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Instruction for use: Olodaterol + Tiotropium bromide (Olodaterolum + Tiotropii bromidum)

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Pharmacological group

M Cholinolytics in combinations

Beta-adrenomimetics in combinations

Nosological classification (ICD-10)

J42 Chronic bronchitis, unspecified

recurrent bronchitis, Bronchitis asthma, wheeze bronchitis, chronic Bronchitis, Inflammatory airways disease, bronchi disease, Qatar smoker, Cough in inflammatory diseases of the lung and bronchus, Exacerbation of Chronic Bronchitis, Chronic bronchitis, Chronic obstructive pulmonary disease, Chronical bronchitis, Chronic bronchitis smokers, Chronic spastic bronchitis, allergic Bronchitis

J43 Emphysema

Interstitial emphysema, Emphysema, Chronic lung disease, Chronic obstructive pulmonary disease, Obstructive pulmonary emphysema, Chronic pulmonary emphysema, Chronic obstructive pulmonary emphysema

J44 Other chronic obstructive pulmonary disease

Allergic bronchitis, Bronchitis asthma, Asthmatic bronchitis, wheeze bronchitis, Bronchitis is an obstructive, bronchi disease, Shortness of sputum in acute and chronic respiratory diseases, Cough in inflammatory diseases of the lung and bronchus, Reversible airflow obstruction, Reversible obstructive airway disease, Obstructive bronchitis disease, Obstructive lung disease, Obstructive bronchitis, Spastic bronchitis, Chronic lung disease, Chronic nonspecific lung diseases, Chronic obstructive pulmonary disease, Chronic obstructive bronchitis, Chronic obstructive airway disease, Chronic obstructive pulmonary disease, Restrictive lung pathology

J44.9 Chronic obstructive pulmonary disease, unspecified

Obstructive pulmonary diseases, Bronchial obstruction, bronchial obstruction, Exacerbation of chronic obstructive pulmonary disease, reversible airflow obstruction, Reversible airway obstruction, panbronchiolitis, Panbronhit, COPD, Chronic pulmonary infection, Chronic infection of the lower respiratory tract, Chronic obstructive pulmonary disease, Chronic obstructive pneumonia, Chronic lung disease, Chronic obstructive pulmonary disease, Chronic bronchopulmonary disease, Chronic broncho-pulmonary diseases, Airway obstruction

Characteristics

Characteristics of substances Olodaterol + Tiotropium bromide

Combined bronchodilator for inhalation.

Pharmacology

Pharmacological action - bronchodilator.

Pharmacodynamics

Olodaterol - beta2-adrenomimetic long-acting - and tiotropium bromide-m-cholinoblocker - provide complementary bronchodilation due to different mechanism of action of active substances and different localization of target receptors in the lungs.

Olodaterol has a high affinity and selectivity to beta2-adrenergic receptors. Activation of beta2-adrenergic receptors in the airways leads to stimulation of intracellular adenylate cyclase, which participates in the synthesis of cAMP. Increased cAMP levels cause bronchodilation, relaxing the smooth muscle cells of the respiratory tract. Olodaterol is a selective agonist of long-acting beta2-adrenoreceptors with a rapid onset of action and a prolonged (not less than 24 hours) effect. Beta2-adrenergic receptors are present not only in smooth muscle cells, but also in many other cells, incl. Epithelial and endothelial cells of the lungs and heart. The exact function of beta2 receptors in the heart is not fully understood, but their presence indicates the possibility of affecting the heart of even highly selective beta2-adrenergic agonists.

Tiotropium bromide is an antagonist of long-acting muscarinic receptors, often called m-holin-blocking agent in clinical practice. Has the same affinity for the m1-m5 subtypes of muscarinic receptors. The result of the inhibition of m3 receptors in the airway is the relaxation of smooth muscles. The bronchodilator effect is dose dependent and persists for at least 24 hours. A significant duration of action is probably associated with a very slow dissociation of tiotropium bromide from m3 receptors: the half-dissociation period is significantly longer than in ipratropium bromide. In the inhalation mode of administration, tiotropium bromide, as the N-quaternary ammonium derivative, exerts a local selective effect (on the bronchi), while at therapeutic doses without causing systemic m-cholinoblocking side effects. Dissociation from m2 receptors occurs faster than from m3 receptors, which indicates a predominance of selectivity for the receptor m3 subtype over m2 receptors. High affinity for receptors and slow dissociation of tiotropium bromide from binding to receptors cause a pronounced and prolonged bronchodilator effect in patients with COPD.

