Toviaz® (Toviaz®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceFesoterodineFesoterodine
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  • Toviaz®
    pills inwards 
    Pfizer Inc.     USA
    • Dosage form: & nbspsustained-release tablets
    Composition:

    1 tablet of prolonged action contains:

    active substance: fesoterodine fumarate 4 mg or 8 mg is equivalent to 3.1 mg or 6.2 mg fesoterodine;

    Excipients:

    dosage of 4 mg: xylitol 36.0 mg; cellonase-100 121.5 mg; hypromellose (methocel K 100) 70.0 mg; hypromellose (methocel K4M) 70.0 mg; glyceryl dibehenate / glyceryl tribehenate 10.0 mg; talc 8.5 mg; film sheath: Opadrai® light blue (II 85G20426) 15.0 mg (contains: polyvinyl alcohol 44.0%, titanium dioxide 19.86%, macrogol-3350 12.35%, talc 20.0%, lecithin soybean 3.5%, indigo carmine aluminum varnish 0.29 %);

    dosage of 8 mg: xylitol 72.0 mg; cellactose-100 77.5 mg; hypromellose (metocel K 100) 120.0 mg; hypromellose (methocel K4M) 24.0 mg; glyceryl dibehenate / glyceryl tribehenate 10.0 mg; talc 8.5 mg; film sheath: Opadrai® blue (II 85G20427) 15.0 mg (contains: polyvinyl alcohol 44.0%, titanium dioxide 17.82%, macrogol-3350 12.35%, talc 20.0%, lecithin soybean 3.5%, indigo carmine aluminum varnish 2.33 %.

    Description:

    Dosage 4 mg: oval, biconcave tablets, covered with a film shell of light blue color, with engraving "FS"on one side. On the cross-section - the core of white color *.

    Dosage of 8 mg: oval, biconcave tablets, covered with a film shell of blue color, with engraving "FT"on one side. On the cross-section - the core of white color *.

    Pharmacotherapeutic group:m-holinoblokator
    ATX: & nbsp

    G.04.B.D.11   Fesoterodine

    Pharmacodynamics:

    Fesoterodine is a competitive, specific antagonist of muscarinic receptors. Fesoterodine reduces the number of urination and episodes of imperative urinary incontinence, increases the average volume with urination.

    Does not change the interval QT on the ECG.

    The preparation is rapidly and intensively hydrolyzed by nonspecific plasma esterases to the 5-hydroxymethyl derivative, the main pharmacologically active metabolite, which determines the activity of fesoterodine.

    Pharmacokinetics:

    Absorption

    After oral administration fesoterodine is not detected in the blood plasma due to rapid and intensive hydrolysis with nonspecific esterases.

    Bioavailability of the active metabolite is 52%. After a single or multiple oral intake of fesoterodine in doses from 4 mg to 28 mg, the concentrations of the active metabolite in the blood plasma increase in proportion to the dose. Time to reach the maximum concentration (TCmOh) in the blood plasma for about 5 hours. Therapeutic concentrations of the drug in the blood plasma are achieved after the first intake of fesoterodine.With multiple admission does not cumulate.

    Distribution

    The active metabolite poorly binds to blood plasma proteins (approximately 50%, mainly with albumins and alpha-1-acid glycoprotein).

    Metabolism

    After oral administration fesoterodine quickly and intensively hydrolyzed to an active metabolite, which is further metabolized in the liver to carboxylated, carboxy-N-disipropylated and N-disipropilated metabolites with the participation of isoenzymes CYP2D6 and CYP3A4. None of these metabolites significantly contributes to the antimuscarinic activity of fesoterodine. The mean values ​​of the maximum concentration in blood plasma (CmOh) and the area under the curve "concentration-time" (AUC) of active metabolite were respectively 1.7 and 2.1 times higher in patients with slow isoenzyme metabolizers CYP2D6, than in fast metabolizers.

    Excretion

    The active metabolite is excreted mainly through the kidneys (approximately 70%).

