Instruction for use: Fesoterodine (Fezoterodinum)

chemical name

[2 - [(1 R) -3- (di (propan-2-ol) amino) -1-phenylpropane] -4- (hydroxymethyl) phenyl] -2-methylpropanoate (as fumarate)

Pharmacological group

m-Cholinolytics

The nosological classification (ICD-10)

N31.1 Reflex neuropathic bladder, not elsewhere classified

hyperreflexia, Overactive Bladder, detrusor hyperreflexia, detrusor hyperreflexia

N39.3 Involuntary urination

Urinary incontinence in women, Anishuriya, Urinary incontinence

R32 Urinary incontinence unspecified

daytime enuresis, Idiopathic bladder instability, Urinary incontinence, nocturia, The disorder of the bladder sphincter function, Spontaneous urination, Mixed forms of urinary incontinence, Functional disorders of micturition, Functional micturition disorders, Functional enuresis in children, Enuresis

R39.1 Other difficulties with micturition

Frequent urination, urinary retention, strangury, Obstructed flow of urine, Violation of urination, Violation of urination, Violation of bladder emptying, Violation of the outflow of urine, Frequent urination, Abnormalities of urination

Code CAS 286930-03-8

Characteristics

Fesoterodine fumarate is a white or almost white powder; Easily soluble in water. Molecular weight 527.66.

Pharmacology

Pharmacological action - m-cholinolytic.

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 QT interval on the ECG.

Electrophysiology of the heart. The effect of fesoterodine at a dose of 4 and 28 mg per QT interval was evaluated in a double-blind, randomized, placebo-controlled and positively-controlled (moxifloxacin 400 mg once daily) parallel study with daily treatment for men and women aged 3 to 261 days 44 to 65 years. ECG parameters were measured during the 24-hour period prior to dose, after the first administration and after the third dose of the drug. The dose of fesoterodine 28 mg was chosen because this dose, when taken by rapid metabolizers according to CYP2D6, leads to the exposure of an active metabolite similar to that of slow metabolizers for CYP2D6 taking fesoterodine at a dose of 8 mg together with CYP3A4 blockers. Corrected intervals QT (QTc) were calculated using Frederic correction and individual correction method. The sensitivity of the study was confirmed by prolongation of QTc under the action of moxifloxacin.

Analysis shows that fesoterodine at doses of 4 and 28 mg / day does not prolong the QT interval.

The intake of fesoterodine is associated with an increase in heart rate, which correlates with an increase in the dose. In the study described above, compared with placebo, the mean increase in heart rate associated with doses of 4 and 28 mg / day was 3 and 11 beats / minute, respectively.

In two placebo-controlled Phase 3 studies in patients with overactive bladder, the mean increase in heart rate compared with placebo was approximately 3-4 beats / minute at a dose of fesoterodine 4 mg / day and 3-5 beats / minute at a dose of 8 mg / Day respectively.

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

Pharmacokinetics

Absorption. After ingestion, 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 of 4 to 28 mg, the concentrations of the active metabolite in the blood plasma increase in proportion to the dose. Tmax in the blood plasma - about 5 hours. With multiple intake does not cumulate.

Absorption. After intake of fesoterodine is well absorbed. Because of rapid and extensive hydrolysis with nonspecific esterases to the active metabolite - 5-hydroxymethyl-tolterodine - fesoterodine is not found in the blood plasma. 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 plasma concentrations of the active metabolite are proportional to the dose. Tmax in plasma is reached after about 5 hours. With repeated use, it does not accumulate.

Effect of food. The intake of food does not have a clinically significant effect on the pharmacokinetics of fesoterodine. In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the AUC of the active metabolite of fesoterodine by approximately 19% and Cmax by 18%. Fesoterodine can be taken regardless of food intake.

Distribution. The active metabolite poorly binds to blood plasma proteins (approximately 50%, mainly with albumins and alpha1-acid glycoprotein).

