Active ingredients: Tolterodina
Tolterodine 2 mg prolonged-release hard capsules
Tolterodine 4 mg prolonged-release hard capsules
Why is Tolterodina used - Generic drug? What is it for?
The active substance in Tolterodine is tolterodine. Tolterodine belongs to a class of medicinal products called antimuscarinics.
Tolterodine is used to treat the symptoms of overactive bladder syndrome. If you have an overactive bladder, it will happen to you
- not being able to control the emission of urine
- having to rush to the bathroom without warning and / or go to the bathroom often.
Contraindications When Tolterodina should not be used - Generic drug
Do not take Tolterodine if:
- you are allergic (hypersensitive) to tolterodine or any of the other ingredients of Tolterodine (see section 6 for a list of excipients)
- unable to pass urine (urinary retention)
- have uncontrolled acute angle glaucoma (high pressure in the eye with loss of vision that is not treated properly)
- suffer from myasthenia gravis (excessive muscle weakness)
- suffer from severe ulcerative colitis (ulceration and inflammation of the colon)
- suffer from severe toxic megacolon (acute dilation of the colon).
Precautions for use What you need to know before taking Tolterodina - Generic drug
Take special care with Tolterodina DOC:
- if you have difficulty urinating and / or have a reduced urine flow
- if you have a gastrointestinal disease that affects the passage and / or digestion of food
- if you have kidney problems (kidney failure).
- if you have liver problems
- if you have a neurological disease that affects blood pressure, bowel or sexual function (any neuropathy of the autonomic nervous system)
- if you have a "hiatal hernia (a" hernia of an abdominal organ)
- if you sometimes have reduced bowel mobility or suffer from severe constipation (reduced gastrointestinal mobility)
- if you have a heart problem such as:
- abnormal cardiac tracing (ECG)
- slow heart rate (bradycardia)
- relevant pre-existing heart conditions such as: cardiomyopathy (weak heart muscle), myocardial ischaemia (reduced blood flow to the heart), arrhythmia (irregular heartbeat) and heart failure
- if you have abnormally low levels of potassium (hypokalaemia), calcium (hypocalcaemia) or magnesium (hypomagnesaemia) in your blood.
Contains approximately 67.2 mg of lactose (33.6 mg glucose and 33.6 mg galactose) per dose. This must be taken into consideration in patients with diabetes mellitus.
This medicinal product contains 0.00404 mmol (or 0.092988 mg) sodium per dose. This should be taken into consideration in patients on a controlled sodium diet.
Check with your doctor or pharmacist before taking Tolterodine if you think any of these apply to you.
Interactions Which drugs or foods can modify the effect of Tolterodine - Generic Drug
Tell your doctor if you are taking or have recently taken any other medicines, even those without a prescription.
Tolterodine, the active substance in Tolterodine, may interact with other medicines.
The use of tolterodine is not recommended with:
- some antibiotics (containing e.g.erythromycin, clarithromycin)
- medicines used to treat fungal infections (containing e.g. ketoconazole, itraconazole)
- medicines used to treat HIV.
Tolterodine should be used with caution together with:
- medicines that affect the passage of food (containing e.g. metoclopramide and cisapride)
- medicines to treat irregular heartbeat (containing eg amiodarone, sotalol, quinidine, procainamide, other medicines with a mechanism of action similar to that of Tolterodine (antimuscarinic properties) or medicines with an opposite mechanism of action to TOLTERODINE (cholinergic properties) Reduced gastric mobility caused by antimuscarinics may affect the absorption of other drugs. Ask your doctor if you are not sure.
Taking Tolterodine with food and drink
Tolterodine can be taken before, during and after a meal.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
You should not use Tolterodine when you are pregnant. Tell your doctor right away if you are pregnant, think you are pregnant or plan to become pregnant.
Feeding time
It is not known whether tolterodine, the active substance in Tolterodine, is excreted in breast milk. Breast-feeding while taking Tolterodine is not recommended.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Tolterodine can make you feel dizzy, tired or have disturbed vision. If this happens to you, do not drive vehicles or use machines.
Important information about some of the ingredients of Tolterodine
This medicinal product contains lactose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Tolterodina - Generic drug: Dosage
Dosage:
Always take Tolterodine Accord exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The prolonged-release hard capsules are for oral use only and should be swallowed whole.