    It is excreted through the kidneys in the form of active metabolite (16%), carboxylated metabolite (34%), carboxy-N-disipropilated metabolite (18%) and N-disipropilated metabolite (1%); a small amount (7%) is excreted through the intestine. The half-life of the active metabolite after oral administration of the drug is approximately 7 hours.

    Age and gender

    Correction of the dose of the drug depending on the age and sex of patients is not required.

    Children

    The pharmacokinetics of fesoterodine in children has not been studied.

    Impaired renal function

    If the renal function is mild and moderate (creatinine clearance (CK) 30-80 ml / min) CmOh increases by a factor of 1.5, AUC - 1.8 times. With severe impairment of kidney function (CK <30 ml / min) CmOh increases 2 times, AUC - 2,3 times.

    Impaired liver function

    If the liver function is of moderate severity (class B according to the Child-Pugh classification) CmOh increases by 1.4 times, AUC - in 2,1 times. The pharmacokinetics of fesoterodine in patients with severe hepatic insufficiency has not been studied.

    Indications:

    Symptomatic therapy of the syndrome of a hyperactive bladder (frequent urination and / or mandatory urination, and / or mandatory urinary incontinence).

    Contraindications:

    Hypersensitivity to peanuts, soy or any of the components of the drug.

    Retention of urine.

    Diseases of the gastrointestinal tract, accompanied by a delayed evacuation of stomach contents.

    Uncontrolled angle-closure glaucoma.

    Myasthenia gravis gravis.

    Severe hepatic insufficiency (class C according to the Child-Pugh classification).

    Joint intake of fesoterodine and potent inhibitors of isoenzyme CYP3A4 patients with severe or moderate impairment of liver or kidney function.

    Ulcerative colitis, toxic megacolon. Pregnancy and lactation.

    Children and teenagers under 18 years of age.

    Toviaz®, tablets with prolonged release of the active substance, contain lactose. Therefore, this drug can not be prescribed to persons suffering from rare congenital metabolic disorders: intolerance to galactose, lactase deficiency or glucose-galactose malabsorption.

    Carefully:

    In obstructive diseases of the urinary system, leading to the development of a delay in urine (for example, with benign prostatic hyperplasia).

    In obstructive diseases of the gastrointestinal tract (for example, pyloric stenosis).

    With gastroesophageal reflux and / or with concurrent administration of drugs that can cause or exacerbate manifestations of esophagitis (eg, oral bisphosphonates).

    With a decrease in the motility of the gastrointestinal tract; Neuropathy; controlled angle-closure glaucoma.

    When the liver function is impaired.

    In case of impaired renal function.

    In patients taking isoenzyme inhibitors CYP3A4 medium and high activity (when combining the above factors (impaired renal function, impaired liver function, taking inhibitors of isoenzyme CYP3A4) an additional increase in exposure and a dose-dependent increase in the risk of side effects caused by blockade of M-holinoretseptorov).

    When used simultaneously with potent inhibitors of isoenzyme CYP2D6.

    Like other M-holinoblokatory, fesoterodine should be used with caution in patients who are at risk of lengthening the interval QT (for example, with hypokalemia, bradycardia, and concurrent administration of drugs capable of lengthening the interval QT) and in the presence of concomitant pathology on the part of the heart (in particular, myocardial ischemia, arrhythmias, chronic heart failure). This is especially important in parallel taking Toviaz® with potent inhibitors of isoenzyme CYP3A4.

    Dosing and Administration:

    Inside, regardless of food intake, swallowing whole, without chewing and washing with liquid.

    The recommended initial dose of fesoterodine is 1 tablet (4 mg) once a day. The dose can be increased to 2 tablets (8 mg) once a day, depending on the individual response to treatment. The maximum recommended daily dose is 8 mg.

    The full therapeutic effect develops between 2-8 weeks of regular intake of the drug. Therefore, the effectiveness of treatment after 8 weeks of therapy should be evaluated.

    In patients with normal liver and kidney function when co-administration of potent inhibitors of isoenzyme CYP3A4 daily dose of the drug Toviaz® should not exceed 4 mg once a day. In parallel with isoenzyme inhibitors CYP3A4 average activity before increasing the dose should evaluate the individual response and tolerability of the drug.

