TOVIAZ 8 MG

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

Toviaz

®

4 mg

Toviaz

®

8 mg

Sustained-release tablets

Each tablet contains:

fesoterodine fumarate 4 mg, 8 mg

A list of inactive and allergenic ingredients in the preparation is in section 6.

Read this leaflet carefully in its entirety before using the medicine. This leaflet contains

concise information about the medicine. If you have further questions, refer to the doctor

or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them,

even if it seems to you that their medical condition is similar. This medicine is not usually

intended for children under the age of 18.

1. WHAT IS THE MEDICINE INTENDED FOR?

For treatment of the symptoms that may occur in patients with overactive bladder syndrome,

such as: urinary frequency, urinary urgency and/or urinary incontinence.

Therapeutic group:

Muscarinic receptor antagonist.

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

x you are sensitive (allergic) to the active ingredient, soya, peanuts or to any of the additional

ingredients contained in the medicine, listed in section 6.

x you have urinary retention or delayed gastric emptying.

x you have severe liver problems.

x you have uncontrolled narrow-angle glaucoma.

x you have severe muscle weakness (myasthenia gravis).

x you have severe ulcerative colitis.

x you have abnormal enlargement or distention of the colon (toxic megacolon).

x you have kidney problems or moderate to severe liver problems and you are taking

medicines containing any of the following active ingredients: itraconazole or ketoconazole

(used to treat a fungal infection), ritonavir, atazanavir, indinavir, saquinavir or nelfinavir

(antiviral medicines used for treating AIDS), clarithromycin, telithromycin (used to treat

bacterial infections) and nefazodone (used to treat depression).

Special warnings regarding the use of the medicine

Before treatment with Toviaz

®

, tell the doctor if:

∙ you have difficulty in completely emptying your bladder (for example, due to prostate

enlargement).

∙ you experienced decreased bowel movements in the past or are suffering from severe

constipation.

∙ you are being treated for an eye disease called narrow-angle glaucoma.

∙ you have serious liver or kidney problems; your doctor may need to adjust your dose.

∙ you have a disease called autonomic neuropathy which you notice from symptoms such

as blood pressure changes or disturbances in the bowel or sexual function.

∙ you have gastrointestinal disease that affects the passage and/or digestion of food.

∙ you have heartburn or belching.

∙ you have an infection of the urinary tract; your doctor may prescribe antibiotics for you.

∙ you have one of the following heart problems:

- you have an ECG disturbance known as QT prolongation or you are taking medicines

which can cause this.

- you have a slow heart rate (bradycardia).

- you suffer from heart disease such as myocardial ischemia (reduced blood flow to the

heart muscle), irregular heartbeat or heart failure.

- you have hypokalemia, a manifestation of abnormally low levels of potassium in your

blood.

If you are taking, or have recently taken, other medicines, including non-prescription

medicines and nutritional supplements, tell the doctor or pharmacist. Especially inform

the doctor or pharmacist if you are taking:

∙ medicines containing the active ingredient amantadine (used to treat Parkinson’s disease),

medicines used to treat psychiatric diseases, such as antipsychotics and antidepressants,

and medicines used to enhance gastrointestinal motility or to relieve cases of stomach

cramps and spasms and travel sickness (for example, medicines containing metoclopramide).

Taking these medicines together with Toviaz

may cause side effects such as: dry mouth,

constipation, difficulty completely emptying the bladder and sleepiness, more severely or

frequently.

∙ medicines containing the following ingredients: St. John’s Wort (an herbal medicine,

Hypericum), rifampicin (used to treat bacterial infections), carbamazepine, phenytoin

and phenobarbital (used, among others, to treat epilepsy). When combined with these

substances, the effect of Toviaz

may be reduced.

∙ medicines containing the following active ingredients may increase the blood levels of

Toviaz

: itraconazole or ketoconazole (used to treat fungal infections), ritonavir, atazanavir,

indinavir, saquinavir or nelfinavir (antiviral medicines used to treat AIDS), clarithromycin or

telithromycin (used to treat bacterial infections), nefazodone (used to treat depression),

fluoxetine or paroxetine (used to treat depression or anxiety), bupropion (used to treat

depression or for smoking cessation), quinidine (used to treat arrhythmias) and cinacalcet

(used to treat hyperparathyroidism).

∙ medicines containing the active ingredient methadone (used to treat severe pain and abuse

problems).

Children and adolescents

Do not give this medicine to children and adolescents under the age of 18; it has not yet

been established whether the medicine is effective and safe for them.