Metabolism. After oral administration, fesoterodine is rapidly and intensively hydrolyzed to the active metabolite, which is further metabolized in the liver to carboxylated, carboxy-N-desisopropyl and N-deisopropyl metabolites with the participation of CYP2D6 and CYP3A4 isoenzymes. None of these metabolites contributes significantly to the antimuscarinic activity of fesoterodine. The mean values of Cmax and AUC of the active metabolite were 1.7 and 2.1 times higher in patients with slow metabolizers by isoenzyme CYP2D6, respectively, than in fast metabolizers.

The variability of CYP2D6 metabolism. Cmax and AUC of the active metabolite were 1.7 and 2 times higher in slow metabolizers for CYP2D6 (approximately 7% of Caucasians and 2% of African Americans), compared with 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%), carboxymetabolite (34%), carboxy-N-desisopropyl metabolite (18%) and N-desisopropyl metabolite (1%); A small amount (7%) is excreted through the intestine. T1 / 2 of the active metabolite after oral administration of fesoterodine is approximately 7 hours.

Dependence of pharmacokinetics parameters on some factors

Age and sex. 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 have not been studied.

Elderly patients. After oral administration of a single dose of fesoterodine 8 mg, the mean (± SD) AUC and Cmax of the active metabolite, 5-hydroxymethyl tolterodine - in 12 elderly men (mean age 67 years) were (51.8 ± 26.1) ng · h / ml And (3.8 ± 1.7) ng / ml, respectively. In the same study, mean (± SD) AUC and Cmax in 12 young men (mean age 30 years) were (52 ± 31.5) ng · h / ml and (4.1 ± 2.1) ng / ml, respectively . The pharmacokinetics of fesoterodine does not depend significantly on age (see "Precautions").

Floor. After a single oral intake of fesoterodine at a dose of 8 mg, the mean (± SD) AUC and Cmax of the active metabolite in 12 elderly men (mean age 67 years) were (51.8 ± 26.1) ng · h / ml and (3.8 ± 1,7) ng / ml, respectively. In the same study, mean (± SD) AUC and Cmax in 12 elderly women (mean age 68 years) were (56 ± 28.8) ng · h / ml and (4.6 ± 2.3) ng / ml, respectively . The pharmacokinetics of fesoterodine does not depend significantly on sex.

Race. The pharmacokinetics of fesoterodine was examined in young male volunteers, among whom were 12 representatives of the Caucasoid and 12 Negroid races, each receiving a single dose of 8 mg of fesoterodine. Mean (± SD) AUC and Cmax of the active metabolite - 5-hydroxymethyl tolterodine - in men of the European race were (73 ± 27.8) ng · h / ml and (6.1 ± 2.7) ng / ml, respectively. The mean (± SD) AUC and Cmax of black men were (65.8 ± 23.2) ng · h / ml and (5.5 ± 1.9) ng / ml, respectively. The pharmacokinetics of fesoterodine does not depend significantly on the race.

Impaired renal function. When the renal function of mild and moderate severity (Cl creatinine 30-80 ml / min) increases, Cmax increases by 1.5 times, AUC - by 1.8 times. With severe renal dysfunction (Cl creatinine <30 ml / min), Cmax increases 2 times, AUC - 2,3 times.

Impaired renal function. When the renal function of mild and moderate severity (Cl creatinine 30-80 ml / min) increases, the Cmax of the active metabolite increases by 1.5 times, AUC - by 1.8 times in comparison with these parameters in healthy volunteers. With severe renal dysfunction (Cl creatinine <30 ml / min), Cmax increases 2 times, AUC - 2,3 times.

Violation of the function of the liver. If the liver function is of moderate severity (class B according to Child-Pugh classification), Cmax increases by 1.4 times, AUC - by 2.1 times. The pharmacokinetics of fesoterodine in patients with severe hepatic insufficiency has not been studied.

Violation of the function of the liver. If the liver function is of moderate severity (class B according to the Child-Pugh classification), Cmax of the active metabolite increases by 1.4 times, AUC - by 2.1 times in comparison with these parameters in healthy volunteers. Pharmacokinetics of fesoterodine in patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) has not been studied.

