Active ingredients: Fesoterodine
TOVIAZ 4 mg prolonged-release tablets
TOVIAZ 8 mg prolonged-release tablets
Why is Toviaz used? What is it for?
TOVIAZ contains an active substance called fesoterodine fumarate and belongs to a class of medicines called antimuscarinics which reduce the activity of the overactive bladder and are used in adults to treat symptoms.
TOVIAZ treats symptoms of overactive bladder such as
- inability to control when emptying the bladder (urge incontinence)
- sudden urge to empty the bladder (urge to urinate)
- need to empty your bladder more often than usual (increased urinary frequency)
Contraindications When Toviaz should not be used
Do not take TOVIAZ
- if you are allergic to fesoterodine, peanut or soya or any of the other ingredients of this medicine (listed in section 6) (see section 2, "TOVIAZ contains lactose and soy oil")
- if you are unable to empty your bladder completely (urinary retention) - if your stomach empties slowly (gastric retention)
- if you have an eye disease called narrow-angle glaucoma (high blood pressure in the eye) which is not sufficiently controlled
- if you have excessive muscle weakness (myasthenia gravis)
- if you have "ulceration and inflammation of the colon (severe ulcerative colitis)
- if you have an enlarged or abnormally distended colon (enlarged colon)
- if you have severe liver problems.
- if you have kidney problems, or moderate to severe liver problems and are taking medicines containing any of the following active substances: itraconazole or ketoconazole (used to treat fungal infections), ritonavir, atazanavir, indinavir, saquinavir or nelfinavir (a antiviral medicine to treat AIDS), clarithromycin or telithromycin (used to treat bacterial infections) and nefazodone (used to treat depression).
Precautions for use What you need to know before you take Toviaz
Fesoterodine may not always be suitable for you. Talk to your doctor before taking TOVIAZ if any of the following apply to you:
- if you have difficulty emptying your bladder completely (for example due to an enlarged prostate)
- if you have ever suffered from decreased bowel movements or if you suffer from severe constipation
- if you are being treated for an eye disease called narrow-angle glaucoma
- if you have severe liver or kidney problems your doctor may need to adjust the dose of the medicine
- if you have a disease called autonomic neuropathy which occurs with symptoms such as changes in blood pressure or disorders of 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
- if you have a urinary tract infection, your doctor may need to prescribe certain antibiotics.
Heart problems: Talk to your doctor if you have any of the following conditions
- have an "abnormal" ECG (heart tracing) known as QT prolongation or are taking a medicine that causes this disturbance
- have a slow heartbeat (bradycardia)
- suffer from a heart disease called myocardial ischaemia (reduced blood supply to the heart muscle), irregular heartbeat or heart failure
- if you have hypokalaemia, which is a manifestation of very low levels of potassium in the blood.
Children and adolescents
Do not give this medicine to children and adolescents under the age of 18, as it has not yet been established whether this medicine is effective and safe for them.
Interactions Which drugs or foods can change the effect of Toviaz
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor will tell you if you can take TOVIAZ with other medicines.
Tell your doctor if you are taking any of the medicines listed in the list below. Taking them at the same time as fesoterodine can aggravate effects such as dry mouth, constipation, difficulty in completely emptying the bladder or sleepiness or cause them to appear more often.
- medicines containing amantadine as the active ingredient (used to treat Parkinson's disease)
- some medicines used to increase gastrointestinal motility or to relieve stomach cramps or spasms and to prevent traveler's disease such as medicines containing metoclopramide
- some medicines used to treat psychiatric diseases, such as antidepressants and neuroleptics.
Also tell your doctor if you are taking any of the following medicines:
- Medicines containing any of the following active substances may increase the breakdown of fesoterodine and thereby reduce its effect: St. John's wort (herbal medicine), rifampicin (used to treat bacterial infections), carbamazepine, phenytoin and phenobarbital ( used, among other indications, for the treatment of "epilepsy)
- medicines containing one of the following active substances may increase the levels of fesoterodine in the blood: 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 stop smoking or to treat depression ), quinidine (used to treat arrhythmias) and cinacalcet (used to treat hyperthyroidism)
- medicines containing the active substance methadone (used to treat severe pain and addiction problems).
Warnings It is important to know that:
Pregnancy and breastfeeding
You should not take TOVIAZ if you are pregnant, as the effects of fesoterodine on pregnancy and the fetus are not known. Talk to your doctor if you are pregnant or planning to become pregnant.
It is not known whether fesoterodine is excreted in human milk; therefore you should not breastfeed while being treated with TOVIAZ.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
TOVIAZ can cause blurred vision, dizziness and sleepiness. Do not drive or use any tools or machines if you experience any of these effects.
TOVIAZ contains lactose and soybean oil
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 medicinal product.
TOVIAZ contains soybean oil. If you are allergic to peanuts or soy, do not use this medicine.
Dose, Method and Time of Administration How to use Toviaz: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The recommended starting dose of TOVIAZ is one 4 mg tablet per day. Based on your response to the medicine, your doctor may increase the dose to one 8 mg tablet per day.
The tablet should be swallowed whole with a glass of water. Do not chew the tablet. TOVIAZ can be taken with or without food.
To remind you to take your medicine, it may be helpful for you to take the medicine at the same time each day.
If you forget to take TOVIAZ
If you forget to take a tablet, take it 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 tablet.
If you stop taking TOVIAZ
Do not stop taking TOVIAZ without talking to your doctor first, as the symptoms of overactive bladder can return or get worse if you stop taking TOVIAZ.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Toviaz
If you have taken more tablets than prescribed, or if someone else has accidentally taken your tablets, contact your doctor or hospital immediately and show them the pack of tablets.
Side Effects What are the side effects of Toviaz
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects can be serious
Serious allergic reactions including angioedema have occurred rarely. Stop taking TOVIAZ and contact your doctor immediately if you experience swelling of the face, mouth or throat.
Other side effects
Very common side effects (may affect more than 1 in 10 people)
Dry mouth may occur. This effect is usually mild or moderate. This can cause an increased risk of tooth decay. Therefore, you should regularly brush your teeth twice a day and consult your dentist if in doubt.
Common side effects (may affect up to 1 in 10 people)
- dry eyes
- constipation
- digestive problems (dyspepsia)
- excessive tension or pain when emptying the bladder (dysuria)
- dizziness
- headache
- stomach ache
- diarrhea
- feeling sick (nausea)
- sleep disturbances (insomnia)
- dryness of the throat
Uncommon side effects (may affect up to 1 in 100 people)
- urinary tract infection
- drowsiness
- taste disturbances (dysgeusia)
- dizziness
- rash
- dryness of the skin
- itch
- unpleasant feeling in the stomach
- intestinal gas (flatulence)
- difficulty completely emptying the bladder (urinary retention)
- delayed passing of urine (delayed urination)
- extreme tiredness (exhaustion)
- rapid heartbeat (tachycardia)
- palpitations
- liver problems
- cough
- nasal dryness
- sore throat
- acid reflux in the stomach
- blurred vision
Rare side effects (may affect up to 1 in 1,000 people)
- urticaria
- confusion
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP". The expiry date refers to the last day of that month.
Do not store above 25 ° C. Store in the original package to protect from moisture.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What TOVIAZ contains
The active ingredient is fesoterodine fumarate.
TOVIAZ 4 mg
- Each prolonged-release tablet contains 4 mg of fesoterodine fumarate corresponding to 3.1 mg of fesoterodine.
TOVIAZ 8 mg
- Each prolonged-release tablet contains 8 mg of fesoterodine fumarate corresponding to 6.2 mg of fesoterodine.
The other ingredients are:
- Tablet core: xylitol, lactose monohydrate, microcrystalline cellulose, hypromellose, glycerin dibeenate, talc.
- Coating: polyvinyl alcohol, titanium dioxide, macrogol, talc, soy lecithin, indigo carmine aluminum lake (E132).
Description of what TOVIAZ looks like and contents of the pack
TOVIAZ 4 mg prolonged-release tablets are light blue, oval, curved outward on both sides, film-coated and debossed with "FS" on one side.
TOVIAZ 8 mg prolonged-release tablets are blue, oval, curved outward on both sides, film-coated and debossed with "FT" on one side.
TOVIAZ is available in blister packs of 7, 14, 28, 30, 56, 84, 98 and 100 prolonged-release tablets.
Additionally, TOVIAZ is also available in HDPE bottles containing 30 or 90 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TOVIAZ PROLONGED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
TOVIAZ 4 mg prolonged-release tablets:
Each prolonged-release tablet contains 4 mg of fesoterodine fumarate corresponding to 3.1 mg of fesoterodine.
TOVIAZ 8 mg prolonged-release tablets:
Each prolonged-release tablet contains 8 mg of fesoterodine fumarate corresponding to 6.2 mg of fesoterodine.
Excipients with known effects:
TOVIAZ 4 mg prolonged-release tablets:
Each 4 mg prolonged-release tablet contains 0.525 mg of soy lecithin and 91.125 mg of lactose.
TOVIAZ 8 mg prolonged-release tablets:
Each 8 mg prolonged-release tablet contains 0.525 mg of soy lecithin and 58,125 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release tablets.
TOVIAZ 4 mg prolonged-release tablets:
The 4 mg tablets are light blue, oval, biconvex, film-coated and debossed with FS "on one side.
TOVIAZ 8 mg prolonged-release tablets:
The 8 mg tablets are blue, oval, biconvex, film-coated and debossed with the siglàFT "on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of symptoms (increased urinary frequency and / or urge urgency and / or urge incontinence) that may occur in adult patients with overactive bladder syndrome.
04.2 Posology and method of administration
Dosage
Adults (including the elderly)
The recommended starting dose is 4 mg once a day. The dose can be increased to 8 mg once daily based on individual response. The maximum daily dose is 8 mg.
The full effect of the treatment was observed between 2 and 8 weeks. Therefore, it is recommended to re-evaluate the efficacy for the individual patient after 8 weeks of therapy.
In subjects with normal renal and hepatic function receiving concomitant treatment with potent CYP3A4 inhibitors, the maximum daily dose of TOVIAZ should be 4 mg once daily (see section 4.5).
Special populations
Renal and hepatic insufficiency
Dosing recommendations for subjects with renal and hepatic impairment in the absence and presence of concomitant therapy with moderate and strong CYP3A4 inhibitors are presented in the following table (see sections 4.3, 4.4, 4.5 and 5.2).
TOVIAZ is contraindicated in subjects with severe hepatic impairment (see section 4.3).
Pediatric population
The safety and efficacy of TOVIAZ in children under the age of 18 have not yet been established,
No data are available.
Method of administration
The tablets should be taken once daily with some liquid and swallowed whole. TOVIAZ can be administered with or without food.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, to peanuts or soy
• Urinary retention
• Gastric retention
• Uncontrolled angle-closure glaucoma
• Myasthenia gravis
• Severe hepatic insufficiency (Child Pugh C)
• Concomitant use of potent CYP3A4 inhibitors in subjects with moderate to severe hepatic or renal impairment
• Severe ulcerative colitis
• Enlarged colon.
04.4 Special warnings and appropriate precautions for use
TOVIAZ should be used with caution in patients with:
• Clinically significant obstruction of bladder outflow at risk of urinary retention (eg clinically significant prostate enlargement due to benign prostatic hyperplasia, see section 4.3)
• Obstructive gastrointestinal disorders (eg pyloric stenosis)
• Gastroesophageal reflux and / or concomitant medication (such as oral bisphosphonates) which can cause or exacerbate esophagitis
• Reduction of gastrointestinal motility
• Autonomic neuropathy
• Controlled angle-closure glaucoma
Caution should be exercised when prescribing fesoterodine or increasing its dose in patients who are expected to increase exposure to the active metabolite (see section 5.1):
- Hepatic failure (see sections 4.2, 4.3 and 5.2)
- Renal failure (see sections 4.2, 4.3 and 5.2)
- Concomitant administration of strong 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).
Increase the dose
In patients with a combination of these factors, further increases in drug exposure are expected. Dose-dependent antimuscarinic associated adverse reactions are likely to occur. In patient populations where the dose can be increased to 8 mg once daily, dose escalation should be preceded by an assessment of individual response and tolerability.
Organic causes must be ruled out before considering any treatment with antimuscarinic drugs. The safety and efficacy of the drug have not yet been established in patients with detrusor hyperactivity of neurogenic origin.
Other causes of frequent urination (treatment of heart failure or kidney disease) should be evaluated before starting treatment with fesoterodine. In the presence of urinary tract infection, an appropriate medical approach should be taken / antibacterial therapy initiated.
Angioedema
Angioedema has been reported with fesoterodine and has occurred in some cases after the first dose. If angioedema occurs, treatment with fesoterodine should be discontinued and appropriate therapy instituted promptly.
Strong inducers of CYP3A4
The concomitant use of fesoterodine and a strong CYP3A4 inducer (eg 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 at risk of QT interval prolongation (eg hypokalaemia, bradycardia and concomitant administration of QT interval prolonging medications) and with a history of related pre-existing heart disease (eg. myocardial ischaemia, arrhythmia, congestive heart failure) (see section 4.8). This particularly applies when taking strong 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.
04.5 Interactions with other medicinal products and other forms of interaction
Drug interactions
Caution should be exercised in case of concomitant administration of fesoterodine with other antimuscarinic agents and medicinal products with anticholinergic properties (e.g. amantadine, tricyclic antidepressants, some neuroleptics) as this may result in more pronounced therapeutic and undesirable effects (e.g. constipation, dryness) mouth, sleepiness, urinary retention).
Fesoterodine may reduce the effect of drugs that stimulate the motility of the gastrointestinal tract, such as metoclopromide.
Pharmacokinetic interactions
The data in vitro demonstrate that, at clinically relevant plasma concentrations, the active metabolite of fesoterodine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 and does not induce CYP1A2, 2B6, 2C9, 2C19 or 3A4. & EGRAVE; therefore, fesoterodine is unlikely to alter the clearance of medicinal products that are metabolised by these enzymes.
CYP3A4 inhibitors
Strong CYP3A4 inhibitors
Following inhibition of CYP3A4 by concomitant administration of ketoconazole 200 mg twice daily, the Cmax and AUC values of the active metabolite of fesoterodine increased 2.0- and 2.3-fold, respectively, in extensive metabolisers of CYP2D6, and 2-fold. , 1 and 2.5-fold in CYP2D6 poor metabolisers. Therefore the maximum dose of fesoterodine should be limited to 4 mg when administered concomitantly with potent CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir (and all treatments with protease inhibitors boosted with ritonavir), saquinavir and telithromycin (see sections 4.2 and 4.4).
Moderate CYP3A4 inhibitors
Following blockade of CYP3A4 by concomitant administration of the moderate CYP3A4 inhibitor fluconazole at a dose of 200 mg twice daily for 2 days, the Cmax and AUC values of the active metabolite of fesoterodine increased by approximately 19% and 27, respectively. %. No dose adjustment is 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 (eg cimetidine) has not been investigated; it is not expected to exceed that of moderate inhibitors.
CYP3A4 inducers
Following induction of CYP3A4 by concomitant administration of rifampicin 600 mg once daily, the Cmax and AUC values of the active metabolite of fesoterodine decreased by approximately 70% and 75%, respectively, after oral administration of fesoterodine 8 mg.
CYP3A4 induction may lead to subtherapeutic plasma levels. Concomitant use of CYP3A4 inducers (eg carbamazepine, rifampicin, phenobarbital, phenytoin, St. John's wort) is not recommended (see section 4.4).
CYP2D6 inhibitors
Interaction with CYP2D6 inhibitors has not been clinically tested. The mean Cmax and AUC values of the active metabolite are 1.7 and 2.0 times higher in CYP2D6 poor metabolisers than in extensive metabolisers, respectively. Concomitant administration of an inhibitor potency of CYP2D6 may lead to an increase in drug exposure and an increase in adverse events. A dose reduction to 4 mg may be required (see section 4.4).
Oral contraceptives
Fesoterodine does not affect ovulation suppression induced by oral hormonal contraception. No changes in plasma concentrations of combined oral contraceptives containing ethinylestradiol and levonorgestrel occur in the presence of fesoterodine.
Warfarin
A clinical study in healthy volunteers showed that once daily administration of 8 mg fesoterodine has no significant effect on the pharmacokinetics or anticoagulant activity of a single dose of warfarin.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data from the use of fesoterodine in pregnant women. Reproductive toxicity studies with fesoterodine in animals show minimal embryotoxicity (see section 5.3). The potential risk for humans is unknown. The use. of TOVIAZ is not recommended during pregnancy.
Feeding time
It is not known whether fesoterodine is excreted in human milk; therefore, it is recommended not to breastfeed during treatment with TOVIAZ.
Fertility
No clinical studies have been conducted to evaluate the effect of fesoterodine on human fertility. Fesoterodine fumarate had no effect on the male or female fertility of the mice, nor any effect on the reproductive function or early embryonic development of the fetus in the mice (for details see section 5.3). Women of childbearing potential should be made aware of the lack of fertility data, and TOVIAZ should only be prescribed after assessing the individual benefits and risks.
04.7 Effects on ability to drive and use machines
TOVIAZ has minor effects on the ability to drive or use machines. Caution should be exercised when driving vehicles or using machines as undesirable effects such as blurred vision, dizziness and somnolence may occur (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
The safety of fesoterodine was evaluated in placebo-controlled clinical trials in a total of 2,859 patients with overactive bladder, of whom 780 received placebo.
Due to the pharmacological properties of fesoterodine, treatment may induce mild to moderate antimuscarinic effects, such as dry mouth, dry eye, dyspepsia and constipation. Episodes of urinary retention may occur uncommonly.
Dry mouth, the only very common adverse reaction, occurred with a frequency of 28.8% in the fesoterodine treatment group compared with 8.5% in the placebo group. Most adverse reactions occurred in the first month of treatment with the exception of those cases, classified as urinary retention or residual urine volume greater than 200 ml, which may occur after long-term treatment and which were more frequent in subjects. male than female.
Table of adverse reactions
The table below shows the frequency of treatment-emergent adverse reactions in placebo-controlled clinical trials and in post-marketing experience. Adverse reactions are presented in this table with the following frequency convention: very common (≥ 1/10 ), common (≥ 1/100,
Within each frequency class, adverse reactions are reported in order of decreasing severity.
Description of selected adverse reactions
In clinical trials with fesoterodine, elevated elevations of liver enzymes were reported with a frequency of occurrence not different from that in the placebo group. The relationship with fesoterodine treatment is unclear.
Electrocardiograms were performed in 782 patients treated with fesoterodine 4 mg, 785 with fesoterodine 8 mg, 222 with fesoterodine 12 mg and 780 with placebo. In patients treated with fesoterodine, the QT interval corrected for heart rate did not differ from that found in patients treated with placebo. The incidence rates of QTc ≥ 500 ms post-baseline or QTc increase ≥ 60 ms are equal to 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 data will depend on individual risk factors and individual patient susceptibility (see section 4.4.).
Cases of urinary retention requiring catheterization have been reported in the post-marketing setting, usually within the first week of treatment with fesoterodine. These cases mainly involved elderly men (≥ 65 years of age) of male gender with a history of benign prostatic hyperplasia (see section 4.4).
04.9 Overdose
Overdose with antimuscarinics, including fesoterodine, can result in severe anticholinergic effects. Treatment should be symptomatic and supportive. In the event of an overdose, ECG monitoring is recommended; standard supportive measures should also be taken to manage QT prolongation. Fesoterodine has been safely administered in clinical studies at doses up to 28 mg / day.
In the event of fesoterodine overdose, patients should be treated with gastric lavage and activated charcoal. Symptoms should be treated as follows:
- Severe central anticholinergic effects (e.g. hallucinations, severe arousal): treat with physostigmine
- Convulsions or marked arousal: treat with benzodiazepines
- Respiratory failure: treat with artificial respiration
- Tachycardia: treat with β-blockers
- Urinary retention: deal with using catheterization
- Mydriasis: treat with pilocarpine eye drops and / or take the patient to a dark room.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: urologicals, urinary antispasmodics, ATC code: G04B D11.
Mechanism of action
Fesoterodine is a specific competitive muscarinic receptor antagonist. It is rapidly and extensively hydrolyzed by non-specific plasma esterases into the 5-hydroxymethyl derivative, its primary active metabolite, which is the main pharmacological active ingredient of fesoterodine.
Clinical efficacy and safetyThe efficacy of fixed doses of fesoterodine 4 mg and 8 mg was evaluated in two 12-week randomized, double-blind, placebo-controlled Phase 3 studies in female (79%) and male (21%) patients. ) and with a mean age of 58 years (range 19 to 91 years). 33% of patients were ≥ 65 years of age and 11% ≥ 75 years.
At the end of treatment, patients treated with fesoterodine had statistically significant mean reductions in the number of urinations over 24 hours and in the number of urge incontinence episodes over 24 hours compared to placebo. Similarly, the response rate (% of patients who reported their condition as "significantly improved" or "improved" using a 4-point Therapeutic Benefits Scale) was significantly higher with fesoterodine than with placebo. Additionally, fesoterodine improved the mean change in voided urinary volume per micturition and the mean change in the number of days with normal continence per week (see Table 1 below).
Table 1: Mean changes from baseline to end of treatment for selected primary and secondary endpoints
# primary endpoints
Cardiac electrophysiology
The effect of fesoterodine 4 mg and 8 mg on the QT interval was carefully evaluated in a double-blind, randomized, parallel-group study conducted on placebo and positive control (moxifloxacin 400 mg) in 261 male and female subjects of age. between 45 and 65 years with daily treatment for a period of 3 days. The changes in QTc from baseline assessed with the Fridericia correction method did not reveal any difference between the active treatment and the placebo group.
05.2 Pharmacokinetic properties
Absorption
Due to the rapid and extensive hydrolysis by non-specific plasma esterases, the presence of fesoterodine in plasma was not detected after oral administration.
The bioavailability of the active metabolite is 52%. Following oral administration of single or multiple doses of 4 mg to 28 mg of fesoterodine, plasma concentrations of the active metabolite are dose proportional. Maximum plasma levels are reached after approximately 5 hours. Therapeutic plasma levels are reached after the first administration of fesoterodine. No accumulation occurs after administration of multiple doses.
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 equal to 169 l.
Biotransformation
Following oral administration, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite, which in turn is further metabolised in the liver to its carboxyl metabolite, carboxyl-N-desisopropyl and N-desisopropyl, with involvement of CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine. The mean Cmax and AUC values of the active metabolite are 1.7 and 2.0-fold higher in CYP2D6 poor metabolisers than in extensive metabolisers, respectively.
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%), carboxylic metabolite (34%), carboxy-N-desisopropyl metabolite (18%) or N-desisopropyl metabolite (1%), and a smaller amount (7%) was found in the faeces. Following oral administration the terminal half-life of the active metabolite is approximately 7 hours and is limited by the rate of absorption.
Age and gender
No dosage adjustment is recommended in these subpopulations. The pharmacokinetics of fesoterodine are not significantly influenced by age and gender.
Pediatric population
The pharmacokinetics of fesoterodine have not been evaluated in pediatric patients.