Use of Toviaz

®

and food

Swallow the tablet whole with a glass of water, with or without food.

Pregnancy and breastfeeding

Do not use the medicine if you are pregnant, as the effects on pregnancy and the unborn

baby are not known.

It is not known whether the medicine is secreted into breast milk. Do not breastfeed during

the treatment.

If you are pregnant or breastfeeding, think you may be pregnant or planning to become

pregnant, refer to the doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Use of the medicine may cause drowsiness, sleepiness, dizziness and blurred vision. If you

experience any of these effects, do not drive or use machines.

Important information about some of the ingredients of this medicine

The medicine contains lactose. If you have been told by the doctor that you have an intolerance

to certain sugars, refer to your doctor before taking this medicine.

The medicine contains soya oil. If you are allergic to peanuts or to soya, do not use this

medicine.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the doctor or pharmacist if

you are uncertain.

The dosage and treatment regimen will be determined by the doctor only.

The recommended starting dosage is usually one 4 mg tablet a day. Based on how you

respond to the medicine, the doctor may prescribe you a higher dose; one 8 mg tablet a

day.

Do not exceed the recommended dose!

Do not crush/halve/chew! This is because the tablets are sustained-release tablets and the

active ingredient should be released gradually and over time.

If you took an overdose or if a child has accidentally swallowed the medicine, refer

immediately to a doctor or proceed to a hospital emergency room, and bring the package

of the medicine with you.

If you forgot to take this medicine at the required time, take the medicine as soon as you

remember, but do not take more than one tablet a day. Do not take a double dose to make

up for a forgotten dose.

Persist with the treatment as recommended by the doctor.

Even if there is an improvement in your medical condition, do not discontinue treatment with

the medicine without consulting with the doctor or pharmacist, as the symptoms of overactive

bladder may come back again or become worse.

Do not take medicines in the dark! Check the label and the dose each time you take medicine.

Wear glasses if you need them.

If you have further questions regarding the use of the medicine, consult the doctor or

pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Toviaz

may cause side effects in some users. Do not be alarmed

by the list of side effects. You may not suffer from any of them.

Stop using and refer to the doctor immediately if you are suffering from a severe allergic

reaction, manifested by swelling of the face, mouth or throat. A severe allergic reaction

including angioedema occurs rarely.

Very common side effects (may affect more than 1 in 10 people):

Dry mouth; this reaction is usually mild or moderate. This may lead to a greater risk of dental

caries. Therefore, you should brush your teeth regularly, twice daily, and see a dentist when

in doubt.

Common side effects (may affect up to 1 in 10 people):

Dry eye, constipation, dyspepsia, strained or painful urination, dizziness, headache, pain in

the stomach, diarrhea, nausea, difficulty sleeping, dry throat.

Uncommon side effects (may affect up to 1 in 100 people):

Urinary tract infection, sleepiness, difficulty tasting, spinning sensation (vertigo), rash, dry skin,

itching, an uncomfortable feeling in the stomach, flatulence, difficulty in completely emptying

the bladder, delay in passing urine, extreme tiredness, increased heart rate, palpitations, liver

problems, cough, nasal dryness, throat pain, stomach acid reflux, blurred vision.

Rare side effects (may affect up to 1 in 1,000 people):

Urticaria (skin disease), confusion.

If one of the side effects gets worse, or when you suffer from a side effect that has not been

mentioned in the leaflet, you should consult the doctor.

Side effects can be reported to the Ministry of Health by clicking on the link “Report Side

Effects of Drug Treatment” found on the Ministry of Health homepage (www.health.gov.il) that

directs you to the online form for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMe

dic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

∙ Avoid poisoning! This medicine and any other medicine should be kept in a closed place out

of the reach of children and/or infants in order to avoid poisoning. Do not induce vomiting

unless explicitly instructed to do so by the doctor.

∙ Do not use the medicine after the expiry date (exp. date) that appears on the package. The

expiry date refers to the last day of that month.

∙ Do not store above 25°C. Store in the original package in order to protect from moisture.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Lactose monohydrate, Microcrystalline cellulose, Hypromellose, Xylitol, Glycerol dibehenate,

Talc, Polyvinyl alcohol, Titanium dioxide, Polyethylene glycol, Lecithin, Indigo carmine

aluminium lake, Purified water.

The medicine contains lactose and soya lecithin:

Toviaz

4 mg – 91.125 mg lactose monohydrate.

Toviaz

8 mg – 58.125 mg lactose monohydrate.