Indications

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

Contraindications

Hypersensitivity, urinary retention, gastrointestinal diseases accompanied by delayed evacuation of stomach contents, uncontrolled closed-angle glaucoma, myasthenia gravis, ulcerative colitis, toxic megacolon, severe hepatic insufficiency (class C according to Child-Pugh classification), joint intake of fesoterodine and strong inhibitors of CYP3A4 isoenzyme in patients with Severe or moderate impairment of liver or kidney function, children and adolescents under 18 years of age.

Restrictions on the use

Obstructive diseases of the urinary system leading to the development of urinary retention (eg BPH), obstructive diseases of the gastrointestinal tract (eg pyloric stenosis), gastroesophageal reflux and / or concomitant use of drugs that can cause or exacerbate the manifestations of esophagitis (eg oral bisphosphonates), decreased gastrointestinal motility, neuropathy , Controlled by closed angle glaucoma, impaired renal function, impaired liver function, simultaneous use of medium and high activity with inhibitors of the CYP3A4 isoenzyme (combining the above factors - renal dysfunction, impaired liver function, inhibition of the CYP3A4 isoenzyme - possible additional exposure and dose-dependent increase Risk of side effects caused by blockade of m-cholinergic receptors), simultaneous application with strong inhibitors of the isoenzyme CYP2D6. Fesoterodine should be used with caution in patients who are at risk of prolonging the QT interval (eg, hypokalemia, bradycardia, and concurrent administration of drugs that prolong the QT interval), and in the presence of concomitant cardiac pathology (in particular myocardial ischemia, arrhythmia, CHF) that Is especially important when taken in parallel with strong inhibitors of the isoenzyme CYP3A4.

pregnancy and lactation

The action category for fetus by FDA is C.

Adequate and strictly controlled studies of the use of fesoterodine in pregnant women have not been conducted. The use of fesoterodine in pregnancy is possible only if the expected effect of therapy exceeds the potential risk to the fetus.

It is not known whether fesoterodine is excreted into the milk of women. Fesoterodine should not be used during breastfeeding, except when the benefit to the mother exceeds the potential risk for the newborn.

Side effects

The most common reactions are 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, a feeling of palpitations.

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 side of 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: infrequently - skin rashes; Dry skin, itchy skin; Rarely - hives, angioedema.

Other: often - insomnia; Infrequently - urinary tract infections, fatigue, increased ALT activity; Increase in GGTP activity; 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.

Results of clinical trials

The safety of fesoterodine was evaluated in controlled clinical trials of Phases 2 and 3, in which 2859 patients with a hyperactive bladder were included, 2,288 of which received fesoterodine. Of the total number of patients, 782 received fesoterodine at a dose of 4 mg / day, and 785 received fesoterodine at a dose of 8 mg / day in phase 2 or 3 studies for 8 or 12 weeks. About 80% of these patients took fesoterodine for more than 10 weeks in these trials.

A total of 1,964 patients participated in two 12-week efficacy and safety studies of phase 3 and subsequent open-label advanced studies. In these two combined studies, 554 patients received fesoterodine at a dose of 4 mg / day, and 566 patients received fesoterodine at a dose of 8 mg / day.

In pooled placebo-controlled Phase 2 and 3 studies, the incidence of serious adverse events in patients treated with placebo, fesoterodine 4 mg, and fesoterodine 8 mg was 1.9; 3.5 and 2.9% respectively. All serious adverse events were evaluated by the investigators as unrelated or unlikely to be associated with the study drug, with the exception of four patients receiving fesoterodine, each of which developed one of the listed serious side effects: angina pectoris, chest pain, gastroenteritis, prolongation of the QT interval at ECG.