    Impaired renal and hepatic function

    Toviaz® for patients suffering from impaired hepatic or renal function in the absence or presence of isoenzyme inhibitors CYP3A4 medium and high activity. The table below shows recommended daily doses

    Inhibitor inhibitors CYP3A4 average (3) or high (4) activity

    No

    Moderate

    inhibition

    Powerful

    inhibition

    Function violation

    kidney (1)

    Easy

    degree

    4 mg-> 8 mg (2)

    4 mg

    Avoid

    Medium

    degree

    4 mg-> 8 mg (2)

    4 mg

    Contraindicated

    Heavy

    degree

    4 mg

    Should

    to avoid

    Contraindicated

    Impaired liver function

    Easy

    degree

    4 mg -> 8 mg (2)

    4 mg

    Avoid

    Medium

    degree

    4 mg

    Should

    to avoid

    Contraindicated

    (1) Violation of the function of the kidneys: mild - KK from 50 ml / min to 80 ml / min; medium degree - SC from 30 ml / min to 50 ml / min; severe - KK <30 ml / min.

    (2) Take care when increasing the dose of the drug.

    (3) Combination studies with isoenzyme inhibitors CYP3A4 the average activity was not carried out.

    (4) Powerful inhibitors of isoenzyme CYP3A4.

    Side effects:

    The most common reactions: dry mouth, constipation, dry eyes and dyspepsia.

    Below are the undesirable reactions that occur very often (≥1 / 10), often (≥1 / 100, but <1/10) or infrequently (≥1 / 1000, but <1/100), rarely (≥1 / 10000, but <1/1000).

    From the cardiovascular system: infrequently - tachycardia, sensation palpitation.

    From the nervous system: often - dizziness, headache; infrequently - perversion of taste, drowsiness.

    From the side of the organ of vision: often - dry eyes, infrequently - blurred vision.

    From the side of the organ of hearing and balance: infrequently - vertigo.

    From the respiratory system: often - dryness in the throat; infrequently - pain in larynx and pharynx, cough, dryness of mucous nasal cavity.

    From the gastrointestinal tract: very often - dryness of the oral mucosa; often - abdominal pain, diarrhea, indigestion, constipation, nausea, flatulence; infrequently - gastroesophageal reflux, discomfort in the abdomen.

    From the urinary system: often - dysuria; infrequently - urinary retention (including a feeling of incomplete emptying of the bladder, violation of urination), difficulty in starting urination.

    From the skin and subcutaneous tissue: infrequent skin rashes; dry skin, itchy skin; rarely - hives, angioedema.

    Other: often - insomnia; infrequently - urinary tract infections, fatigue, increased activity of alanine aminotransferase (ALT); increased activity of gamma-glutamyltranspeptidase (GGTP); rarely confusion. In clinical studies, cases of increased activity of liver enzymes in the fesoterodine group were recorded at the same frequency compared with that in the placebo group.

    Overdose:

    Overdose of M-cholinoblocking agents, including fesoterodine, can lead to the development of severe anticholinergic effects. In clinical trials fesoterodine showed itself as a safe drug in doses up to 28 mg / day inclusive.

    Recommended symptomatic therapy, gastric lavage, the appointment of activated charcoal, ECG monitoring and interval correction QT.

    With the development of severe central anticholinergic effects (eg, hallucinations, marked exaltation), the appointment of physostigmine is recommended.

    With convulsions or pronounced excitation, benzodiazepines are prescribed. With respiratory failure, artificial ventilation is performed. With tachycardia, beta-blockers are used. When the urine is delayed, the bladder is catheterized. With mydriasis, eye drops with pilocarpine are prescribed.

    Interaction:

    Pharmacological interaction

    Caution should be exercised when concurrent administration with fesoterodine of other M-holinoblokatorov (for example, amantadine, tricyclic antidepressants, some neuroleptics), as this can lead to increased therapeutic and side effects (in particular, constipation,dryness of the oral mucosa, drowsiness, and urinary retention).

    Fesoterodine can reduce the effectiveness of drugs that stimulate the motility of the gastrointestinal tract, such as metoclopramide.

    Pharmacokinetic interaction

    The active metabolite of fesoterodine in therapeutic concentrations does not inhibit the activity of isoenzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 and does not induce the activity of isoenzymes CYP1A2, 2B6, 2C9, 2C19 or 4A. Thus, the probability of the effect of fesoterodine on the clearance of drugs metabolized with the participation of these enzymes is negligible.

    Powerful inhibitors of isoenzyme CYP3A4

    When ketoconazole is used at a dose of 200 mg twice a day oppression of the isoenzyme is noted CYP3A4, which leads to an increase in Cmax and AUC Fesoterodine, respectively, 2.0 and 2.3 times in fast isoenzyme metabolizers CYP2D6 and in 2.1 and 2.5 for slow isoenzyme metabolizers CYP2D6.

    With the parallel intake of potent inhibitors of isoenzyme CYP3A4 (for example: atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir (and all ritonavir-enhanced antiretroviral regimens based on protease inhibitors), saquinavir and telithromycin), the maximum dose of fesoterodine should not exceed 4 mg.

    Inhibitor inhibitors CYP3A4 average activity

    Studies evaluating the effect of inhibitors of isoenzyme CYP3A4 medium activity (for example, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil) on the pharmacokinetics of fesoterodine was not performed. However, in this case, an increase in the exposure of the active metabolite of fesoterodine is also expected, albeit to a lesser degree than with the parallel intake of potent inhibitors of the isoenzyme CYP3A4.

    Inductors of isoenzyme CYP3A4

    When rifampicin is used at a dose of 600 mg, the induction of isoenzyme is noted once a day CYP3A4, which leads to a decrease in Cmax and AUC of the active metabolite of fesoterodine by 70% and 75%, respectively, after 8 mg of fesoterodine was administered orally. The terminal half-life of the active metabolite did not change. Induction of isoenzyme CYP3A4 can lead to a decrease in the concentration of fesoterodine below the therapeutic level. Reception together with fesoterodine powerful isoenzyme inducers CYP3A4 (for example, carbamazepine, rifampicin, phenobarbital, phenytoin, preparations of St. John's wort perfumed) is not recommended.

    Inhibitor inhibitors CYP2D6

    Joint reception of fesoterodine with potent inhibitors of isoenzyme CYP2D6 can lead to an increase in exposure and the risk of development of adverse events. It may be necessary to reduce the dose of fesoterodine to 4 mg.

    Oral contraceptives

    Fesoterodine does not interfere with the suppression of ovulation caused by oral hormonal contraceptives. In the presence of fesoterodine, changes in plasma concentrations of components of combined oral contraceptives containing ethinyl estradiol and levonorgestrel, was not noted.

    Special instructions:

    There are reports of the development of angioedema in the use of fesoterodine. In some cases, this side effect developed after the first dose of the drug. If angioedema develops, Toviaz® should be withdrawn and appropriate therapy prescribed.

    As with other drugs intended for treatment of bladder hyperactivity, organic causes of symptoms should be excluded before starting M-holinoblockers. To date, the safety and efficacy of Toviaz® in patients with detrusor neurogenic hyperactivity have not been established.

    Before the appointment of fesoterodine, it is necessary to evaluate other causes of rapid urination (ongoing treatment for heart failure or kidney disease). If there are infections of the urinary tract, appropriate antibiotic therapy should be carried out.

    Effect on the ability to drive transp. cf. and fur:

    As with other M-holinoblokatorov, you should be careful when driving and working with mechanisms due to the possible development of side effects such as reduced clarity of vision, dizziness and drowsiness.

    Form release / dosage:

    Tablets of prolonged action, 4 mg and 8 mg.

    Packaging:

    For 7 tablets in a blister of PVC / polyamide / aluminum foil.

    For 2, 3 or 8 blisters together with instructions for medical use in a cardboard pack.

    Storage conditions:

    In dry, dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002016
    Date of registration:27.02.2013
    The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA
    Manufacturer: & nbsp
    Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation
    Information update date: & nbsp18.09.2015
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