What does the medicine look like and what is the content of the package:

Toviaz

4 mg – an oval, light blue, sustained-release tablet, with “FS” imprinted on one

side.

Toviaz

8 mg – an oval, blue, sustained-release tablet, with “FT” imprinted on one side.

Manufacturer: R-PHARM Germany GmbH, Illertissen, Germany.

Registration holder: Pfizer Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach

46725.

Registration number of the medicine in the National Drug Registry of the Ministry of

Health:

Toviaz

4 mg – 139.55.31658.00

Toviaz

8 mg – 139.56.31659.00

This leaflet was checked and approved by the Ministry of Health in October 2013 and updated

according to the guidelines of the Ministry of Health in January 2018.

Toviaz 4 mg and 8 mg LPD, Israel, 11 January 2018

2017-0024823, 2016-0016728

Toviaz

®

4 mg

Toviaz

®

8 mg

1.

NAME OF THE MEDICINAL PRODUCT

TOVIAZ 4 mg sustained release tablets

TOVIAZ 8 mg sustained release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

TOVIAZ 4 mg tablets

Each sustained release tablet contains fesoterodine fumarate 4 mg corresponding to 3.1 mg of fesoterodine.

TOVIAZ 8 mg tablets

Each sustained release tablet contains fesoterodine fumarate 8 mg corresponding to 6.2 mg of fesoterodine.

Excipients with known effect

TOVIAZ 4 mg tablets

Each 4 mg sustained release tablet contains 0.525 mg of soya lecithin and 91.125 mg of lactosemonohydrate.

TOVIAZ 8 mg tablets

Each 8 mg sustained release tablet contains 0.525 mg of soya lecithin and 58.125 mg of lactosemonohydrate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Sustained release tablet.

TOVIAZ 4 mg tablets

The 4 mg tablets are light blue, oval, biconvex, film-coated, and engraved on one side with the letters ‘FS’.

TOVIAZ 8 mg tablets

The 8 mg tablets are blue, oval, biconvex, film-coated, and engraved on one side with the letters ‘FT’.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of the symptoms (increased urinary frequency and/or urgency and/or urgency incontinence) that

may occur in patients with overactive bladder syndrome.

4.2

Posology and method of administration

Posology

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.

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

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.

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).

Special population

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

or potent

CYP3A4 inhibitors

None

Moderate

Potent

Renal impairment

Mild

4→8 mg

4 mg

Should be avoided

Moderate

4→8 mg

4 mg

Contraindicated

Severe

4 mg

Should be avoided

Contraindicated

Hepatic impairment

Mild

4→8 mg

4 mg

Should be avoided

Moderate

4 mg

Should be avoided

Contraindicated

Mild GFR = 50-80 ml/min; Moderate GFR = 30-50 ml/min; Severe GFR = <30 ml/min

Cautious dose increase. See sections 4.4, 4.5 and 5.2

Moderate CYP3A4 inhibitors. See section 4.5

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

The safety and efficacy of TOVIAZ in children below 18 years of age have not yet been established. No data

are available.

Method of administration

Tablets are to be taken once daily with liquid and swallowed whole. TOVIAZ can be administered with or

without food.

4.3

Contraindications

Hypersensitivity to the active substance or to peanut or soya or to any of the excipients listed in

section 6.1

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.

4.4

Special warnings and precautions for use

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)

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

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 sections 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).

Dose increases

In patients with a combination of these factors, additional exposure increases are expected. Dose dependent

antimuscarinic adverse reactions 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.

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.

Angioedema

Angioedema has been reported with fesoterodine and has occurred after the first dose in some cases. If

angioedema occurs, fesoterodine should be discontinued and appropriate therapy should be promptly

provided.

Potent CYP3A4 inducers

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).

QT prolongation

TOVIAZ should be used with caution in patients with risk for QT prolongation (e.g. hypokalaemia,

bradycardia and concomitant administration of medicines known to prolong QT interval) and relevant pre-

existing cardiac diseases (e.g. myocardial ischaemia, arrhythmia, congestive heart failure), (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 medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Pharmacological interactions

Caution should be exercised in coadministration of fesoterodine with other antimuscarinics 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.

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

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

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

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

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

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.

Paediatric population

Interaction studies have only been performed in adults.

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of fesoterodine in pregnant women. Reproductive toxicity studies

with fesoterodine in animals show minor embryotoxicity. In animal reproduction studies, oral administration

of fesoterodine to pregnant mice and rabbits during organogenesis resulted in fetotoxicity at maternal

exposures that were 6 and 3 times the maximum recommended human dose (MRHD), respectively, based on

AUC (see section 5.3). The potential risk for humans is unknown. TOVIAZ is not recommended during

pregnancy.