The most frequent side effect in patients receiving fesoterodine was dryness in the oral cavity. The frequency of this effect was higher in patients taking fesoterodine at a dose of 8 mg / day (35%) than at a dose of 4 mg / day (19%), compared with placebo (7%). Dryness in the mouth led to cessation of treatment at 0.4; 0,4 and 0,8% of cases in patients receiving placebo, fesoterodine 4 mg and fesoterodine 8 mg, respectively. Among the reports from patients about dry mouth, most of the reports were during the first month of treatment.

The second most common side effect is constipation. The incidence of constipation was 2% in patients taking placebo, 4% - fesoterodine at a dose of 4 mg / day and 6% - fesoterodine at a dose of 8 mg / day.

Side effects observed in double-blind, placebo-controlled trials of Phases 2 and 3 with a treatment duration of 12 weeks

Side effects observed in patients who received fesoterodine at doses of 4 mg / day (n = 554) or 8 mg / day (n = 554) or placebo (n = 566) for 12 weeks; Adverse effects noted in at least 1% of patients and exceeding the placebo frequency were indicated.

Next to the name, the incidence of this side effect is indicated with a dose of fesoterodine 4/8 mg, in parentheses - similar data in the placebo group.

On the part of the digestive tract: dryness in the oral cavity 18.8 / 34.6% (7%), constipation 4.2 / 6% (2%), indigestion 1.6 / 2.3% (0.5%), Nausea 0.7 / 1.9% (1.3%), pain in the upper abdomen 1.1 / 0.5% (0.5%).

Infections: urinary tract infection 3.2 / 4.2% (3.1%), upper respiratory tract infection 2.5 / 1.8% (2.2%).

From the side of the eyes: dry eyes 1.4 / 3.7% (0%).

On the part of the genitourinary system: dysuria 1.3 / 1.6% (0.7%), urinary retention 1.1 / 1.4% (0.2%).

On the part of the respiratory system: cough 1.6 / 0.9% (0.5%), dryness in the throat 0.9 / 2.3% (0.4%).

General disorders: peripheral edema 0.7 / 1.2% (0.7%).

From the side of the musculoskeletal system: back pain 2 / 0,9% (0,4%).

From the side of the central nervous system: insomnia 1.3 / 0.4% (0.5%).

From the skin: rash 0.7 / 1.1% (0.5%).

Changes in laboratory indicators: an increase in ALT 0.5 / 1.2% (0.9%), an increase in GGT 0.4 / 1.2% (0.4%).

Patients also received fesoterodine for up to 3 years in one open expanded phase 2 study and two controlled phase 3 trials. According to combined data from all open trials, 857, 701, 529 and 105 patients received fesoterodine for at least 6 months, 1 year, 2 Year and 3 years respectively. The adverse effects observed during long open trials were similar to those observed in 12-week placebo-controlled studies and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. The most common side effects - dry mouth and constipation - were in most cases mild to moderate in severity.

Serious side effects, possibly associated with fesoterodine intake and noted more than 1 time during an open triennial study, include the following: urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases) , Prolongation of the QT interval on the ECG (2 cases).

Post-marketing experience

From the eyes: blurred vision.

From the CCC: palpitation.

General disorders: hypersensitivity reactions, including angioedema, with airway obstruction, facial edema.

From the side of the central nervous system: dizziness, headache, drowsiness.

From the skin: urticaria, itching.

Since these messages are spontaneous, their frequency and cause-and-effect relationship with fesoterodine intake can not be reliably determined.

Interaction

Pharmacological interaction

Caution should be exercised when concomitant administration with fesoterodine of other m-holinoblokatorov (eg amantadine, tricyclic antidepressants, some antipsychotics), t. This can lead to increased therapeutic and side effects (in particular, constipation, dryness of the oral mucosa, drowsiness, urinary retention).

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

Antimuscarinic drugs. The combined use of fesoterodine with other antimuscarinic drugs that cause dryness in the mouth, constipation, urinary retention and other anticholinergic pharmacological effects may increase the frequency and / or severity of such effects. Anticholinergics can potentially alter the absorption of some concomitantly used drugs due to anticholinergic effects on the gastrointestinal motility.

