1
Weak or moderate inhibitors of CYP3A4: Effects on 5-HMT pharmacokinetics not studied; pharmacokinetic interaction is expected, albeit less than that observed with potent CYP3A4 inhibitors.1 Carefully assess tolerability at 4-mg daily dosage of fesoterodine fumarate prior to increasing dosage to 8 mg daily in patients concomitantly receiving weak or moderate CYP3A4 inhibitors.1
Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma 5-HMT concentrations); no dosage adjustments are recommended.1
Inhibitors of CYP2D6: Effects on 5-HMT pharmacokinetics not tested clinically.1 However, increased plasma 5-HMT concentrations observed in subjects with poor metabolizer phenotype for CYP2D6; no dosage adjustments recommended when CYP2D6 inhibitors are used concomitantly.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP1isoenzymeA2 s, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4: Pharmacokinetic interactions unlikely.1
Orally Administered Drugs
Potential pharmacokinetic interaction (altered absorption because of anticholinergic effects on GI motility).1 (See Decreased GI Motility under Cautions.)
Potential increased frequency and/or severity of adverse anticholinergic effects (e.g., dry mouth, constipation, urinary retention) 1
Azole antifungals (itraconazole, ketoconazole)
Possible increased plasma 5-HMT concentrations1
Ketoconazole: Increased plasma 5-HMT concentrations1
Do not exceed a fesoterodine fumarate dosage of 4 mg daily when used concomitantly1
Possible increased plasma 5-HMT concentrations1
Do not exceed a fesoterodine fumarate dosage of 4 mg daily when used concomitantly1
Hormonal contraceptives, oral (ethinyl estradiol-levonorgestrel)
Pharmacokinetic interaction unlikely1
Effects on 5-HMT pharmacokinetics not studied; pharmacokinetic interaction is expected1
Carefully assess tolerability at fesoterodine fumarate 4-mg daily dosage prior to increasing dosage to 8 mg daily1
Decreased plasma 5-HMT concentrations and AUC1
No fesoterodine fumarate dosage adjustments recommended1
Advice to Patients
Importance of reading manufacturer’s patient information before beginning fesoterodine therapy.1 5
Risk of dry mouth, constipation, dry eyes, urinary retention, decreased sweating and heat prostration (when used in a hot environment).1 5
May cause blurred vision and drowsiness.1 5 Use caution when driving or performing dangerous activities until effects are known.5 Alcohol may enhance the drowsiness caused by fesoterodine.1 5
Importance of taking fesoterodine with liquids and swallowing the extended-release tablet whole; do not chew, divide, or crush.1 5
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 5
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 5
Importance of advising patients of other important precautionary information.1 (See Cautions.)
What are some things I need to know or do while I take Toviaz?
- Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
- Avoid driving and doing other tasks or actions that call for you to be alert or have clear eyesight until you see how Toviaz affects you.
- Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
- Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
- A very bad reaction called angioedema has happened with this medicine. Sometimes, this may be life-threatening. Signs may include swelling of the hands, face, lips, eyes, tongue, or throat; trouble breathing; trouble swallowing; or unusual hoarseness. Talk with the doctor.
- If you are 75 or older, use Toviaz with care. You could have more side effects.
- Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
- Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
How is this medicine (Toviaz) best taken?
Use Toviaz as ordered by your doctor. Read all information given to you. Follow all instructions closely.
- Take with or without food.
- Swallow whole. Do not chew, break, or crush.
- Take with a full glass of water.
- To gain the most benefit, do not miss doses.
- Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
What do I do if I miss a dose?
- Skip the missed dose and go back to your normal time.
- Do not take more than 1 dose of Toviaz in the same day.
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 C30H41NO7 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
Mechanism of Action
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.
In a urodynamic study involving patients with involuntary detrusor contractions, the effects after the administration of fesoterodine on the volume at first detrusor contraction and bladder capacity were assessed. Administration of fesoterodine increased the volume at first detrusor contraction and bladder capacity in a dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder.
Cardiac Electrophysiology: The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 24-hour period at pre-dose, after the first administration, and after the third administration of study medication. Fesoterodine 28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers, results in an exposure to the active metabolite that is similar to the exposure in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade. Corrected QT intervals (QTc) were calculated using Fridericia's correction and a linear individual correction method. Analyses of 24-hour average QTc, time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin.
Toviaz is associated with an increase in heart rate that correlates with increasing dose. In the study described above, when compared to placebo, the mean increase in heart rate associated with a dose of 4 mg/day and 28 mg/day of fesoterodine was 3 beats/minute and 11 beats/minute, respectively.
In the two, phase 3, placebo-controlled studies in patients with overactive bladder, the mean increase in heart rate compared to placebo was approximately 3–4 beats/minute in the 4 mg/day group and 3–5 beats/minute in the 8 mg/day group.
Absorption: After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be 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. No accumulation occurs after multiple-dose administration.
A summary of pharmacokinetic parameters for the active metabolite after a single dose of Toviaz 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 2.
|Toviaz 4 mg||Toviaz 8 mg|
|Parameter||EM (n=16)||PM (n=8)||EM (n=16)||PM (n=8)|
|EM = extensive CYP2D6 metabolizer, PM = poor CYP2D6 metabolizer, CV = coefficient of variation|
|Cmax = maximum plasma concentration, AUC0–tz = area under the concentration time curve from zero up to the last measurable plasma concentration, tmax = time to reach Cmax, t½ = terminal half-life|
|* Data presented as median (range)|
|Cmax (ng/mL)||1.89 [43%]||3.45 [54%]||3.98 [28%]||6.90 [39%]|
|AUC0–tz (ng*h/mL)||21.2 [38%]||40.5 [31%]||45.3 [32%]||88.7 [36%]|
|tmax (h)*||5 [2–6]||5 [5–6]||5 [3–6]||5 [5–6]|
|t½ (h)||7.31 [27%]||7.31 [30%]||8.59 [41%]||7.66 [21%]|
Effect of Food: There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine. In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the active metabolite of fesoterodine AUC by approximately 19% and Cmax by 18% [see Dosage and Administration (2)].
Distribution: Plasma protein binding of the active metabolite is low (approximately 50%) and is primarily 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, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine.
Variability in CYP2D6 Metabolism: A subset of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6. Cmax and AUC of the active metabolite are increased 1.7- and 2-fold, respectively, in CYP2D6 poor metabolizers, as compared to extensive metabolizers.
Excretion: Hepatic 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 feces.
The terminal half-life of the active metabolite is approximately 4 hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately 7 hours.
Pharmacokinetics in Specific Populations:
Geriatric Patients: Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 young men (mean age 30 years) were 52.0 ± 31.5 h*ng/mL and 4.1 ± 2.1 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by age [see Use in Specific Populations (8.5)].
Pediatric Patients: The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients [see Use in Specific Populations (8.4)].
Gender: Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and Cmax in 12 elderly women (mean age 68 years) were 56.0 ± 28.8 h*ng/mL and 4.6 ± 2.3 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by gender [see Use in Specific Populations (8.8)].
Race: The effects of Caucasian or Black race on the pharmacokinetics of fesoterodine were examined in a study of 12 Caucasian and 12 Black African young male volunteers. Each subject received a single oral dose of 8 mg fesoterodine. The mean (±SD) AUC and Cmax for the active metabolite 5-hydroxymethyl tolterodine in Caucasian males were 73.0 ± 27.8 h*ng/mL and 6.1 ± 2.7 ng/mL, respectively. The mean (±SD) AUC and Cmax in Black males were 65.8 ± 23.2 h*ng/mL and 5.5 ± 1.9 ng/mL, respectively. The pharmacokinetics of fesoterodine were not significantly influenced by race [see Use in Specific Populations (8.9)].
Renal Impairment: In patients with mild or moderate renal impairment (CLCR ranging from 30–80 mL/min), Cmax and AUC of the active metabolite are increased up to 1.5- and 1.8-fold, respectively, as compared to healthy subjects. In patients with severe renal impairment (CLCR < 30 mL/min), Cmax and AUC are increased 2.0- and 2.3-fold, respectively. [see Use in Specific Populations (8.6), Warnings and Precautions (5.7), and Dosage and Administration (2)].