Kidney failure
In patients with mild or moderate renal impairment (GFR 30-80 ml / min), the Cmax and AUC values of the active metabolite are increased by up to 1.5 and 1.8 times, respectively, compared to healthy subjects. In patients with severe renal insufficiency (GFR
Hepatic insufficiency
In patients with moderate hepatic impairment (Child Pugh B), the Cmax and AUC values of the active metabolite increased 1.4- and 2.1-fold, respectively, compared to healthy subjects. The pharmacokinetics of fesoterodine in patients with severe hepatic impairment have not been studied.
05.3 Preclinical safety data
In non-clinical studies of safety pharmacology, general toxicity, genotoxicity and carcinogenicity no clinically relevant effects have been observed, with the exception of those related to the pharmacological effect of the active ingredient.
Reproduction studies have shown minimal embryotoxicity at doses similar to those toxic to the mother (increased cases of resorption, pre-implantation and post-implantation losses).
Concentrations of the active metabolite of fesoterodine higher than the therapeutic ones showed an inhibition of the current of K + ions in cloned channels of the human ether-à-go-go-related gene (hERG) and a prolongation of the duration of the action potential (70 % and 90% repolarization) in isolated canine Purkinje fibers. However, in conscious dogs following fesoterodine 8 mg once daily the active metabolite had no effect on the QT and QTc intervals at plasma exposures of at least 33-fold. higher than the mean peak free plasma concentration found in human subjects recognized as extensive metabolisers, and 21-fold higher than those measured in subjects recognized as poor metabolisers of CYP2D6.
In a fertility and early embryonic development study in mice, fesoterodine had no effect on male or female fertility at the highest dose evaluated, i.e. 45 mg / kg / day. In mice, fesoterodine had no effect on reproductive function or early embryonic development of the fetus at non-toxic maternal doses, although a slight decrease in corpora lutea, implantation sites and viable fetuses was reported at the toxic dose. maternal of 45 mg / kg / day. Both the no effect dose (No-Observed-Effect Level - NOEL) maternal and the NOEL value for the effects on reproduction and on the early stages of embryonic development were both 15 mg / kg / day. Based on AUC, systemic exposure was 0.6 to 1.5 times higher in mice than in humans at the maximum recommended human dose (MRHD), while considering peak plasma concentrations l " exposure in mice was 5 to 9 times higher.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Xylitol
Lactose monohydrate
Microcrystalline cellulose
Hypromellose
Glycerin dibeenate
Talc
Coating film
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol
Talc
Soy lecithin
Aluminum lake, containing indigo carmine (E132)
06.2 Incompatibility
Not relevant
06.3 Period of validity
2 years
06.4 Special precautions for storage
Do not store above 25 ° C.
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
TOVIAZ 4 mg prolonged-release tablets:
TOVIAZ 4 mg tablets are packaged in aluminum-aluminum blisters in cartons containing 7, 14, 28, 30, 56, 84, 98 or 100 tablets. In addition, TOVIAZ 4 mg tablets are packaged in HDPE bottles containing 30 or 90 tablets.
TOVIAZ 8 mg prolonged-release tablets:
TOVIAZ 8 mg tablets are packaged in aluminum-aluminum blisters in cartons containing 7, 14, 28, 30, 56, 84, 98 or 100 tablets. In addition, TOVIAZ 8 mg tablets are packaged in HDPE bottles containing 30 or 90 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
08.0 MARKETING AUTHORIZATION NUMBER
TOVIAZ 4 mg prolonged-release tablets:
EU / 1/07/386 / 001-005
038699017
038699029
038699031
038699043
038699056
EU / 1/07/386/011
038699118
EU / 1/07/386 / 013-014
EU / 1/07/386/017
EU / 1/07/386/019
038699195
TOVIAZ 8 mg prolonged-release tablets:
EU / 1/07/386 / 006-010
038699068
038699070
038699082
038699094
038699106
EU / 1/07/386/012
038699120
EU / 1/07/386 / 015-016
EU / 1/07/386/018
EU / 1/07/386/020
038699207
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 April 2007
Date of most recent renewal: April 20, 2012
10.0 DATE OF REVISION OF THE TEXT
September 15, 2012