Pharmacokinetic interaction

At therapeutic concentrations of the active metabolite of fesoterodine does not inhibit the activity of isozymes CYP1A2, CYP2V6, CYP2S8, CYP2C9, CYP2C19, of CYP2D6, CYP2E1 and CYP3A4, and does not induce the activity of isozymes CYP1A2, CYP2V6, CYP2C9, CYP2C19 or CYP3A4. Thus, the probability of the influence of fesoterodine on the clearance of drugs metabolized with the participation of these enzymes is negligible.

Strong inhibitors of the isoenzyme CYP3A4. When applying ketoconazole at a dose of 200 mg twice a day for 5 days inhibition observed isoenzyme CYP3A4, resulting in an increase in Cmax and AUC of the active metabolite of fesoterodine after receiving 8 mg fesoterodine 2 and 2.3 times respectively at the rapid metabolizers by isoenzyme CYP2D6 and In 2,1 and 2,5 times for slow metabolizers on the isoenzyme CYP2D6.

In parallel receiving strong inhibitors of isoenzyme CYP3A4 (eg atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, saquinavir, telithromycin, ritonavir and all ritonavir-boosted regimens of antiretroviral therapy based on protease inhibitors), the maximum dose of fesoterodine should not exceed 4 mg.

Inhibitors of the CYP3A4 isoenzyme of moderate activity. Studies evaluating the impact of inhibitors of CYP3A4 activity medium (eg amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, grapefruit juice) on the pharmacokinetics of fesoterodine, have been conducted. 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 simultaneous intake of strong inhibitors of the CYP3A4 isoenzyme.

Inhibitors of CYP3A4. When the joint application of fesoterodine and ketoconazole (200 mg, 2 times a day for 5 days) - a potent inhibitor of CYP3A4 - Cmax and AUC of the active metabolite of fesoterodine increased by 2 and 2.3 times, respectively, after oral administration of fesoterodine 8 mg by rapid metabolizers CYP2D6. In slow metabolizers for CYP2D6, Cmax and AUC of the active metabolite of fesoterodine increased by 2.1 and 2.5 times, respectively, with co-administration of ketoconazole (200 mg twice daily for 5 days). Cmax and AUC were 4.5 and 5.7 times higher, respectively, in individuals who were slow metabolizers for CYP2D6 and received ketoconazole compared to subjects who were fast metabolizers for CYP2D6 and did not take ketoconazole. In a separate study in the combined use of fesoterodine with ketoconazole (200 mg 1 time per day for 5 days) C max and AUC of the active metabolite of fesoterodine was increased 2.2 times in rapid metabolizers on CYP2D6 and 1.5 and 1.9 times Respectively in weak metabolizers for CYP2D6. Cmax and AUC were 3.4 and 4.2 times higher, respectively, in individuals who were slow metabolizers for CYP2D6 and were taking ketoconazole, compared to subjects who were fast metabolizers for CYP2D6 and did not take ketoconazole.

Clinically significant effect of moderate inhibitors of CYP3A4 on the pharmacokinetics of fesoterodine was not revealed. In a study of drug interaction assessing the combined use of a moderate inhibitor of CYP3A4-fluconazole (200 mg twice daily for 2 days) with a single dose of 8 mg of fesoterodine taken 1 hour after the first dose of fluconazole on day 1 of the study, the mean ( 90% confidence interval) of Cmax and AUC of the active metabolite of fesoterodine were approximately 19% (11-28%) and 27% (18-36%), respectively.

The effect of weak inhibitors of CYP3A4 (eg, cimetidine) was not assessed; It is not expected that it will exceed the effect of moderate inhibitors.

