ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
TOVIAZ 4 mg prolonged-release tablets
Each prolonged-release tablet contains fesoterodine fumarate 4 mg corresponding to 3.1 mg of
fesoterodine.
Excipients
Each 4 mg prolonged-release tablet contains 0.525 mg of soya lecithin and 91.125 mg lactose
monohydrate.
For a full list of excipients, see section 6.1.
Prolonged-release tablets
The 4 mg tablets are light blue, oval, biconvex, film-coated, and engraved on one side with the letters
‘FS’.
Treatment of the symptoms (increased urinary frequency and/or urgency and/or urgency incontinence)
that may occur in patients with overactive bladder syndrome.
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.
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 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 sections 4.3,
4.4, 4.5 and 5.2).
Moderate
(3)
or potent
(4)
CYP3A4 inhibitors
None
Moderate
Potent
Renal impairment
(1)
Mild
4→8 mg
(2)
4 mg
Should be avoided
Moderate
4→8 mg
(2)
4 mg
Contraindicated
2
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
TOVIAZ is contraindicated in subjects with severe hepatic impairment (see section 4.3).
Paediatric population
TOVIAZ is not recommended for use in children and adolescents below 18 years of age due to lack of
data on safety and efficacy (see section 5.2).
Hypersensitivity to the active substance or to peanut or soya or any of the excipients
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.
TOVIAZ should be used with caution in patients with:
-
Clinically significant bladder outflow obstruction at risk of urinary retention (e.g. clinically
significant prostate enlargement due to benign prostatic hyperplasia, see section 4.3)
-
Gastrointestinal obstructive disorders (e.g. pyloric stenosis)
-
Gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as
oral bisphosphonates) that can cause or exacerbate oesophagitis
-
Decreased gastrointestinal motility
-
Autonomic neuropathy
-
Controlled narrow-angle glaucoma
Caution should be exercised when prescribing or uptitrating fesoterodine to patients in whom an
increased exposure to the active metabolite (see section 5.1) is expected:
-
Hepatic impairment (see sections 4.2, 4.3 and 5.2)
-
Renal impairment (see section 4.2, 4.3 and 5.2)
-
Concomitant administration of potent or moderate CYP3A4 inhibitors (see sections 4.2 and
4.5)
-
Concomitant administration of a potent CYP2D6 inhibitor (see sections 4.5 and 5.2).
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.
3
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 fesoterodine. If urinary tract infection is present, an appropriate medical
approach should be taken/antibacterial therapy should be started.
The 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).
As with other antimuscarinics, fesoterodine 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).
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 medicinal product.
Pharmacological interactions
Caution should be exercised in coadministration of fesoterodine with other antimuscarinic agents 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 interactions
In 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.
CYP3A4 Inhibitors
Potent CYP3A4 Inhibitors
Following inhibition of CYP3A4 by co-administration of ketoconazole 200 mg twice daily, C
max
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), saquinavir and telithromycin
(see sections 4.2 and 4.4)).
4
Moderate CYP3A4 Inhibitors
Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole
200 mg twice a day for 2 days, C
max
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 Inhibitors
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 inhibitor.
CYP3A4 Inducers
Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, C
max
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 Inhibitors
The interaction with CYP2D6 inhibitors was not tested clinically. Mean C
max
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 contraceptives
Fesoterodine 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.
Warfarin
A 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.
Pregnancy
There 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.
Lactation
It is not known whether fesoterodine is excreted into human milk; therefore, breast-feeding is not
recommended during treatment with TOVIAZ.
No studies on the effects on the ability to drive and use machines have been performed. As with other
antimuscarinic agents, caution should be exercised when driving or using machines due to possible
occurrence of side effects such as blurred vision, dizziness, and somnolence (see section 4.8).
5
The 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 event, occurred with a frequency of 28.8% in the fesoterodine
group compared to 8.5% in the placebo group. The majority of ADRs 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.