Do not chew the capsules.
Adults:
The usual dose is one 4 mg prolonged-release capsule, hard per day.
Patients with liver or kidney problems:
In patients with liver or kidney problems your doctor may reduce the dose to 2 mg Tolterodine per day.
Children:
Tolterodine is not recommended for children.
If you forget to take Tolterodine
If you forget to take a dose at the usual time, take it as soon as you remember, unless it is almost time for your next dose. In this case, skip the missed dose and follow the normal treatment schedule.
Do not take a double dose to make up for a forgotten tablet.
If you stop taking Tolterodine
Your doctor will tell you how long your treatment with Tolterodine should last. Do not stop treatment sooner as you do not notice an immediate effect. Your bladder needs some time to adjust. Finish the course of prolonged-release capsules your doctor has prescribed. If you don't notice any effect by then, please tell your doctor.
The benefit of the treatment should be reassessed after 2 to 3 months. Always consult your doctor if you think about stopping treatment.
If you have any further questions on the use of Tolterodine, ask your doctor or pharmacist.
Overdose What to do if you have overdosed Tolterodine - Generic drug
If you or someone else takes too many prolonged-release capsules, contact your doctor or pharmacist immediately. Symptoms of overdose include hallucinations, excitement, a faster-than-normal heart rate, dilated pupils, and an inability to urinate and breathe normally.
Side Effects What are the side effects of Tolterodine - Generic drug
Like all medicines, Tolterodine can cause side effects, although not everybody gets them.
See your doctor or the nearest hospital emergency department immediately if you experience any of the symptoms of angioedema, such as:
- swelling of the face, tongue or pharynx
- difficulty swallowing
- hives and difficulty in breathing.
You should also contact your doctor if you experience symptoms of a hypersensitivity reaction (e.g. itching, rash, hives, difficulty in breathing). This is uncommon (occurs in less than 1 in 100 patients).
See your doctor or the nearest hospital emergency department immediately if you experience any of the following symptoms:
- chest pain, difficulty breathing or getting tired (even at rest), difficulty breathing at night, swelling of the legs.
These can be symptoms of heart failure. This is not common (occurs in less than 1 in 100 patients).
The following side effects have been observed during treatment with tolterodine, with the frequencies indicated.
Very common side effects (occurring in more than 1 in 10 patients) are:
- Dry mouth
Common side effects (occurring in less than 1 in 10 patients) are:
- Sinusitis
- Dizziness
- Drowsiness
- Headache
- Dry eyes
- Blurred vision
- Digestive difficulties (dyspepsia)
- Constipation
- Abdominal pain
- Excessive amount of air or gas in the stomach and intestines
- Pain or difficulty in urinating
- Diarrhea
- Fluid retention that causes swelling (for example in the ankles)
- Tiredness
Uncommon side effects (occurring in less than 1 in 100 patients) are:
- Allergic reactions
- Heart failure
- Nervousness
- Irregular heartbeat
- Palpitations
- Chest pain
- Inability to empty the bladder
- Tingling in the hands and feet
- Dizziness
- Memory impairment
Other reported reactions include severe allergic reactions, confusion, hallucinations, rapid heart rate, flushing of the skin, heartburn, vomiting, angioedema, dry skin and disorientation. There have also been reports of worsening of dementia symptoms in patients being treated for dementia.
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.
Expiry and Retention
Keep Tolterodine out of the reach and sight of children.
Do not use TOLTERODINA DOC after the expiry date which is stated on the label / carton. The expiry date refers to the last day of the month.
Do not store above 25 ° C.
HDPE bottle: the shelf life after first opening is 200 days.
Medicines should not be disposed of 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 TOLTERODINE DOC
The active substance in Tolterodine 2 mg prolonged-release hard capsules is 2 mg tolterodine tartrate, equivalent to 1.37 mg tolterodine.
The active substance in Tolterodine 4 mg prolonged-release hard capsules is 4 mg tolterodine tartrate, equivalent to 2.74 mg tolterodine.