Inductors of the isoenzyme CYP3A4. When rifampicin is used at a dose of 600 mg once a day, induction of the isoenzyme CYP3A4 is noted, which leads to a decrease of Cmax and AUC of the active metabolite of fesoterodine by 70 and 75%, respectively, after 8 mg of fesoterodine is administered orally. Terminal T1 / 2 of the active metabolite did not change. Induction of the CYP3A4 isoenzyme may lead to a decrease in the concentration of fesoterodine below the therapeutic level. Admission together with fesoterodine strong inducers of the isoenzyme CYP3A4 (eg carbamazepine, rifampicin, phenobarbital, phenytoin, preparations of St. John's wort perfumed) is not recommended.

Inhibitors of the isoenzyme CYP2D6. The simultaneous administration of fesoterodine with strong inhibitors of the CYP2D6 isoenzyme may lead to an increase in exposure and the risk of developing 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, there were no changes in plasma concentrations of the components of combined oral contraceptives containing ethinylestradiol and levonorgestrel.

Oral contraceptives. The interaction was studied in 30 healthy women taking oral contraceptives containing 0.03 mg of ethinyl estradiol and 0.15 mg of levonorgestrel in a cross-over study with 2 periods. Patients were randomized to concomitantly receive placebo or fesoterodine (8 mg once daily) on the 1-14th day of the hormonal cycle for 2 consecutive cycles. The pharmacokinetics of ethinyl estradiol and levonorgestrel were evaluated on the 13th day of each cycle. Fesoterodine increased AUC and Cmax ethinylestradiol by 1-3% and reduced AUC and Cmax levonorgestrel by 11-13%.

Warfarin. In a cross-sectional study, 14 healthy male volunteers (18-55 years of age) received a single oral dose of warfarin 25 mg, or received the same dose on the third day after fesoterodine 1 times a day for 9 days at a dose of 8 mg. Compared with the use of warfarin alone, Cmax and AUC of S-warfarin were lower by ~ 4%, while Cmax and AUC of R-warfarin were lower by approximately 8% and 6% when taken concomitantly, implying no significant pharmacokinetic interaction.

There were no statistically significant changes in the measured pharmacodynamic parameters of the anticoagulant activity of warfarin (MNmax, AUCMNO), only a slight decrease in MNOmax ~ 3% was observed when combined with the use of only one warfarin.

Overdose

Symptoms: an overdose of m-holinoblokiruyuschih funds, incl. Fesoterodine, can lead to the development of severe anticholinergic effects. In clinical studies, fesoterodine has shown itself to be a safe drug in doses up to 28 mg / day inclusive.

Treatment: symptomatic therapy, gastric lavage, administration of activated carbon, ECG monitoring and QT interval correction.

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. When respiratory failure is carried out IVL. With tachycardia, beta-blockers are used. When the urine is delayed, the bladder is catheterized. With mydriasis, eye drops with pilocarpine are prescribed.

Routes of administration

Inside.

Precautions

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 drugs. In the case of angioedema development, fesoterodine should be withdrawn and appropriate therapy prescribed.

Angioedema. There are reports of edema of the face, lips, tongue and / or larynx when taking fesoterodine. In some cases, angioedema has developed after the first dose. Angioedema, associated with obstruction of the upper respiratory tract, can be life threatening. With the development of angioedema, fesoterodine therapy should be immediately discontinued and appropriate therapy and / or measures to ensure airway patency should be carried out immediately.

Before the initiation of fesoterodine therapy, organic causes of the symptomatology should be excluded. To date, the safety and efficacy of fesoterodine in patients with neurogenic detrusor 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.

Childhood. Safety and efficacy of fesoterodine in children have not been investigated.

Elderly age. There is no need to adjust the dose in elderly people. The pharmacokinetics of fesoterodine are not significantly affected by age.

Of the 1567 patients who received fesoterodine at a dose of 4 or 8 mg / day in placebo-controlled studies of the efficacy and safety of fesoterodine in phases 2 and 3, 515 (33%) were 65 years of age or older and 140 (9%) aged 75 years and older. In these studies, there was no difference in the safety or efficacy of fesoterodine between patients younger than 65 years of age and people 65 years of age or older. Nevertheless, the percentage of antimuscarinic adverse effects, incl. Dry mouth, constipation, dyspepsia, increased residual urine, dizziness (only at a dose of 8 mg), and urinary tract infection, was higher in patients aged 75 years and older, compared with younger patients.