The table below gives the frequency of treatment emergent adverse reactions from placebo-controlled
clinical trials and from post-marketing experience. The adverse reactions reported in this table are
those events that were very common (≥1/10), common (≥1/100 to <1/10), uncommon (1/1,000 to
<1/100) or rare (1/10,000 to <1/1,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System Organ Class Very common Common
Uncommon
Rare
Cardiac disorders
Tachycardia;
Palpitations
Nervous system
disorders
Dizziness;
Headache
Dysgeusia;
Somnolence
Eye disorders
Dry eye
Blurred vision
Ear and labyrinth
disorders
Vertigo
Respiratory, thoracic
and mediastinal
disorders
Dry throat
Pharyngolaryng
eal pain; Cough;
Nasal dryness
Gastrointestinal
disorders
Dry mouth
Abdominal
pain;
Diarrhoea;
Dyspepsia;
Constipation;
Nausea
Abdominal
discomfort;
Flatulence,
Gastroesophage
al reflux
Renal and urinary
disorders
Dysuria
Urinary
retention
(including
feeling of
residual urine;
micturition
disorder);
Urinary
hesitation
Skin and subcutaneous
tissue disorders
Rash; Dry skin;
Pruritus
Angioedema;
Urticaria
Infections and
infestations
Urinary tract
infection
General disorders and
Fatigue
6
System Organ Class Very common Common
Uncommon
Rare
administration site
conditions
Hepatobiliary disorders
ALT increased;
GGT increased
Psychiatric disorders
Insomnia
Confusional
state
In 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 catheterization 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).
effects. Treatment should be symptomatic and supportive. In the event of overdose, ECG monitoring
is recommended; standard supportive measures for managing QT prolongation should be adopted.
Fesoterodine has been safely administered in clinical studies at doses up to 28 mg/day.
In the event of fesoterodine overdose, treat with gastric lavage and give activated charcoal. Treat
symptoms as follows:
- Severe central anticholinergic effects (e.g. hallucinations, severe excitation): treat with
physostigmine
- Convulsions or pronounced excitation: treat with benzodiazepines
- Respiratory insufficiency: treat with artificial respiration
- Tachycardia: treat with beta-blockers
- Urinary retention: treat with catheterisation
- Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Urinary antispasmodics, ATC code: G04B D11.
Fesoterodine 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.
The 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.
7
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 Fesoterodine
4 mg
Fesoterodine
8 mg
Active
comparator
Placebo Fesoterodine
4 mg
Fesoterodine
8 mg
Number of micturitions per 24 hours#
N=279
N=265
N=276
N=283
N=266
N=267
N=267
Baseline
12.0
11.6
11.9
11.5
12.2
12.9
12.0
Change from
baseline
-1.02
-1.74
-1.94
-1.69
-1.02
-1.86
-1.94
p-value
<0.001
<0.001
0.032
<0.001
Responder rate (treatment response)#
N=279
N=265
N=276
N=283
N=266
N=267
N=267
Responder rate 53.4%
74.7%
79.0%
72.4%
45.1%
63.7%
74.2%
p-value
<0.001
<0.001
<0.001
<0.001
Number of urge incontinence episodes per 24 hours
N=211
N=199
N=223
N=223
N=205
N=228
N=218
Baseline
3.7
3.8
3.7
3.8
3.7
3.9
3.9
Change from
baseline
-1.20
-2.06
-2.27
-1.83
-1.00
-1.77
-2.42
p-value
0.001
<0.001
0.003
<0.001
Number of continent days per week
N=211
N=199
N=223
N=223
N=205
N=228
N=218
Baseline
0.8
0.8
0.6
0.6
0.6
0.7
0.7
Change from
baseline
2.1
2.8
3.4
2.5
1.4
2.4
2.8
p-value
0.007
<0.001
<0.001
<0.001
Voided volume per micturition (ml)
N=279
N=265
N=276
N=283
N=266
N=267
N=267
Baseline
150
160
154
154
159
152
156
Change from
baseline
10
27
33
24
8
17
33
p-value
<0.001
<0.001
0.150
<0.001
# primary end points
8
Cardiac electrophysiology:
The effect of fesoterodine 4 mg and 28 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.
5.2 Pharmacokinetic properties
Absorption
After 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.
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, 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 C
max
and AUC of the
active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolisers as compared
to extensive metabolisers.
Elimination
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 faeces. The terminal half-life of the active metabolite following oral administration is
approximately 7 hours and is absorption rate-limited.
Age and gender
No dose adjustment is recommended in these subpopulations. The pharmacokinetics of fesoterodine
are not significantly influenced by age and gender.
Paediatric patients
The pharmacokinetics of fesoterodine have not been evaluated in paediatric patients.
Renal impairment
In patients with mild or moderate renal impairment (GFR 30 – 80 ml/min), C
max
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), C
max
and AUC are increased 2.0 and 2.3-
fold, respectively.