The other ingredients are: lactose monohydrate, microcrystalline cellulose, poly (vinyl acetate), povidone, silica, sodium lauryl sulfate, sodium docusate, magnesium stearate, hydroxypropylmethylcellulose.
Composition of the capsule: indigo carmine red (E132), quinoline yellow (only in 2 mg) (E104), titanium dioxide (E171), gelatin.
Tablet coating inside: ethyl cellulose, triethyl citrate, methacrylic acid - ethyl acrylate copolymer, 1,2-propylene glycol.
What Tolterodine looks like and contents of the pack
Tolterodine are prolonged-release hard capsules for single daily dose.
Tolterodine 2 mg prolonged-release hard capsules are opaque green-opaque green.
Tolterodine 4 mg prolonged-release hard capsules are opaque blue - opaque blue.
Tolterodine 2 mg prolonged-release hard capsules are available in the following pack sizes:
- 14, 28, 30, 50, 84, 100 prolonged-release hard capsules in blisters
- 30, 100 and 200 prolonged-release hard capsules in HDPE bottle.
Tolterodine 4 mg prolonged-release hard capsules are available in the following pack sizes:
- 7, 14, 28, 49, 84, 98 prolonged-release hard capsules in blister packs
- 30, 100 and 200 prolonged-release hard capsules in HDPE bottle
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
TOLTERODINA DOC 2 - 4 MG
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release capsule, hard contains: tolterodine tartrate 2 mg corresponding to 1.37 mg tolterodine.
Each prolonged-release capsule, hard contains: tolterodine tartrate 4 mg corresponding to 2.74 mg tolterodine.
Each 2 mg prolonged-release capsule, hard contains 32.704 - 34.496 mg of lactose monohydrate.
Each 4 mg prolonged-release capsule, hard contains 65.408 - 68.992 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release hard capsules.
Tolterodine 2 mg: opaque green to opaque green hard gelatin capsule, size 1, containing 2 white, round, biconvex, coated tablets.
Tolterodine 4 mg: opaque blue to opaque blue hard gelatin capsule, size 1, containing 4 white, round, biconvex, coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Tolterodine is indicated for the symptomatic treatment of urge incontinence and / or increased urinary frequency and urgency in patients with overactive bladder syndrome.
04.2 Posology and method of administration
Adults (including elderly patients) :
The recommended dose is 4 mg once daily, except in patients with hepatic impairment or severe renal impairment (GFR ≤ 30 ml / min) for whom the recommended dose is 2 mg once daily ( see sections 4.4 and 5.2). In case of troublesome side effects the dose can be reduced from 4 mg to 2 mg once a day.
The prolonged-release hard capsules can be taken with or without food and should be swallowed whole.
The treatment effect should be re-evaluated after 2-3 months (see section 5.1).
Pediatric patients :
The efficacy of Tolterodine in children has not been demonstrated (see section 5.1). Therefore, Tolterodine is not recommended in children.
04.3 Contraindications
Tolterodine is contraindicated in patients with:
- Hypersensitivity to the active substance or to any of the excipients
- Urinary retention
- Uncontrolled narrow angle glaucoma
- Myasthenia gravis
- Severe ulcerative colitis
- Toxic megacolon.
04.4 Special warnings and appropriate precautions for use
Tolterodine should be used with caution in patients with:
- Significant obstruction of the bladder neck with risk of urinary retention
- Obstructive gastrointestinal disorders, eg. pyloric stenosis
- Renal impairment (see sections 4.2 and 5.2)
- Liver disease (see sections 4.2 and 5.2)
- Neuropathy affecting the autonomic nervous system
- Hiatal hernia
- Risk of decreased gastrointestinal motility.
Administration of multiple daily doses of 4 mg (therapeutic) and 8 mg (supratherapeutic) of immediate-release tolterodine has been observed to prolong the QTc interval (see section 5.1). The clinical relevance of these data is unclear and it depends on the risk factors and the predisposition of the individual patient.
Tolterodine should be used with caution in patients with risk factors for QT prolongation, including:
- Prolongation of congenital or acquired and documented QT
- Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcemia
- Bradycardia
- Pre-existing major coronary heart disease (cardiomyopathy, myocardial ischaemia, arrhythmia, congestive heart failure)
- Concomitant administration of drugs that prolong the QT interval including Class 1A (eg quinidine, procainamide) and Class III (eg amiodarone, sotalol) antiarrhythmics.
This applies particularly when taking a potent CYP3A4 inhibitor (see section 5.1). Concomitant treatment with potent CYP3A4 inhibitors should be avoided (see section 4.5 Interactions).
As with all other treatments for urinary urgency symptoms or urge incontinence, possible organic causes for urgency and frequency should be considered prior to treatment.
This product contains approximately 67.2 mg of lactose (33.6 mg of glucose and 33.6 mg of galactose) per dose. This must be taken into consideration in patients with diabetes mellitus. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product contains 0.00404 mmol (or 0.092988 mg) sodium per dose. This should be taken into consideration by patients on a low-sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction
In patients with poor CYP2D6 metabolism, systemic concomitant treatment with potent CYP3A4 inhibitors such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole and itraconazole) and protease inhibitors is not recommended due to increased serum concentrations. tolterodine, with (consequent) risk of overdose (see section 4.4).
Concomitant treatment with other drugs that possess antimuscarinic properties can lead to more pronounced therapeutic effects and adverse reactions. Conversely, the therapeutic effect of tolterodine may be reduced following concomitant treatment with cholinergic muscarinic receptor agonists. The reduction in gastric motility caused by antimuscarinics may affect the absorption of other drugs.
The effect of prokinetic drugs such as metoclopramide and cisapride may be diminished by tolterodine.
Concomitant treatment with fluoxetine (a potent CYP2D6 inhibitor) does not result in a clinically significant interaction since tolterodine and its CYP2D6-dependent metabolite, 5-hydroxymethyl tolterodine, are equivalent.
Drug interaction studies have shown no interactions with warfarin or combination oral contraceptives (ethinylestradiol / levonorgestrel).
A clinical study indicated that tolterodine is not a metabolic inhibitor of CYP2D6, 2C19, 2C9, 3A4 or 1A2. Therefore, an increase in plasma levels of drugs metabolised via these isoenzymes is not expected when administered in combination with tolterodine.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data on the use of tolterodine in pregnant women.
Studies in animals have shown reproductive toxicity effects (see section 5.3). The potential risk in humans is unknown.
Therefore tolterodine is not recommended during pregnancy.
Feeding time
There are no data on the excretion of tolterodine in breast milk. The use of tolterodine should be avoided during lactation.
Fertility
No data from fertility studies are available.
04.7 Effects on ability to drive and use machines
As this medicine can cause accommodation disturbances and affect reaction time, the ability to drive and use machines may be adversely affected.
04.8 Undesirable effects
In view of its pharmacological characteristics, tolterodine can cause mild to moderate antimuscarinic effects, such as dry mouth, dyspepsia and dry eyes.
Adverse reactions are listed below by system organ class and by frequency. Frequencies are defined as: very common (≥1 / 10), common (≥1 / 100a
The table below shows the data obtained from clinical studies conducted with tolterodine and those from pharmacovigilance.The most commonly reported adverse reaction was dry mouth, which occurred in 23.4% of patients treated with prolonged-release tolterodine and in 7.7% of patients treated with placebo.
After initiation of tolterodine therapy in patients taking cholinesterase inhibitors for the treatment of dementia, there have been reports of worsening of symptoms of dementia (eg confusion, disorientation, hallucinations).
Pediatric population
In two randomized, double-blind, placebo-controlled phase III pediatric studies involving 710 pediatric patients for 12 weeks, the proportion of patients with urinary tract infection, diarrhea and abnormal behavior was higher in patients treated with tolterodine than in those treated. with placebo (urinary tract infection: tolterodine 6.8%, placebo 3.6%; diarrhea: tolterodine 3.3%, placebo 0.9%; abnormal behavior: tolterodine 1.6%, placebo 0.4% (see paragraph 5.1)
04.9 Overdose
The highest dose of tolterodine tartrate administered as a single dose to healthy volunteers in the immediate release formulation was 12.8 mg. The most serious adverse effects observed were accommodation disturbances and urination difficulties.
In case of overdose, perform gastric lavage and administer activated charcoal.
Treat the symptoms as follows:
- Severe central anticholinergic effects (eg hallucinations, severe excitement): administer physostigmine.
- Convulsions or pronounced excitation: administer benzodiazepines.
- Respiratory insufficiency: give artificial respiration.
- Tachycardia: administer? -Blockers.
- Urinary retention: use of the catheter.
- Mydriasis: administer pilocarpine eye drops and / or keep the patient in the dark.
An increase in the QT interval was observed with a single daily dose of 8 mg immediate-release tolterodine (twice the recommended daily dose of the immediate-release formulation and equivalent to three times the maximum exposure of the prolonged-release formulation) administered. over 4 days. In the event of an overdose of tolterodine, standard supportive measures for management of QT interval prolongation should be employed.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: genitourinary system and sex hormones.
Pharmacotherapeutic sub-group: urinary antispasmodics.
ATC code: G04B D07.
Tolterodine is a specific competitive muscarinic receptor antagonist that demonstrates selectivity for the urinary bladder over salivary glands in vivo. One of the metabolites of tolterodine (5-hydroxymethyl derivative) exhibits a similar pharmacological profile to that of the parent compound. In extensive metabolisers this metabolite contributes significantly to the therapeutic effect of tolterodine (see section 5.2).
The effects of the treatment can be expected within 4 weeks.
In the Phase III program, the primary endpoint was the reduction in the number of incontinence episodes per week and the secondary endpoints were the reduction in the number of micturitions per 24 hours and the increase in the mean volume of urine per micturition. These parameters are shown in the following table.
The effects of treatment with tolterodine 4 mg prolonged release, once daily, after 12 weeks, compared to placebo. Absolute and percentage changes from baseline. Treatment difference tolterodine vs. placebo: mean change estimated according to the least squares method and 95% confidence interval.
* 97.5% confidence interval according to Bonferroni
After 12 weeks of treatment, 23.8% (121/507) in the prolonged-release tolterodine group and 15.7% (80/508) in the placebo group reported that they subjectively had little or no bladder problems.
The effects of tolterodine have been evaluated in patients undergoing examination for the basic urodynamic evaluation who, following the result of the urodynamic tests, were placed in the positive urodynamic (motor urgency) or negative urodynamic (sensory urgency) groups. Within each group, patients were randomized to receive both tolterodine and placebo. The study did not produce convincing evidence that tolterodine has any effect over placebo in patients with sensory urgency.
The clinical effects of tolterodine on the QT interval i are based on ECGs obtained from over 600 treated patients, including elderly patients and patients with pre-existing cardiovascular disease. treated group.
The effect of tolterodine on QT prolongation was further investigated in 48 healthy volunteers (male and female) aged 18-55 years. Subjects were given 2 mg bid and 4 mg bid of tolterodine in the immediate release formulation. The results (corrected according to Fridericia's formula) at maximum tolterodine concentrations (1 hour) showed an average increase in the QTc interval of 5.0 and 11.8 msec for the 2 mg tolterodine doses, respectively. bid and 4 mg bid and 19.3 msec for mofloxacin (400 mg) used as the control drug. A pharmacokinetic / pharmacodynamic model showed that the QTc interval is increased in poor metabolisers (CYP2D6-free) treated with tolterodine 2 mg bid comparable to that observed in fast metabolisers treated with 4 mg bid. At both doses of tolterodine, no subject, regardless of metabolic profile, exceeded 500 msec of the absolute QTcF value or showed changes from baseline of 60 msec. These changes are considered particularly significant threshold values. The dose of 4 mg bid corresponds to a maximum exposure (Cmax) equal to three times that obtained with the highest therapeutic dose of the prolonged-release tolterodine capsules.
Pediatric population
Efficacy in the pediatric population has not been demonstrated. Two 12-week randomized, double-blind, placebo-controlled Phase III pediatric studies with prolonged-release tolterodine capsules were conducted. 710 pediatric patients (486 treated) were studied. with tolterodine and 224 treated with placebo) aged 5 to 10 years with increased urinary frequency and urinary urgency.
In both studies, no significant change from baseline was observed between the two groups in the total number of incontinence episodes / week (see section 4.8).
05.2 Pharmacokinetic properties
Pharmacokinetic characteristics specific to this formulation: Tolterodine prolonged-release capsules results in slower absorption of tolterodine than immediate-release tablets. As a result, maximum serum concentrations are observed 4 (2-6) hours after administration of the capsules. The apparent half-life of tolterodine administered as capsules is approximately 6 hours in extensive metabolisers and approximately 10 hours in poor metabolisers (CYP2D6 deficient).
After administration of the capsules, steady state concentrations are achieved within 4 days.
There is no effect of food on the bioavailability of the capsules.
Absorption: After oral administration, tolterodine undergoes first pass metabolism in the liver catalysed by CYP2D6, leading to the formation of the 5-hydroxymethyl metabolite, a major pharmacologically equipotent metabolite.
The absolute bioavailability of tolterodine is 17% in extensive metabolisers and 65% in poor metabolisers (CYP2D6 deficiency).
Distribution: Tolterodine and the 5-hydroxymethyl metabolite bind mainly to orosomucoside.
The unbound fractions are 3.7% and 36% respectively. The volume of distribution of tolterodine is 113 liters.
Elimination: Tolterodine is extensively metabolised by the liver following oral administration.
The primary metabolic pathway is mediated by the polymorphic enzyme CYP2D6 and leads to the formation of the 5-hydroxymethyl metabolite. Further metabolism leads to the formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which respectively constitute 51% and 29% of the metabolites found in the urine. A proportion (about 7%) of the population is deficient in CYP2D6 activity. The metabolism profile identified for these patients (with poor metabolic capacity) is dealkylation via CYP3A4 enzymes to dealkylated N-tolterodine, which does not cause clinical effects. .
The remainder of the population consists of fast metabolisers. In extensive metabolisers, the serum systemic clearance of tolterodine is approximately 30 l / hour. In patients with poor metabolic capacity, reduced clearance results in significantly increased serum concentrations of tolterodine (approximately 7-fold) and indeterminable concentrations of the 5-hydroxymethyl metabolite are found.
The 5-hydroxymethyl metabolite is pharmacologically active and equipotent with respect to tolterodine.
Due to differences in the protein binding characteristics of tolterodine and the 5-hydroxymethyl metabolite, the exposure (AUC) of free tolterodine in patients with poor metabolic capacity is similar to that of the combined free tolterodine and 5-hydroxymethyl metabolite in patients with CYP2D6 activity when given at the same dose Safety, tolerability and clinical response are similar regardless of phenotype.
The excretion of radioactivity after administration of [14C] -tolterodine is approximately 77% in the urine and 17% in the faeces. Less than 1% of the dose is excreted unchanged and approximately 4% as the 5-hydroxymethyl metabolite. The carboxylated metabolite and the corresponding dealkylated metabolite account for approximately 51% and 29% of urinary recovery, respectively.
In the therapeutic dosage range, the pharmacokinetics are linear.
Particular groups of patients
Hepatic impairment: In subjects with liver cirrhosis, approximately 2-fold higher exposure of free tolterodine and its 5-hydroxymethyl metabolite is seen (see sections 4.2 and 4.4).
Renal impairment: The mean exposure of free tolterodine and its metabolite 5-hydroxymethyl is doubled in patients with severe renal impairment [inulin clearance (GFR) ≤ 30 ml / min].
In these patients the plasma levels of the other metabolites were markedly increased (up to 12-fold).
The clinical relevance of the increased exposure of these metabolites is unknown.
No data are available in cases of mild to moderate renal impairment (see sections 4.2 and 4.4).
Pediatric population
The exposure of the active substance per dose / mg is similar in adults and adolescents. The mean exposure of the active substance per dose / mg is approximately two times higher in children aged 5 to 10 years than in adults (see sections 4.2 and 5.1 )
05.3 Preclinical safety data
Clinically significant effects were not observed in toxicity, mutagenicity, carcinogenicity and safety pharmacology studies, except those related to the pharmacological effects of the drug.
Reproductive toxicity studies were conducted in mice and rabbits.
In mice, there were no effects of tolterodine on fertility or reproductive function.
Tolterodine resulted in embryonic mortality and fetal malformations following plasma exposure (Cmax or AUC) 20 or 7 times higher than those seen in treated men.
No effects on malformations were observed in rabbits, but the studies were conducted at plasma exposure values (Cmax or AUC) that were 20 or 3 times higher than those expected in humans.
Tolterodine, as well as its active metabolites in humans, prolongs the duration of action potential (90% of repolarization) in canine purkinje fibers (14-75 times therapeutic levels) and blocks the flow of K + in hERG channels ( cloned human ether-a-go-go-related gene) (0.5-26.1 times therapeutic levels).
In studies conducted in dogs following administration of tolterodine and its active human metabolites (doses 3.1 to 61.0 times higher than therapeutic levels), prolongation of the QT interval was observed.
The clinical relevance of this effect is unknown.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Microcrystalline cellulose
Poly (vinyl acetate)
Povidone
Silica
Sodium lauryl sulfate
Sodium docusate
Magnesium stearate (E470b)
Hydroxypropylmethylcellulose
Composition of the capsule:
- Indigo red (E132)
- Quinoline yellow (only in 2 mg) (E104)
- Titanium dioxide (E171)
- Jelly
The coating consists of:
- Ethylcellulose
- Triethyl citrate
- Methacrylic acid - ethyl acrylate copolymer
- 1,2-Propylene glycol
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
HDPE bottle: the shelf life after opening is 200 days.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Cardboard box containing the appropriate number of PVC / PE / PVDC Aluminum blisters and a package leaflet.
Pack sizes for 2.0 mg capsules:
blister packs of 14, 28, 30, 50, 84, 100 prolonged-release capsules
Pack sizes for 4.0 mg capsules:
blister packs of 7, 14, 28, 49, 84, 98 prolonged-release capsules
Cardboard box containing an opaque white HDPE bottle containing the appropriate number of capsules, with screw cap and package leaflet.
Packs of 30, 100, 200 capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
DOC Generici S.r.l. - Via Turati 40 - 20121 Milan - Italy.
08.0 MARKETING AUTHORIZATION NUMBER
AIC 040824017 / M - 2 mg prolonged-release hard capsules - 14 capsules in PVC / PE / PVDC-AL blister
AIC 040824029 / M - 2 mg prolonged-release hard capsules - 28 capsules in PVC / PE / PVDC-AL blister
AIC 040824031 / M - 2 mg prolonged-release hard capsules - 84 capsules in PVC / PE / PVDC-AL blister
AIC 040824043 / M - 2 mg prolonged-release hard capsules - 30 capsules in HDPE bottle
AIC 040824056 / M - 2 mg prolonged-release hard capsules - 100 capsules in HDPE bottle
AIC 040824068 / M - 2 mg prolonged-release hard capsules - 200 capsules in HDPE bottle
AIC 040824070 / M - 4 mg prolonged-release hard capsules - 7 capsules in PVC / PE / PVDC-AL blister
AIC 040824082 / M - 4 mg prolonged-release capsules, hard - 14 capsules in PVC / PE / PVDC-AL blister
AIC 040824094 / M - 4 mg prolonged-release hard capsules - 28 capsules in PVC / PE / PVDC-AL blister
AIC 040824106 / M - 4 mg prolonged-release hard capsules - 49 capsules in PVC / PE / PVDC-AL blister
AIC 040824118 / M - 4 mg prolonged-release hard capsules - 84 capsules in PVC / PE / PVDC-AL blister
AIC 040824120 / M - 4 mg prolonged-release hard capsules - 98 capsules in PVC / PE / PVDC-AL blister
AIC 040824132 / M - 4 mg prolonged-release hard capsules - 30 capsules in HDPE bottle
AIC 040824144 / M - 4 mg prolonged-release hard capsules - 100 capsules in HDPE bottle
AIC 040824157 / M - 4 mg prolonged-release hard capsules - 200 capsules in HDPE bottle
AIC 040824169 / M - 2 mg prolonged-release hard capsules - 30 capsules in PVC / PE / PVDC-AL blister
AIC 040824171 / M - 2 mg prolonged-release hard capsules - 50 capsules in PVC / PE / PVDC-AL blister
AIC 040824183 / M - 2 mg prolonged-release capsules, hard - 100 capsules in PVC / PE / PVDC-AL blister
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
March 2013.
10.0 DATE OF REVISION OF THE TEXT
March 2013.