Bronchodilation, which develops after inhalation of tiotropium bromide, is caused, first of all, by local action (on the respiratory tract), and not by systemic action.

Clinical studies have shown that the combination of olodaterol + tiotropium bromide, applied once a day in the morning, led to a rapid (within 5 minutes after the first dose) improvement in lung function. The effect of the combination of olodaterol + tiotropium bromide was superior to the effect of tiotropium bromide at a dose of 5 μg and olodaterol at a dose of 5 μg used as monotherapy (the volume of forced exhalation in the first second (FEV1) increased with a 0.131 liter combination of olodaterol + tiotropium bromide Intake of tiotropium bromide alone - by 0,058 liters and when taking only olodaterol - by 0,125 liters).

With the use of a combination of olodaterol + tiotropium bromide, compared with the use of tiotropium bromide and olodaterol as monotherapy, a more significant bronchodilating effect was achieved, and the peak volumetric expiratory flow rate in the morning and evening hours increased.

The use of a combination of olodaterol + tiotropium bromide led to a reduction in the risk of exacerbations of COPD compared with placebo.

The combination of olodaterol + tiotropium bromide significantly improved the inspiratory capacity compared to tiotropium bromide, olodaterol or placebo, used as monotherapy.

The combination of olodaterol + tiotropium bromide compared with placebo significantly improved the time of exercise tolerance.

Pharmacokinetics

The pharmacokinetics of the combination of olodaterol + tiotropium bromide is equivalent to the pharmacokinetics of separately used olodaterol and tiotropium bromide.

Olodaterol and tiotropium bromide are characterized by linear pharmacokinetics.

Steady state of pharmacokinetics of olodaterol was achieved after 8 days with application once a day, and the degree of exposure increased in comparison with the use of a single dose of 1.8 times. The steady state of pharmacokinetics of tiotropium bromide was applied once a day after 7 days.

Suction. Olodaterol is rapidly absorbed, after inhalation a combination of olodaterol + tiotropium bromide Cmax of olodaterol is usually achieved within 10-20 minutes. In healthy volunteers, after inhalation, the combination of olodaterol + tiotropium bromide, the absolute bioavailability of olodaterol was about 30%, while the absolute bioavailability of olodaterol after ingestion as a solution was <1%.

Thus, the systemic effect of olodaterol after inhalation is mainly realized by absorption in the lungs, and the contribution of the swallowed portion of the dose to the systemic effect is negligible.

After inhalation of a solution of tiotropium bromide, about 33% of the inhalation dose arrives in the systemic circulation. Absolute bioavailability with oral administration is 2-3%. Cmax is observed 5-7 min after inhalation.

Distribution. The binding of olodaterol to plasma proteins is approximately 60%, Vd - 1100 liters.

The binding of tiotropium bromide to plasma proteins is 72%, Vd is 32 l / kg. Preclinical studies have shown that tiotropium bromide does not penetrate the BBB.

Biotransformation. Olodaterol is largely metabolized by direct glucuronization and O-demethylation followed by conjugation. Of the six identified metabolites with beta2 receptors, only one unconjugated demethylated derivative (SOM 1522) binds, but this metabolite is not detected in the plasma after prolonged inhalation at the recommended therapeutic dose or at doses exceeding the therapeutic dose by 4 times. In o-demethylation of olodaterol, cytochrome P450 (isozymes CYP2C9, CYP2C8 and to a small extent CYP3A4) is involved. In the formation of glucuronides of olodaterol involved isoforms of uridine diphosphate glycosyltransferase UGT2B7; UGT1A1, 1A7 and 1A9.

The degree of biotransformation of tiotropium bromide is negligible. This is confirmed by the fact that after intravenous administration of tiotropium bromide to healthy young volunteers, 74% is excreted by the kidneys unchanged. Tiotropium bromide is an ester that is split into ethanol-N-methylskopine and dithienylglycolic acid; These compounds do not bind to muscarinic receptors.

In vitro studies have shown that some part of the drug (<20% of the dose after intravenous administration) is metabolized by oxidation with cytochrome P450 (CYP2D6 and 3A4), followed by conjugation with glutathione and the formation of various metabolites.