Hepatic impairment
In patients with moderate hepatic impairment (Child Pugh B), C
max
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.
9
5.3 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.
Reproduction studies have shown minor embryotoxicity at doses close to maternally toxic ones
(increased number of resorptions, pre-implantation and post-implantation losses).
Supratherapeutic concentrations of the active metabolite of fesoterodine, have been shown to inhibit
K
+
current in cloned human ether-à-go-go-related gene (hERG) channels and prolong action potential
duration (70% and 90% repolarisation) in canine isolated Purkinje fibres. However in conscious dogs,
the active metabolite had no effect on the QT interval and QTc interval at plasma exposures at least
33-fold higher than mean peak free plasma concentration in human subjects who are extensive
metabolisers and 21-fold higher than measured in subjects who are poor CYP2D6 metabolisers after
fesoterodine 8 mg once daily.
6.1 List of excipients
Tablet core
Xylitol
Lactose monohydrate
Microcrystalline cellulose
Hypromellose
Glycerol dibehenate
Talc
Film-coat
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol (3350)
Talc
Soya lecithin
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25C.
Store in the original package to protect from moisture.
6.5 Nature and contents of container
TOVIAZ 4 mg tablets are packed in aluminium-aluminium blisters in cartons containing 7, 14, 28, 56,
84, 98 or 100 tablets. In addition, TOVIAZ 4 mg tablets are also packed in HDPE bottles containing
30 or 90 tablets.
10
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/07/386/001-005
EU/1/07/386/011
EU/1/07/386/013-014
EU/1/07/386/017
20/04/2007
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
11
TOVIAZ 8 mg prolonged-release tablets
Each prolonged-release tablet contains fesoterodine fumarate 8 mg corresponding to 6.2 mg of
fesoterodine.
Excipients
Each 8 mg prolonged-release tablet contains 0.525 mg of soya lecithin and 58.125 mg lactose
monohydrate.
For a full list of excipients, see section 6.1.
Prolonged-release tablets
The 8 mg tablets are blue, oval, biconvex, film-coated, and engraved on one side with the letters ‘FT’.
Treatment of the symptoms (increased urinary frequency and/or urgency and/or urgency incontinence)
that may occur in patients with overactive bladder syndrome.
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.
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 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 sections 4.3,
4.4, 4.5 and 5.2).
Moderate
(3)
or potent
(4)
CYP3A4 inhibitors
None
Moderate
Potent
Renal impairment
(1)
Mild
4→8 mg
(2)
4 mg
Should be avoided
Moderate
4→8 mg
(2)
4 mg
Contraindicated
12
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
TOVIAZ is contraindicated in subjects with severe hepatic impairment (see section 4.3).
Paediatric population
TOVIAZ is not recommended for use in children and adolescents below 18 years of age due to lack of
data on safety and efficacy (see section 5.2).
Hypersensitivity to the active substance or to peanut or soya or any of the excipients
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.
TOVIAZ should be used with caution in patients with:
-
Clinically significant bladder outflow obstruction at risk of urinary retention (e.g. clinically
significant prostate enlargement due to benign prostatic hyperplasia, see section 4.3)
-
Gastrointestinal obstructive disorders (e.g. pyloric stenosis)
-
Gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as
oral bisphosphonates) that can cause or exacerbate oesophagitis
-
Decreased gastrointestinal motility
-
Autonomic neuropathy
-
Controlled narrow-angle glaucoma
Caution should be exercised when prescribing or uptitrating fesoterodine to patients in whom an
increased exposure to the active metabolite (see section 5.1) is expected:
-
Hepatic impairment (see sections 4.2, 4.3 and 5.2)
-
Renal impairment (see section 4.2, 4.3 and 5.2)
-
Concomitant administration of potent or moderate CYP3A4 inhibitors (see sections 4.2 and
4.5)
-
Concomitant administration of a potent CYP2D6 inhibitor (see sections 4.5 and 5.2).
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.
13
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 fesoterodine. If urinary tract infection is present, an appropriate medical
approach should be taken/antibacterial therapy should be started.
The 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).
As with other antimuscarinics, fesoterodine 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).
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 medicinal product.
Pharmacological interactions
Caution should be exercised in coadministration of fesoterodine with other antimuscarinic agents 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 interactions
In 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.