Violation of the function of the liver. In severe hepatic insufficiency (class C according to the Child-Pugh classification), the use of fesoterodine is contraindicated (see "Contraindications", "Pharmacokinetics"), t. Studies in this group of patients did not. In patients with impaired liver function of mild and moderate severity (class B according to the Child-Pugh classification), dose adjustment is not required (see "Pharmacokinetics").

Impaired renal function. In severe renal dysfunction (Cl creatinine <30 ml / min), it is not recommended to take a dose of fesoterodine more than 4 mg. In patients with impaired renal function of mild and moderate severity (Cl creatinine from 30 to 80 ml / min) (see "Pharmacokinetics"), dose adjustment is not required.

Floor. Adjusting the dose according to the sex of patients is not required.

Race. Adjustment of the dose in patients of the Caucasian and Negroid race is not required.

Pseudo-paralytic myasthenia gravis (myasthenia gravis). Fesoterodine should be used with caution in patients with myasthenia gravis - a disease characterized by a decrease in cholinergic activity in the neuromuscular synapse.

Combined use with inhibitors of the isoenzyme CYP3A4. Doses of fesoterodine greater than 4 mg are not recommended in patients taking strong inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, clarithromycin).

In the presence of moderate inhibitors of CYP3A4 (eg erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice), dose adjustment is not required. Although the effect of weak CYP3A4 inhibitors (eg cimetidine) has not been evaluated in a clinical trial, some pharmacokinetic interaction was expected, although less than that observed with moderate inhibitors of CYP3A4 (see "Interaction").

Combined use with inhibitors of the isoenzyme CYP3A4

The combined use of fesoterodine and strong inhibitors of the isoenzyme CYP3A4 in patients with severe (Cl creatinine ≤30 ml / min) and moderate (Cl creatinine 30 to 50 ml / min) is contraindicated in impaired renal function or impaired liver function of moderate severity. Fesoterodine should be avoided with strong inhibitors of CYP3A4 in patients with mild renal dysfunction (Cl creatinine 50 to 80 ml / min) and mild liver function disorder.

Simultaneous use of fesoterodine with moderate inhibitors of CYP3A4 should be avoided in patients with impaired renal function of severe degree or with impaired liver function of moderate severity.

With the simultaneous use of fesoterodine and moderate inhibitors of the isoenzyme CYP3A4, patients with mild to moderate renal insufficiency or a mild liver function disorder should not exceed a dose of 4 mg.

In patients with normal liver and kidney function when the combined intake of strong inhibitors of the isoenzyme CYP3A4 (including ketoconazole, itraconazole, clarithromycin) daily dose should not exceed 4 mg once a day; When administered with moderate inhibitors of CYP3A4 (including erythromycin, fluconazole, diltiazem, verapamil, grapefruit juice), an individual response and tolerability of fesoterodine should be evaluated before increasing the dose.

Influence on the ability to drive vehicles and use sophisticated technology. Care should be taken when driving and working with machinery due to the possible development of side effects such as reduced vision, dizziness and drowsiness.

Influence on the central nervous system. The intake of fesoterodine is associated with anticholinergic effects from the central nervous system (see "Side effects"). A variety of anticholinergic effects have been reported from the CNS, including such as headache, dizziness and drowsiness. Patients should be monitored to detect signs of anticholinergic effects from the CNS, especially at the beginning of treatment and with increasing doses. It should be advised patients not to drive the vehicle and do not work with complex equipment until they know how fesoterodine affects them. If the patient develops anticholinergic effects from the central nervous system, consideration should be given to reducing the dose or stopping fesoterodine.

special instructions

Tablets with prolonged release of fesoterodine contain lactose. Therefore, they can not be prescribed to persons suffering from rare congenital metabolic disorders: intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption.