Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
Toviaz is contraindicated in patients with any of
the following:
- known or
suspected hypersensitivity to Toviaz or any of its
ingredients, or to tolterodine tartrate tablets or tolterodine tartrate
extended-release capsules [see
Clinical Pharmacology (12.1)]. Reactions have included angioedema [see Warnings and Precautions (5.1)].
- urinary
retention [see Warnings and
Precautions (5.2)]
- gastric
retention [see Warnings and
Precautions (5.3)]
5
Warnings and Precautions
5.1 Angioedema
Additions and/or
revisions underlined:
1Angiodemia of the face,
lips, tongue, and/or larynx has been reported with Toviaz. In some
cases, angioedema occurred after the first dose; however, cases have been
reported to occur hours after the first dose or after multiple doses.
Angioedema associated with upper airway swelling may be life-threatening.
Toviaz is
contraindicated in patients with a known or suspected hypersensitivity to
Toviaz or any of its ingredients [see
Contraindications (4)]. 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.
Additions and/or
revisions underlined:
5.2 Urinary
Retention in Adult Patients with Bladder Outlet Obstruction
The use of Toviaz, like
other antimuscarinic drugs, in patients with clinically significant bladder
outlet obstruction, including patients with urinary retention, may result in
further urinary retention and kidney injury. The use of Toviaz is not
recommended in patients with clinically significant bladder outlet obstruction,
and is contraindicated in patients with urinary retention [see Contraindications (4) and Adverse
Reactions (6.1)].
Additions and/or
revisions underlined:
5.3 Decreased
Gastrointestinal Motility
Toviaz is
associated with decreased gastric motility. Toviaz is contraindicated in
patients with gastric retention [see
Contraindications (4)]. The use of Toviaz is not recommended in patients with
decreased gastrointestinal motility, such as those with severe constipation.
Additions and/or
revisions underlined:
5.4 Worsening
of Narrow-Angle Glaucoma
Toviaz can worsen
controlled narrow-angle glaucoma. Toviaz is contraindicated in patients with
uncontrolled narrow-angle glaucoma [see
Contraindications (4)]. Toviaz should be
used with caution in patients being treated for narrow-angle glaucoma.
Additions and/or
revisions underlined:
5.6 Worsening
of Myasthenia Gravis Symptoms
Toviaz should be used with
caution in patients with myasthenia gravis due to the risk of worsening of
symptoms of the disease.
6
Adverse Reactions
Newly added bulled
line listing:
The following
clinically significant adverse reactions are described elsewhere in labeling:
Angioedema
[see Warnings and Precautions (5.1)]
Urinary
Retention [see Warnings and Precautions
(5.2)]
Decreased
Gastrointestinal Motility [see Warnings
and Precautions (5.3)]
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
Because clinical
trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates observed
in practice.
Adult Overactive
Bladder (OAB)
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
…
Table 4: Adverse
Events with an Incidence Exceeding the Placebo Rate and Reported by greater
than or equal to 1% of Patients from Double-Blind, Placebo-Controlled Phase 3
Trials of 12-weeks Treatment Duration
Newly added
information:
Pediatric
Neurogenic Detrusor Overactivity (NDO)
The safety of
Toviaz was evaluated in a total of 131 pediatric patients with NDO. Patients
received Toviaz 4 mg or Toviaz 8 mg orally once daily in two clinical trials
(Studies 3 and 4).
Study 3 was a
Phase 3 study in pediatric patients with NDO from 6 years to 17 years of age
and weighing greater than 25 kg. This study consisted of a 12-week efficacy
phase, in which 84 patients received Toviaz, followed by a 12-week safety
extension phase in which 103 patients received Toviaz. Of the 103 patients who
received Toviaz in the safety extension phase, 67 continued Toviaz from the
efficacy phase and 36 switched from an active comparator in the efficacy phase
to Toviaz in the safety extension phase.
Study 4 (N=11) was
an 8-week, Phase 2 pharmacokinetic (PK) and safety study in pediatric patients
with NDO from 8 years to 17 years of age. The most commonly reported adverse
reactions in pediatric patients with NDO who received Toviaz 4 mg or 8 mg in
Study 3 (greater than or equal to 2%) were diarrhea, UTI, dry mouth,
constipation, abdominal pain, nausea, weight increased and headache.
Table 5 lists the
adverse reactions reported at an incidence greater than or equal to 2% in
either treatment group in the Study 3 efficacy phase.
Table 5: Adverse
Reactions Reported in greater than or equal to 2% of Patients with NDO Aged 6
Years to 17 Years in the 12-Week Efficacy
Phase of Study 3 (Newly added table; please refer to label for
complete information.
Newly added information:
Ophthalmological Adverse Reactions
Ophthalmological adverse reactions, including myopia, accommodation
disorder and blurred vision, were reported in 8 of 131 (6.1%) pediatric
patients with NDO who received Toviaz 4 mg or Toviaz 8 mg in Study 3 (both
efficacy and safety extension phases) and Study 4. The ophthalmological adverse
reactions did not result in discontinuation of Toviaz in any patient.
Increases in Heart Rate
Increases in heart rate were reported in pediatric patients with NDO who
received Toviaz 4 mg and Toviaz 8 mg in Study 3. The mean heart data are
described in Table 6.
Table 6: Mean Baseline
and Mean Changes from Baseline in Heart Rate in Pediatric Patients Weighing
Greater than 25 kg in Study 3 (Newly added table; please refer to label
for complete information.
Newly added
information:
The proportion of
patients with heart rates greater than the 99th percentile for age also
increased from baseline in patients who received Toviaz 4 mg and Toviaz 8 mg in
Study 3. These data are described in Table 7.
Table 7: Proportion
of Pediatric Patients with Heart Rate Greater than the 99th Percentile for Age
and Weighing Greater than 25 kg in Study 3 (Newly added
table; please refer to label for complete information)
Newly added
information:
Increases from
baseline in the proportion of patients with a heart rate greater than the 99th
percentile for age were most pronounced in patients less than 12 years of age
who received Toviaz 8 mg.
Increases in heart
rate in patients who received Toviaz 4 mg and Toviaz 8 mg in Study 3 were not
associated with clinical symptoms and did not result in discontinuation of
therapy with Toviaz.
6.2 Post-marketing
Experience
Additions and/or
revisions underlined:
The following adverse
reactions have been identified during post-approval use of Toviaz.
Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure …
7
Drug Interactions
7.2 CYP3A4 Inhibitors
Additions and/or
revisions underlined:
Doses of Toviaz
greater than 4 mg are not recommended in adult patients taking strong
CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin [see Dosage and Administration (2.5)]. The
Toviaz dose in pediatric patients taking strong CYP3A4 inhibitors is
recommended to be reduced to 4 mg once daily in patients >35 kg and is not
recommended in patients weighing greater than 25 kg and up to 35 kg [see Dosage and Administration (2.5)].
In a study in
adults, coadministration
of the strong CYP3A4 inhibitor ketoconazole with fesoterodine led to
approximately a doubling of the maximum concentration (Cmax) …
8
Use in Specific Populations
8.1 Pregnancy
Risk Summary
Additions and/or
revisions underlined:
There are no available
data with the use of Toviaz in pregnant women and adolescents to evaluate
for a drug- associated risk of major birth defects, miscarriage or
adverse maternal or fetal outcomes. In animal reproduction studies …
8.4 Pediatric Use
Newly added information:
The safety and
effectiveness of Toviaz have been established for the treatment of neurogenic
detrusor overactivity (NDO) in pediatric patients aged 6 years and older and
weighing greater than 25 kg. The information on this use is discussed throughout
labeling. Use of Toviaz for treatment of NDO is supported by evidence from a
randomized, open-label trial with an initial 12-week efficacy phase followed by
a 12-week safety extension phase in pediatric patients from 6 years to 17 years
of age (Study 3) [see Adverse Reactions
(6.1) and Clinical Studies (14.2)].Study results demonstrated that
treatment with Toviaz 4 mg and 8 mg daily resulted in improvements from
baseline to Week 12 in maximum cystometric bladder capacity (MCBC) for patients
weighing greater than 25 kg [see Clinical
Studies (14.2) and Clinical Pharmacology (12.3)]. The most commonly
reported adverse reactions in patients who received Toviaz 4 mg or 8 mg in
Study 3 (greater than or equal to 2%) were diarrhea, UTI, dry mouth, constipation,
abdominal pain, nausea, weight increase and headache [see Adverse Reactions (6.1)]. Mean increases from baseline in
heart rate were reported with both the 4 mg and 8 mg daily doses of Toviaz,
with larger mean increases reported in pediatric patients who received the 8 mg
daily dose [see Adverse Reactions (6.1)].
The safety and
effectiveness of Toviaz have not been established in pediatric patients younger
than 6 years of age or weighing 25 kg or less.
8.5 Geriatric Use
Additions and/or
revisions underlined:
Of the 1,567
patients who received Toviaz 4 mg or 8 mg orally once daily in Phase 2
and 3, placebo-controlled, efficacy and safety studies for OAB, 515
(33%) were 65 years of age or older, and 140 (9%) were 75 years of age or
older. No overall difference in effectiveness was 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 reactions,
including dry mouth, constipation …
8.6 Renal
Impairment
Additions and/or
revisions underlined:
In adult
patients with severe renal impairment (CLCR <30 mL/min), Cmax and AUC are
increased 2.0- and 2.3-fold, respectively. Doses of Toviaz greater than 4 mg
are not recommended in adult patients with severe
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. No dose adjustment is
recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3) and
Dosage and Administration (2.2, 2.3)].