Excretion. The total clearance of olodaterol in healthy volunteers is 872 ml / min, and the renal clearance is 173 ml / min. The final T1 / 2 after iv application of olodaterol is 22 hours, while the final T1 / 2 after inhalation is approximately 45 hours. It follows that in the latter case the excretion is more dependent on absorption.

The total isotope-labeled dose of olodaterol, excreted through the kidneys (including the parent compound and all metabolites), was 38% after intravenous administration, after oral administration - 9%. The total isotope-labeled dose, excreted through the kidneys, of unaltered olodaterol was 19% after intravenous administration. The total isotope-labeled dose, excreted through the intestine, was 53% after intravenous administration, after oral administration - 84%.

More than 90% of the dose of olodaterol was withdrawn after intravenous administration for 5 days and after ingestion - for 6 days. After inhalation, the excretion of unaltered olodaterol by the kidney during the dosing interval was 5-7% of the dose value in healthy volunteers during the steady state of pharmacokinetics.

Tiotropium bromide after intravenous administration is mainly excreted by the kidneys unchanged (74%). The total clearance after intravenous administration of tiotropium bromide to young healthy volunteers is 880 ml / min. After inhalation solution in patients with COPD, renal excretion is 18.6% (0.93 μg), the remaining unabsorbed part is excreted through the intestine. The renal clearance of tiotropium bromide exceeds the creatinine clearance, which indicates its tubular secretion. Terminal T1 / 2 tiotropium bromide after inhalation is from 27 to 45 h.

Pharmacokinetics in elderly patients. Clinical studies have shown that, despite the influence of age, sex and body weight on systemic exposure to olodaterol, dose adjustment is not required.

In the elderly, there is a decrease in renal clearance of tiotropium (347 ml / min in patients with COPD before the age of 65 and 275 ml / min in patients with COPD over 65 years old). However, the ego did not lead to an increase in the values of AUC0-6, ss and Cmax, ss.

Race. Comparison of the pharmacokinetic data obtained in clinical studies of olodaterol revealed a trend towards a higher systemic exposure to olodaterol in patients from Japan and other patients of the Asian race compared with patients of the European race. In clinical studies of olodaterol, used in doses that exceeded the recommended therapeutic dose by a factor of 2, there was no safety concern in the patients of the Caucasian and Asian races.

Patients with impaired renal function. In patients with severe renal insufficiency (Cl creatinine <30 ml / min) systemic exposure to olodaterol increased by an average of 1.4 times. This increased exposure does not raise concerns about safety, given the experience gained with the use of olodaterol in clinical trials.

After inhalation of tiotropium bromide 1 times a day during a period of steady state pharmacokinetics in patients with COPD and mild renal insufficiency (Cl creatinine 50-80 ml / min) there was a small increase in AUC0-6, ss by 1.8-30% and Cmax, ss compared with patients with normal renal function (Cl creatinine> 80 mL / min). In patients with COPD and moderate to severe renal insufficiency (Cl creatinine <50 mL / min), iv administration of tiotropium bromide resulted in a twofold increase in the total exposure to tiotropium bromide (AUC0-4 increased 82% and Cmax increased 52%) compared with patients with normal renal function. A similar increase in plasma concentration was noted after inhalation of dry powder.

Patients with impaired liver function. In patients with hepatic insufficiency of mild and moderate severity, the systemic effect of olodaterol did not change. The systemic effect of olodaterol in patients with hepatic insufficiency of severe severity has not been studied.

It is assumed that liver failure does not significantly affect the pharmacokinetics of tiotropium bromide, t. Tiotropium bromide is mainly excreted by the kidneys and by non-enzymatic cleavage of the ester bond to form derivatives that do not possess pharmacological activity.

Indications

The combination of olodaterol + tiotropium bromide applied once a day is indicated for prolonged maintenance therapy in patients with chronic obstructive pulmonary disease, chronic bronchitis and emphysema to reduce airway obstruction and concomitant dyspnea, reduce the frequency of exacerbations, improve exercise tolerance and quality of life.

Contraindications

Hypersensitivity to olodaterol and tiotropium bromide, a previous hypersensitivity to atropine or its derivatives (eg ipratropium bromide and oxytropium bromide), children under 18 years of age (due to lack of data on efficacy and safety).

Restrictions on the use

Ostrogenous glaucoma, prostatic hyperplasia and bladder neck obstruction; Cardiovascular diseases, incl. Coronary insufficiency, heart rhythm disturbances, QT interval prolongation, hypertrophic obstructive cardiomyopathy, arterial hypertension, thyrotoxicosis, seizures; Presence in the anamnesis of such diseases as myocardial infarction or hospitalization for heart failure (during the previous year), life-threatening arrhythmia, paroxysmal tachycardia with heart rate> 100; Unusual reactions to sympathomimetic amines.

pregnancy and lactation

There are no clinical data on the effect of the combination of olodaterol + tiotropium bromide on pregnancy. Pre-clinical studies using high doses of olodaterol, several times the therapeutic dose, established the effects typical of beta2-adrenomimetics. The inhibitory effect of olodaterol on the uterine contractility should be considered. The combination of olodaterol + tiotropium bromide should not be used in pregnant women, unless the potential benefit to the mother does not exceed the potential risk to the fetus.

Clinical data on the use of a combination of olodaterol + tiotropium bromide in breastfeeding women are not available. The combination of olodaterol + tiotropium bromide should not be used in breast-feeding women, unless the potential benefit to the mother does not exceed the potential risk for the child.

For the period of application of a combination of olodaterol + tiotropium bromide, breast-feeding should be stopped.

Side effects

Adverse reactions were revealed on the basis of data obtained during clinical trials of a combination of olodaterol + tiotropium bromide.

Infections and infestations: nasopharyngitis.

From the side of metabolism and nutrition: dehydration.

From the nervous system: dizziness, insomnia.

From the side of the organ of vision: an increase in IOP, glaucoma, fuzzy vision.

From the CCC: ciliary arrhythmia, palpitations, tachycardia, supraventricular tachycardia, increased blood pressure.

On the part of the respiratory, thorax and mediastinal organs: cough, nosebleeds, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.

From the gastrointestinal tract: insignificant dryness in the mouth, constipation, candidiasis of the oral cavity, dysphagia, gastroesophageal reflux, gingivitis, glossitis, stomatitis, intestinal obstruction, including paralytic intestinal obstruction.

From the skin: skin infections and ulcers on the skin, dry skin.

Allergic reactions: rash, itching, angioedema, hives, hypersensitivity, including reactions of immediate type.

From the musculoskeletal system and connective tissue: arthralgia, swelling in the joint region, back pain (this side effect is attributed to the dosage form, and not to the components of the combination).

From the kidney and urinary system: dysuria, urinary retention (more often in men with predisposing factors), urinary tract infection.

Many of these unwanted effects are due to the anticholinergic action of tiotropium bromide or beta2-adrenomimetic action of olodaterol. Therefore, it is necessary to take into account the possibility of undesirable effects that are characteristic of the whole class of beta-adrenomimetics, such as arrhythmia, myocardial ischaemia, angina pectoris, hypotension, tremor, headache, nervousness, nausea, muscle spasms, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.

Long-acting beta2-adrenergic agonists such as olodaterol, one of the active components of the combination of olodaterol + tiotropium bromide, increase the risk of fatal asthma-related accidents. The combination of olodaterol + tiotropium bromide is not indicated for the treatment of asthma (see "Precautions").

The following side reactions are discussed in more detail in other sections of this description:

- immediate type hypersensitivity reactions (see "Precautions");

- Paradoxical bronchospasm (see "Precautions");

- impairment of visual functions in closed-angle glaucoma (see "Precautions");

- increased urinary retention (see "Precautions").

Results of clinical trials in COPD

Since clinical trials have been conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not coincide with those obtained in other studies and observed in clinical practice.

The clinical program for the combination of olodaterol + tiotropium bromide included 7151 patients with COPD in two 52-week active control trials, one 12-week placebo-controlled trial, three 6-week placebo-controlled cross-over trials and four additional shorter duration trials. A total of 1988 patients received at least 1 dose of a combination of olodaterol + tiotropium bromide. Adverse reactions observed in studies lasting less than or equal to 12 weeks were consistent with those observed in 52-week trials in which a primary safety database was being formed.

The primary safety database consisted of a pool of data obtained from two 52-week, double-blind, confirmatory trials with active control and parallel groups. In these trials, 4162 adult patients with COPD (72.9% male and 27.1% female) aged 40 years and older participated. Of these, 1029 patients received a combination of olodaterol + tiotropium bromide 1 time per day. This group consisted mainly of representatives of the Caucasoid race (71.1%) with an average age of 63.8 years and an average calculated baseline FEV1 level of 43.2%. In these two studies, 5 μg of tiotropium bromide and 5 μg of olodaterol were used as active controls, placebo was not used.