Hepatic Impairment: In patients with moderate (Child-Pugh B) hepatic impairment, Cmax and AUC of the active metabolite are increased 1.4- and 2.1-fold, respectively, as compared to healthy subjects.
Subjects with severe hepatic impairment (Child-Pugh C) have not been studied [see Use in Specific Populations (8.7), Warnings and Precautions (5.6), and Dosage and Administration (2)].
Drugs Metabolized by Cytochrome P450: At therapeutic concentrations, 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 in vitro [see Drug Interactions (7.5)].
CYP3A4 Inhibitors: Following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg twice a day for 5 days, Cmax and AUC of the active metabolite of fesoterodine 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 fesoterodine increased 2.1- and 2.5-fold, respectively, during coadministration of ketoconazole 200 mg twice a day for 5 days. Cmax and AUC were 4.5- and 5.7-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole. In a separate study coadministering fesoterodine with ketoconazole 200 mg once a day for 5 days, the Cmax and AUC values of the active metabolite of fesoterodine were increased 2.2-fold in CYP2D6 extensive metabolizers and 1.5- and 1.9-fold, respectively, in CYP2D6 poor metabolizers. Cmax and AUC were 3.4- and 4.2-fold higher, respectively, in subjects who were CYP2D6 poor metabolizers and taking ketoconazole compared to subjects who were CYP2D6 extensive metabolizers and not taking ketoconazole.
There is no clinically relevant effect of moderate CYP3A4 inhibitors on the pharmacokinetics of fesoterodine. In a drug-drug interaction study evaluating the coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, a single 8 mg dose of fesoterodine was administered 1 hour following the first dose of fluconazole on day 1 of the study. The average (90% confidence interval) for the increase in Cmax and AUC of the active metabolite of fesoterodine was approximately 19% (11% – 28%) and 27% (18% – 36%) respectively.
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 inhibitors [see Drug Interactions (7.2)], Warnings and Precautions (5.8), and Dosage and Administration (2)].
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 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 [see Drug Interactions (7.3)].
CYP2D6 Inhibitors: The interaction with CYP2D6 inhibitors was not studied. 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. [see Drug Interactions (7.4)].
Oral Contraceptives: Thirty healthy female subjects taking an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel were evaluated in a 2-period crossover study. Each subject was randomized to receive concomitant administration of either placebo or fesoterodine 8 mg once daily on days 1 – 14 of hormone cycle for 2 consecutive cycles. Pharmacokinetics of ethinyl estradiol and levonorgestrel were assessed on day 13 of each cycle. Fesoterodine increased the AUC and Cmax of ethinyl estradiol by 1 – 3% and decreased the AUC and Cmax of levonorgestrel by 11 – 13% [see Drug Interactions (7.6)].
Warfarin: In a cross-over study in 14 healthy male volunteers (18–55 years), a single oral dose of warfarin 25 mg was given either alone or on day 3 of once daily dosing for 9 days with fesoterodine 8 mg. Compared to warfarin alone dosing, the Cmax and AUC of S-warfarin were lower by ~ 4 %, while the Cmax and AUC of R-warfarin were lower by approximately 8 % and 6% for the co-administration, suggesting absence of a significant pharmacokinetic interaction.
There were no statistically significant changes in the measured pharmacodynamic parameters for anti-coagulant activity of warfarin (INRmax, AUCINR), with only a small decrease noted in INRmax of ~ 3 % with the co-administration relative to warfarin alone. INR versus time profiles across individual subjects in the study suggested some differences following co-administration with fesoterodine, although there was no definite trend with regard to the changes noted [see Drug Interactions (7.7)].
What is Toviaz?
Toviaz (fesoterodine) reduces spasms of the bladder muscles.
Toviaz is used to treat overactive bladder with symptoms of urinary frequency, urgency, and incontinence.
Toviaz may also be used for purposes not listed in this medication guide.
What happens if I miss a dose?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
Common side effects of Toviaz include: xerostomia. Other side effects include: constipation. See below for a comprehensive list of adverse effects.