CYP3A4 Inhibitors
Potent CYP3A4 Inhibitors
Following inhibition of CYP3A4 by co-administration of ketoconazole 200 mg twice daily, C
max
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), saquinavir and telithromycin
(see sections 4.2 and 4.4)).
Moderate CYP3A4 Inhibitors
Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole
200 mg twice a day for 2 days, C
max
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).
14
Weak CYP3A4 Inhibitors
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 inhibitor.
CYP3A4 Inducers
Following induction of CYP3A4 by coadministration of rifampicin 600 mg once a day, C
max
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 Inhibitors
The interaction with CYP2D6 inhibitors was not tested clinically. Mean C
max
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 contraceptives
Fesoterodine 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.
Warfarin
A 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.
Pregnancy
There 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.
Lactation
It is not known whether fesoterodine is excreted into human milk; therefore, breast-feeding is not
recommended during treatment with TOVIAZ.
No studies on the effects on the ability to drive and use machines have been performed. As with other
antimuscarinic agents, caution should be exercised when driving or using machines due to possible
occurrence of side effects such as blurred vision, dizziness, and somnolence (see section 4.8).
The 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 event, occurred with a frequency of 28.8% in the fesoterodine
group compared to 8.5% in the placebo group. The majority of ADRs occurred during the first month
15
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.
The table below gives the frequency of treatment emergent adverse reactions from placebo-controlled
clinical trials and from post-marketing experience. The adverse reactions reported in this table are
those events that were very common (≥1/10), common (≥1/100 to <1/10), uncommon (1/1,000 to
<1/100) or rare (1/10,000 to <1/1,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System Organ Class
Very common
Common
Uncommon
Rare
Cardiac disorders
Tachycardia;
Palpitations
Nervous system disorders
Dizziness;
Headache
Dysgeusia;
Somnolence
Eye disorders
Dry eye
Blurred vision
Ear and labyrinth disorders
Vertigo
Respiratory, thoracic and
mediastinal disorders
Dry throat
Pharyngolaryngea
l pain; Cough;
Nasal dryness
Gastrointestinal disorders
Dry mouth
Abdominal pain;
Diarrhoea;
Dyspepsia;
Constipation;
Nausea
Abdominal
discomfort;
Flatulence,
Gastroesophageal
reflux
Renal and urinary disorders
Dysuria
Urinary retention
(including feeling
of residual urine;
micturition
disorder); Urinary
hesitation
Skin and subcutaneous
tissue disorders
Rash; Dry skin;
Pruritus
Angioedema;
Urticaria
Infections and infestations
Urinary tract
infection
General disorders and
administration site
conditions
Fatigue
Hepatobiliary disorders
ALT increased;
GGT increased
Psychiatric disorders
Insomnia
Confusional state
In 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).
16
Post-marketing cases of urinary retention requiring catheterization 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).
effects. Treatment should be symptomatic and supportive. In the event of overdose, ECG monitoring
is recommended; standard supportive measures for managing QT prolongation should be adopted.
Fesoterodine has been safely administered in clinical studies at doses up to 28 mg/day.
In the event of fesoterodine overdose, treat with gastric lavage and give activated charcoal. Treat
symptoms as follows:
- Severe central anticholinergic effects (e.g. hallucinations, severe excitation): treat with
physostigmine
- Convulsions or pronounced excitation: treat with benzodiazepines
- Respiratory insufficiency: treat with artificial respiration
- Tachycardia: treat with beta-blockers
- Urinary retention: treat with catheterisation
- Mydriasis: treat with pilocarpine eye drops and/or place patient in dark room.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Urinary antispasmodics, ATC code: G04B D11.
Fesoterodine 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.