In the two clinical trials listed above, adverse reactions were observed in 74% of patients receiving the combination of olodaterol + tiotropium bromide, compared with 76.6 and 73.3% in the groups receiving 5 μg of olodaterol and 5 μg of tiotropium bromide, respectively. The proportion of patients who discontinued treatment due to adverse reactions was 7.4% in the group receiving the combination of olodaterol + tiotropium bromide, compared with 9.9 and 9% for groups of patients receiving 5 μg of olodaterol and 5 μg of tiotropium bromide. Most often, the reason for refusing treatment was an exacerbation of COPD.

The most frequent serious adverse reactions were exacerbation of COPD and pneumonia.

Combined data on the number and incidence of adverse reactions that occurred in> 2% of COPD patients aged 40 years and more (and more often than in any of the comparison groups using tiotropium bromide and / or olodaterol) in two 52-week-old double Blind confirmatory trials with active control and parallel groups. The first group of figures is the data for the group receiving the combination of olodaterol + tiotropium bromide 1 time per day (N = 1029, in parentheses in percent), the second for the control group receiving tiotropium bromide at a dose of 5 μg once a day (N = 1033 , In brackets in percent) and the third for the control group receiving oligoterol at a dose of 5 μg once a day (N = 1038, in parentheses in percent).

Infections and infestations: nasopharyngitis 128 (12.4%); 121 (11.7%) and 131 (12.6%).

On the part of the respiratory, thorax and mediastinal organs: cough 40 (3.9%); 45 (4.4%) and 31 (3%).

From the musculoskeletal system and connective tissue: back pain 37 (3.6%); 19 (1.8%) and 35 (3.4%).

Other adverse drug reactions in patients receiving the combination of olodaterol + tiotropium bromide, which occurred at a frequency of or less than 3% during clinical trials, are listed below.

From the side of metabolism and nutrition: dehydration.

From the nervous system: dizziness, insomnia.

On the part of the organ of vision: glaucoma, increased IOP, blurred vision.

From the CCC: atrial fibrillation, severe palpitation, supraventricular tachycardia, tachycardia, hypertension.

On the part of the respiratory, thorax and mediastinal organs: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.

From the gastrointestinal tract: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, GERD, gingivitis, glossitis, stomatitis, intestinal obstruction, including paralytic ileus.

From the skin of the subcutaneous tissue: rash, itching, angioedema, hives, skin infection, skin ulceration, dry skin, hypersensitivity reactions (including immediate reactions).

From the musculoskeletal system and connective tissue: arthralgia, swelling of the joints.

From the kidney and urinary system: urinary retention, dysuria, infection of the urinary tract.

Interaction

Although no special studies of drug interactions were conducted, tiotropium bromide was used in conjunction with other drugs for COPD, including methylxanthines, steroids for oral administration and inhalation, with no clinical signs of drug interactions.

Long-term combined use of tiotropium bromide with other m-holinoblokatorami not studied. Therefore, long-term combined use of a combination of olodaterol + tiotropium bromide with other m-cholinoblocking drugs is not recommended.

The simultaneous use of other adrenergic drugs may increase the undesirable effects of the combination of olodaterol + tiotropium bromide.

The simultaneous use of xanthine derivatives, steroids or diuretics (not belonging to the group of potassium-sparing agents) can enhance the hypokalemic effect of adrenomimetics.

Beta-adrenoblockers can weaken the effect of olodaterol or counteract this effect. In this case, the use of beta 1-blockers is preferable, although they should be used with caution.

MAO inhibitors, tricyclic antidepressants or other drugs capable of prolonging the QTc interval can enhance the action of the combination of olodaterol + tiotropium bromide on CCC.

The combined use of olodaterol with ketoconazole increased the systemic exposure to olodaterol by a factor of 1.7, which did not affect safety. A dose change is not required.

Adrenergic drugs. Caution should be exercised with the additional administration of adrenergic drugs with any route of administration. It is possible to enhance the sympathomimetic effect of olodaterol, one of the components of a combination of olodaterol + tiotropium bromide (see "Precautions").

Sympathomimetics, xanthine derivatives, steroids or diuretics. Tiotropium bromide was used in conjunction with sympathomimetics (beta-agonists) of short and long-acting, bronchodilators, methylxanthines and oral or inhaled steroids without increasing adverse reactions. Joint use of xanthine derivatives, steroids or diuretics can enhance any hypokalemic action of olodaterol (see "Precautions").