Breast-feeding

It is unknown whether fesoterodine/metabolites are excreted into human milk; therefore, breast-feeding is

not recommended during treatment with TOVIAZ.

Fertility

No clinical trials have been conducted to assess the effect of fesoterodine on human fertility. Findings in

mice at exposures approximately 5 to 19 times those at the MRHD show an effect on female fertility,

however, the clinical implications of these animal findings are not known (see section 5.3). Women of child

bearing potential should be made aware of the lack of human fertility data, and TOVIAZ should only be

given after consideration of individual risks and benefits.

4.7

Effects on ability to drive and use machines

TOVIAZ has minor influence on the ability to drive and use machines.

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).

4.8

Undesirable effects

Summary of the safety profile

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 adverse reactions, occurred with a frequency of 28.8% in the fesoterodine

group compared to 8.5% in the placebo group. The majority of adverse reactions 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.

Tabulated list of adverse reactions

The table below gives the frequency of treatment emergent adverse reactions from placebo-controlled

clinical trials and from post-marketing experience. The adverse reactions are reported in this table with the

following frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (

1/1,000 to

<1/100), rare (

1/10,000 to <1/1,000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Very common

Common

Uncommon

Rare

Infections and

infestations

Urinary tract

infection

Psychiatric disorders

Insomnia

Confusional

state

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

System organ class

Very common

Common

Uncommon

Rare

Nervous system

disorders

Dizziness;

Headache

Dysgeusia;

Somnolence

Eye disorders

Dry eye

Blurred vision

Ear and labyrinth

disorders

Vertigo

Cardiac disorders

Tachycardia;

Palpitations

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

Hepatobiliary disorders

ALT increased;

GGT increased

Skin and subcutaneous

tissue disorders

Rash; Dry skin;

Pruritus

Angioedema;

Urticaria

Renal and urinary

disorders

Dysuria

Urinary

retention

(including

feeling of

residual urine;

micturition

disorder);

Urinary

hesitation

General disorders and

administration site

conditions

Fatigue

Description of selected adverse reactions

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 catheterisation 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il ).

4.9

Overdose

Overdose with antimuscarinics, including fesoterodine can result in severe anticholinergic 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.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, Urinary antispasmodics, ATC code: G04BD11.

Mechanism of action

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.

Clinical efficacy and safety

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

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

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

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

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

Change from

baseline

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

Change from

baseline

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.

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

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

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.

Biotransformation

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

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 population

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

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

and AUC are increased 2.0 and 2.3-fold, respectively.

Hepatic impairment

In patients with moderate hepatic impairment (Child Pugh B), C

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.

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.

In a study of fertility and early embryonic development in mice, fesoterodine had no effect on male

reproductive function or fertility at doses up to 45 mg/kg/day. At 45 mg/kg/day, a lower number of corpora

lutea, implantation sites and viable foetuses was observed in female mice administered fesoterodine for 2

weeks prior to mating and continuing through day 7 of gestation. The maternal No-Observed-Effect Level

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

(NOEL) and the NOEL for effects on reproduction and early embryonic development were both

15 mg/kg/day. Based on AUC, the systemic exposure was 0.6 to 1.5 times higher in mice than in humans at

the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Xylitol

Lactose monohydrate

Microcrystalline cellulose

Hypromellose

Glycerol dibehenate

Talc

Film-coating

Opadry

light blue

(4mg) or

Opadry

blue

(8mg) contains:

Polyvinyl alcohol

Titanium dioxide

Polyethylene glycol

Talc

Lecithin

Indigo carmine aluminium lake

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Special precautions for storage

Do not store above 25

Store in the original package in order to protect from moisture.

6.5

Nature and contents of container

TOVIAZ 4 mg and 8 mg tablets are packed in aluminium-aluminium blisters in cartons containing 7, 14, 28

or 56 tablets.

Not all the pack sizes may be marketed.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MANUFACTURER

R-PHARM Germany GmbH, Illertissen, Germany.

8. LICENSE HOLDER

Pfizer Pharmaceuticals Israel Ltd., 9 Shenkar st., Herzeliya 46725.

Toviaz 4 mg and 8 mg LPD, Israel, 261117

2017-0025873, 2017-0024823, 2016-0016728

The content of this leaflet was approved by the Ministry of Health in October 2013 and updated according to

the guidelines of the Ministry of Health in January 2018.