The 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
17
Number of micturitions per 24 hours#
N=279
N=265
N=276
N=283
N=266
N=267
N=267
Baseline
12.0
11.6
11.9
11.5
12.2
12.9
12.0
Change from
baseline
-1.02
-1.74
-1.94
-1.69
-1.02
-1.86
-1.94
p-value
<0.001
<0.001
0.032
<0.001
Responder rate (treatment response)#
N=279
N=265
N=276
N=283
N=266
N=267
N=267
Responder rate 53.4%
74.7%
79.0%
72.4%
45.1%
63.7%
74.2%
p-value
<0.001
<0.001
<0.001
<0.001
Number of urge incontinence episodes per 24 hours
N=211
N=199
N=223
N=223
N=205
N=228
N=218
Baseline
3.7
3.8
3.7
3.8
3.7
3.9
3.9
Change from
baseline
-1.20
-2.06
-2.27
-1.83
-1.00
-1.77
-2.42
p-value
0.001
<0.001
0.003
<0.001
Number of continent days per week
N=211
N=199
N=223
N=223
N=205
N=228
N=218
Baseline
0.8
0.8
0.6
0.6
0.6
0.7
0.7
Change from
baseline
2.1
2.8
3.4
2.5
1.4
2.4
2.8
p-value
0.007
<0.001
<0.001
<0.001
Voided volume per micturition (ml)
N=279
N=265
N=276
N=283
N=266
N=267
N=267
Baseline
150
160
154
154
159
152
156
Change from
baseline
10
27
33
24
8
17
33
p-value
<0.001
<0.001
0.150
<0.001
# primary end points
Cardiac electrophysiology:
The effect of fesoterodine 4 mg and 28 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.
18
5.2 Pharmacokinetic properties
Absorption
After 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.
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, 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 C
max
and AUC of the
active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolisers as compared
to extensive metabolisers.
Elimination
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 faeces. The terminal half-life of the active metabolite following oral administration is
approximately 7 hours and is absorption rate-limited.
Age and gender
No dose adjustment is recommended in these subpopulations. The pharmacokinetics of fesoterodine
are not significantly influenced by age and gender.
Paediatric patients
The pharmacokinetics of fesoterodine have not been evaluated in paediatric patients.
Renal impairment
In patients with mild or moderate renal impairment (GFR 30 – 80 ml/min), C
max
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), C
max
and AUC are increased 2.0 and 2.3-
fold, respectively.
Hepatic impairment
In patients with moderate hepatic impairment (Child Pugh B), C
max
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.
5.3 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.
19
Reproduction studies have shown minor embryotoxicity at doses close to maternally toxic ones
(increased number of resorptions, pre-implantation and post-implantation losses).
Supratherapeutic concentrations of the active metabolite of fesoterodine, have been shown to inhibit
K
+
current in cloned human ether-à-go-go-related gene (hERG) channels and prolong action potential
duration (70% and 90% repolarisation) in canine isolated Purkinje fibres. However in conscious dogs,
the active metabolite had no effect on the QT interval and QTc interval at plasma exposures at least
33-fold higher than mean peak free plasma concentration in human subjects who are extensive
metabolisers and 21-fold higher than measured in subjects who are poor CYP2D6 metabolisers after
fesoterodine 8 mg once daily.
6.1 List of excipients
Tablet core
Xylitol
Lactose monohydrate
Microcrystalline cellulose
Hypromellose
Glycerol dibehenate
Talc
Film-coat
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol (3350)
Talc
Soya lecithin
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25C.
Store in the original package to protect from moisture.
6.5 Nature and contents of container
TOVIAZ 8 mg tablets are packed in aluminium-aluminium blisters in cartons containing 7, 14, 28, 56,
84, 98 or 100 tablets. In addition, TOVIAZ 8 mg tablets are also packed in HDPE bottles containing
30 or 90 tablets.
Not all pack sizes may be marketed.
20
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/07/386/006-010
EU/1/07/386/012
EU/1/07/386/015-016
EU/1/07/386/018
20/04/2007
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
21
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
22
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Pfizer Manufacturing Deutschland GmbH
Heinrich Mack Str. 35
89257 Illertissen
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
23
ANNEX III
LABELLING AND PACKAGE LEAFLET
24
A. LABELLING
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Outer Carton 4 mg
TOVIAZ 4 mg prolonged-release tablets
fesoterodine fumarate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
1 tablet contains 4 mg fesoterodine fumarate
3. LIST OF EXCIPIENTS
Contains lactose and soya lecithin: see the package leaflet for further information.
7 prolonged-release tablets
14 prolonged-release tablets
28 prolonged-release tablets
56 prolonged-release tablets
84 prolonged-release tablets
98 prolonged-release tablets
100 prolonged-release tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Do not store above 25
o
C.
Store in the original package to protect from moisture.