Newly added
information:
The recommended
dosage of Toviaz in pediatric patients weighing greater than 25 kg and up to 35
kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2) is 4 mg
once daily and Toviaz is not recommend in those with severe renal impairment
(eGFR 15 to 29 mL/min/1.73m2). In pediatric patients weighing greater than 35
kg with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2), the recommended
starting dosage of Toviaz is 4 mg orally once daily, with increase to the
recommended dosage of Toviaz 8 mg orally once daily, and in those with severe
renal impairment (eGFR 15 to 29 mL/min/1.73m2) the recommended dose is 4 mg
once daily [see Dosage and Administration
(2.2, 2.4)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
Angioedema
Inform patients and/or
their caregivers that Toviaz may cause angioedema, which
could result in life- threatening airway obstruction. Advise patients and/or
their caregivers to promptly discontinue Toviaz and seek immediate
medical attention if they experience edema of the lips, tongue or
laryngopharynx, or difficulty breathing.
PATIENT INFORMATION
Additions and/or
revisions underlined:
What
is TOVIAZ?
TOVIAZ is a prescription
medicine used:
in
adults to treat symptoms of a condition called overactive bladder (OAB) …
in children 6 years of age and older with a body
weight greater than 55 pounds (25 kg) to treat neurogenic detrusor overactivity
(NDO). TOVIAZ is used to increase the amount of urine your bladder can hold and
reduce urine leakage.
It is not known if
TOVIAZ is safe and effective in children younger than 6 years of age or with a
body weight 55 pounds (25 kg) or less.
Before you take
TOVIAZ, tell your healthcare provider about all your medical conditions,
including if you:
are receiving treatment for an eye problem called
narrow-angle glaucoma.
are
pregnant or plan to become pregnant. It is not known if TOVIAZ will harm your
unborn baby. Talk to your healthcare provider if you are pregnant or plan to
become pregnant.
Tell your
healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal products.
TOVIAZ may affect the way other medicines work, and other medicines may affect
how TOVIAZ works. Especially tell your healthcare provider if you are taking antimuscarinic,
antibiotics, or antifungal medicines.
How should I take
TOVIAZ?
Your
healthcare provider may lower your dose of TOVIAZ if you are an adult
with severe kidney problems.
Your healthcare provider may lower or stop your dose
of TOVIAZ if you are a child 6 years of age and older with a body weight
greater than 77 pounds (35 kg) and have severe kidney problems or are taking certain
medicines.
What
should I avoid while taking TOVIAZ?
TOVIAZ can cause blurred vision, dizziness, and
drowsiness. Do not drive, operate machinery, or do other dangerous
activities until you know how TOVIAZ affects you.
Use caution in hot environments. Decreased sweating
and severe heat illness can happen when medicines such as TOVIAZ are used in a
hot environment.
Drinking alcohol while taking medicines such as
TOVIAZ may cause increased drowsiness.
What are the
possible side effects of TOVIAZ?
TOVIAZ may cause
serious side effects, including:
serious
allergic reactions. Symptoms of a serious allergic reaction may include
swelling of the face, lips, throat, or tongue. If you have any of these
symptoms, you should stop taking TOVIAZ and get emergency medical help right
away.
inability to empty bladder (urinary retention). TOVIAZ
may increase your chances of not being able to empty your bladder if you have
bladder outlet obstruction. Tell your healthcare provider right away if you are
unable to empty your bladder.
central nervous system (CNS) effects. Talk to your
healthcare provider right away if you get any of these side effects: headache,
dizziness, and drowsiness.
worsening of Myasthenia Gravis symptoms.
The most common
side effects of TOVIAZ in adults include:
The most common
side effects of TOVIAZ in children 6 years of age and older include:
diarrhea
dry mouth
stomach pain
weight gain
urinary tract
infection
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Risk Summary
There are no data with the use of Toviaz in pregnant women to
inform a drug associated risk for birth defects or miscarriage. 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, respectively, the maximum recommended human dose
(MRHD) of 8 mg/day based on AUC. The background risk of major birth defects and
miscarriage for the indicated population are unknown. However, in the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
No dose-related teratogenicity was observed in reproduction studies
performed in mice and rabbits…
In rabbits treated at 3 to 11 times the MRHD (27 mg/kg/day, oral),
incompletely ossified sternebrae (retardation of bone development) and
reduced survival were observed in fetuses…
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Risk Summary
There is no information on the presence of fesoterodine in human
milk, the effects on the breastfed child, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for Toviaz and any potential adverse
effects on the breastfed child from Toviaz or from the underlying maternal
condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Advise the patient to read the FDA-Approved Patient Labeling (Patient Information)
Angioedema
Patients should be informed that fesoterodine may produce angioedema,
which could result in life-threatening airway obstruction…
Antimuscarinic Effects
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…
Alcohol
Patients should also be informed that alcohol may enhance the
drowsiness caused by Toviaz, like other anticholinergic agents…
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