26
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/07/386/001 7 tablets
EU/1/07/386/002 14 tablets
EU/1/07/386/003 28 tablets
EU/1/07/386/004 56 tablets
EU/1/07/386/005 98 tablets
EU/1/07/386/011 84 tablets
EU/1/07/386/017 100 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
TOVIAZ 4 mg
27
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister label 4 mg
TOVIAZ 4 mg prolonged-release tablets
fesoterodine fumarate
Pfizer Ltd (as MA Holder logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Immediate Packaging HDPE Bottle – 4 mg
TOVIAZ 4 mg prolonged-release tablets
fesoterodine fumarate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
1 tablet contains 4 mg fesoterodine fumarate
3. LIST OF EXCIPIENTS
Contains lactose and soya lecithin: see the package leaflet for further information.
30 prolonged-release tablets
90 prolonged-release tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Do not store above 25
o
C.
Store in the original package to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
29
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/07/386/013 30 tablets
EU/1/07/386/014 90 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
30
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Outer Carton 8 mg
TOVIAZ 8 mg prolonged-release tablets
fesoterodine fumarate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
1 tablet contains 8 mg fesoterodine fumarate
3. LIST OF EXCIPIENTS
Contains lactose and soya lecithin: see the package leaflet for further information.
7 prolonged-release tablets
14 prolonged-release tablets
28 prolonged-release tablets
56 prolonged-release tablets
84 prolonged-release tablets
98 prolonged-release tablets
100 prolonged-release tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Do not store above 25
o
C.
Store in the original package to protect from moisture.
31
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/07/386/006 7 tablets
EU/1/07/386/007 14 tablets
EU/1/07/386/008 28 tablets
EU/1/07/386/009 56 tablets
EU/1/07/386/010 98 tablets
EU/1/07/386/012 84 tablets
EU/1/07/386/018 100 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
TOVIAZ 8 mg
32
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister label 8 mg
TOVIAZ 8 mg prolonged-release tablets
fesoterodine fumarate
Pfizer Ltd (as MA Holder logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Immediate Packaging HDPE Bottle – 8 mg
TOVIAZ 8 mg prolonged-release tablets
fesoterodine fumarate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
1 tablet contains 8 mg fesoterodine fumarate
3. LIST OF EXCIPIENTS
Contains lactose and soya lecithin: see the package leaflet for further information.
30 prolonged-release tablets
90 prolonged-release tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
Do not store above 25
o
C.
Store in the original package to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
34
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
EU/1/07/386/015 30 tablets
EU/1/07/386/016 90 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
35
B. PACKAGE LEAFLET
36
PACKAGE LEAFLET: INFORMATION FOR THE USER
TOVIAZ 4 mg prolonged-release tablets
TOVIAZ 8 mg prolonged-release tablets
fesoterodine fumarate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What TOVIAZ is and what it is used for
2.
Before you take TOVIAZ
3.
How to take TOVIAZ
4.
Possible side effects
5.
How to store TOVIAZ
6.
Further information
1. WHAT TOVIAZ IS AND WHAT IT IS USED FOR
TOVIAZ is a so called antimuscarinic medicinal product which
reduces the activity of an overactive
bladder and treats the symptoms.
TOVIAZ treats the symptoms of an overactive bladder such as
not being able to control when you empty your bladder (called urgency incontinence)
suddenly needing to empty your bladder (called urgency)
having to empty your bladder more than usual (called increased urinary frequency)
2. BEFORE YOU TAKE TOVIAZ
Do not take TOVIAZ
-
if you are allergic (hypersensitive) to fesoterodine or to peanut or soya or to any of the other
ingredients of TOVIAZ (see section 2, “Important information about some of the ingredients of
TOVIAZ”)
-
if you are not able to completely empty your bladder (urinary retention)
-
if your stomach empties slowly (gastric retention)
-
if you have an eye disease called narrow angle glaucoma (
high pressure in the eye), which is not
under
control
-
if you have excessive weakness of the muscles (myasthenia gravis)
-
if you have ulceration and inflammation of the colon (severe ulcerative colitis)
-
if you have an abnormally large or distended colon (toxic megacolon)
-
if you have severe liver problems.
Take special care with TOVIAZ
Fesoterodine may not always be suitable for you. Talk to your doctor before you take TOVIAZ, if any
of the following apply to you:
- if you have difficulties in completely emptying your bladder (for example due to prostate
enlargement)
37
-
if you ever experience decreased bowel movements or suffer from severe constipation
-
if you are being treated for an eye disease called narrow angle glaucoma
-
if you have serious kidney or liver problems, your doctor may need to adjust your dose
-
-
if you have a disease called autonomic neuropathy which you notice from symptoms such as
changes in your blood pressure or disorders in the bowel or sexual function
-
if you have a gastrointestinal disease that affects the passage and/or digestion of food
-
if you have heartburn or belching.
Heart problems: Talk to your doctor if you suffer from any of the following conditions
- you have an ECG (heart tracing) abnormality known as QT prolongation or you are taking any
medicine known to cause this
- you have a slow heart rate (bradycardia)
- you suffer from heart disease such as myocardial ischaemia (reduced blood flow to the heart
muscle), irregular heartbeat or heart failure
- you have abnormally low levels of potassium in your blood.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines you do not have a prescription for. Your doctor will tell you whether you can
take TOVIAZ with other medicines.
Please inform your doctor if you are taking medicines according to the following list. Concomitant
treatment with fesoterodine may make side effects such as dry mouth, constipation, difficulty in
completely emptying your bladder or drowsiness more serious or occur more often.
-
medicines containing the active substance amantadine (used to treat Parkinson’s disease)
-
certain medicines used to enhance gastrointestinal motility or to relieve stomach cramps or
spasm and to prevent travel sickness
-
certain medicines used to treat psychiatric diseases.
Please also inform your doctor if you are taking any of the following medicines:
-
medicines containing any of the following active substances may increase the break-down of
fesoterodine and thus decrease its effect: St. John’s Wort (herbal medicinal product), rifampicin
(used to treat bacterial infections), carbamazepine, phenytoin and phenobarbital (used, among
others, to treat epilepsy)
-
medicines containing any of the following active substances may increase the blood levels of
fesoterodine: itraconazole or ketoconazole (used to treat fungal infections), ritonavir,
atazanavir, indinavir, saquinavir or nelfinavir (antiviral medication for treating HIV),
clarithromycin or telithromycin (used to treat bacterial infections) and nefazodone (used to treat
depression)
-
medicines containing the active substance methadone (used in the treatment of severe pain and
abuse problems).
Taking TOVIAZ with food and drink
TOVIAZ can be taken with or without food. However, grapefruit juice should be avoided since
grapefruit juice may alter the effect of the medicine.
Pregnancy and breast-feeding
You should not take TOVIAZ if you are pregnant, as the effects of fesoterodine on pregnancy and the
unborn baby are not known. Tell your doctor if you are pregnant or planning to become pregnant.
It is not known whether fesoterodine is excreted into human milk; therefore, breast-feeding is not
recommended during treatment with TOVIAZ.
Ask your doctor or pharmacist for advice before taking any medicine.
38
Driving and using machines
TOVIAZ can cause blurred vision, dizziness, and sleepiness. If you experience any of these effects, do
not drive or use any tools or machines.
Important information about some of the ingredients of TOVIAZ
TOVIAZ contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicine.
TOVIAZ contains soya oil. If you are allergic to peanut or soya, do not use this medicinal product.
3. HOW TO TAKE TOVIAZ
Always take TOVIAZ exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The recommended starting dose of TOVIAZ is one 4 mg tablet a day. Based on how you respond to
the medicine, your doctor may prescribe you a higher dose; one 8 mg tablet a day.
You should swallow your tablet whole with a glass of water. Do not chew the tablet.
To help you remember to take TOVIAZ, you may find it easier to take it at the same time every day.
If you take more TOVIAZ than you should
If you have taken more tablets than you have been told to take, or if someone else accidentally takes
your tablets, contact your doctor or hospital for advice immediately. Show them your pack of tablets.
If you forget to take TOVIAZ
If you forget to take a tablet, take your tablet as soon as you remember, but do not take more than one
tablet in one day. Do not take a double dose to make up for a forgotten tablet.
If you stop taking TOVIAZ
Do not stop taking TOVIAZ without talking to your doctor, as your symptoms of overactive bladder
may come back again or become worse once you stop taking TOVIAZ.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, TOVIAZ can cause side effects, although not everybody gets them.
Very common side effects
(more than one in 10 patients)
You may get a dry mouth. This effect is usually mild or moderate. This may lead to a greater risk of
dental caries. Therefore, you should brush your teeth regularly with fluoride toothpaste twice daily.
Common side effects
(between one in 100 patients and one in 10 patients)
dry eye
constipation
trouble digesting food (dyspepsia)
straining or pain when emptying the bladder (dysuria)
dizziness
headache
pain in the stomach
diarrhoea
feeling sick (nausea)
39
difficulty sleeping (insomnia)
dry throat
Uncommon side effects
(occuring in 1 in 1,000 to 1 in 100 patients)
urinary tract infection
sleepiness (somnolence)
difficulty tasting (dysgeusia)
vertigo
rash
dry skin
itching
an uncomfortable feeling in the stomach
wind (flatulence)
difficulty in completely emptying the bladder (urinary retention)
delay in passing urine (urinary hesitation)
extreme tiredness (fatigue)
increased heart beat (tachycardia)
palpitations
liver problems
cough
nasal dryness
throat pain
stomach acid reflux
blurred vision
Rare side effects
angioedema
urticaria
confusion
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5. HOW TO STORE TOVIAZ
Keep out of the reach and sight of children.
Do not use TOVIAZ after the expiry date which is stated on the carton and the blister after “EXP”.
The expiry date refers to the last day of that month.
Do not store above 25C.
Store in the original package in order to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What TOVIAZ contains
40
The active substance is fesoterodine fumarate.
TOVIAZ 4 mg
1 prolonged-release tablet contains 4 mg fesoterodine fumarate, equivalent to 3.1 mg of fesoterodine.
TOVIAZ 8 mg
1 prolonged-release tablet contains 8 mg fesoterodine fumarate, equivalent to 6.2 mg of fesoterodine.
The other ingredients are:
The tablet core: xylitol, lactose monohydrate, microcrystalline cellulose, hypromellose, glycerol
dibehenate, talc.
The coating: polyvinyl alcohol, titanium dioxide, macrogol, talc, soya lecithin, indigo carmine
aluminium lake (E132)
What TOVIAZ looks like and contents of the pack
TOVIAZ 4 mg prolonged-release tablets are light blue, oval, curved outwards on both sides, film-
coated tablets, and engraved on one side with the letters ‘FS’.
TOVIAZ 8 mg prolonged-release tablets are blue, oval, curved outwards on both sides, film-coated
tablets, and engraved on one side with the letters ‘FT’.
TOVIAZ is available in blister packs of 7, 14, 28, 56, 84, 98 and 100 prolonged-release tablets. In
addition, TOVIAZ is also available in HDPE bottles containing 30 or 90 tablets.
Please note that not all the above pack sizes may be marketed.
Marketing Authorisation Holder
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
Manufacturer
Pfizer Manufacturing Deutschland GmbH
Heinrich Mack Str. 35
89257 Illertissen
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België /Belgique / Belgien
Pfizer S.A./ N.V.
Tél/Tel: +32 (0)2 554 62 11
Luxembourg/Luxemburg
Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11
България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333
Magyarország
Pfizer Kft.
Tel.: + 36 1 488 37 00
Česká republika
Pfizer s.r.o.
Tel: +420-283-004-111
Malta
V.J. Salomone Pharma Ltd.
Tel: + 356 21 22 01 74
41
Danmark
Pfizer ApS
Tlf: +45 44 20 11 00
Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055 51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL, Eesti filiaal
Tel: +372 6 405 328
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τλ: +30 210 6785800
Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00
España
Pfizer S.A.
Tel: +34 91 490 99 00
Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500
France
Pfizer
Tél: +33 (0)1 58 07 34 40
România
Pfizer România S.R.L.
Tel: +40 (0)21 207 28 00
Ireland
Pfizer Healthcare Ireland
Slovenija
Pfizer Luxembourg SARL, Pfizer, podružnica za
svetovanje s področja farmacevtske dejavnosti,
Ljubljana
Tel: + 386 (0)1 52 11 400
Tel: 1800 633 363 (toll free)
Tel: +44 (0)1304 616161
Ísland
Icepharma hf.
Sími: + 354 540 8000
Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421–2–3355 5500
Italia
Pfizer Italia S.r.l.
Tel: +39 06 33 18 21
Suomi/Finland
Pfizer Oy
Puh/Tel: +358(0)9 43 00 40
Κύπρος
GEO. PAVLIDES & ARAOUZOS LTD
Τηλ: +35722818087
Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00
Latvija
Pfizer Luxembourg SARL, filiāle Latvijā
Tel: +371 670 35 775
United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161
Lietuva
Pfizer Luxembourg SARL, filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last revised on
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
42
Source: European Medicines Agency
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