Non-potassium-sparing diuretics. Beta agonists can greatly impair ECG changes and / or hypokalemia resulting from the use of non-potassium-sparing diuretics (such as loop or thiazide diuretics), especially when the recommended dose of beta-agonist is exceeded. The clinical significance of these effects is unknown, nevertheless caution should be exercised when using a combination of olodaterol + tiotropium bromide with non-potassium-sparing diuretics.

MAO inhibitors, tricyclic antidepressants, drugs that extend the QTc interval. With special care, a combination of olodaterol + tiotropium bromide, as well as other drugs containing beta2 agonists, should be used in patients receiving MAO inhibitors or tricyclic antidepressants, or other drugs with a known ability to extend the QTc interval. These drugs can enhance the effect of adrenomimetics on CCC. A drug with a known ability to extend the QTc interval may be associated with an increased risk of developing ventricular arrhythmias.

Beta-blockers. Antagonists of beta-adrenergic receptors (beta-adrenoblockers) and olodaterol - a component of the combination of olodaterol + tiotropium bromide - in a joint application can mutually adversely affect the effect of each of these drugs. Beta-adrenoblockers not only block the effects of beta-agonists, but can also cause severe bronchospasm in patients with COPD. In this regard, patients with COPD, as a rule, should not receive treatment with beta-blockers. Nevertheless, under certain conditions (eg prophylaxis after myocardial infarction), beta-blockers do not have an acceptable alternative for use in patients with COPD. In such cases, cardioselective beta-blockers should be used, although they should be administered with caution.

Anticholinergic drugs. There is the possibility of additive interaction with jointly used anticholinergic drugs. In this regard, the combined use of a combination of olodaterol + tiotropium bromide with other drugs containing the anticholinergic component should be avoided. This can lead to increased anticholinergic side effects (see "Precautions").

Inhibitors of cytochrome P450 and transport protein P-gp. In a study of drug interaction with the use of ketoconazole, a strong inhibitor of CYP and P-gp, a 1.7-fold increase in Cmax and AUC of olodaterol was observed. Olodaterol was evaluated in clinical trials lasting up to 1 year at doses exceeding the recommended therapeutic dose by 2 times. Correction of the dose of a combination of olodaterol + tiotropium bromide is not required.

Overdose

Symptoms: an overdose of olodaterol can lead to pronounced effects typical of beta2-adrenomimetics, for example, myocardial ischemia, increased or decreased blood pressure, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, spasm Muscle, nausea, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.

When high doses of tiotropium bromide are used, manifestations of m-cholinoblocking action are possible. After a 14-day inhalation application of tiotropium bromide in doses as high as 40 μg, no significant adverse events were observed in healthy individuals, except for the dryness of the nasal mucous membranes and the oropharynx, whose frequency depended on the dose (10-40 μg per day). The exception was a clear reduction in salivation, starting from the 7th day of application.

Treatment: taking a combination of olodaterol + tiotropium bromide should be discontinued. Supportive and symptomatic treatment is indicated. In severe cases, hospitalization is necessary. The use of beta1-blockers may be recommended, but only with the utmost care, because The use of these drugs can cause bronchospasm.

The risks associated with overdose of each component of the combination of olodaterol + tiotropium bromide are listed below.

Tiotropium bromide. The use of high doses of tiotropium bromide can cause anticholinergic signs and symptoms. However, no systemic anticholinergic side effects were observed after a single dose of up to 282 μg of tiotropium bromide in 6 healthy volunteers. In studies involving 12 healthy volunteers after a single inhalation of 141 μg of tiotropium bromide, bilateral conjunctivitis and dry mouth were observed. Dryness in the mouth / larynx and dryness of the nasal mucous membranes were observed in healthy volunteers after a 14-day inhalation of a solution of tiotropium bromide at a dose of 40 μg in a dose-dependent study (10-40 μg daily).

Olodaterol. The expected signs and symptoms of an overdose of olodaterol are the same as in excessive beta-adrenergic stimulation and include cases of myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmia, rapid heartbeat, dizziness, nervousness, insomnia, anxiety, headache, tremor, dryness In the mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis. As with other sympathomimetic drugs, cases of cardiac arrest and even death may be associated with an overdose of olodaterol.

Treatment of an overdose includes the abolition of the use of a combination of olodaterol + tiotropium bromide and the appointment of appropriate symptomatic and maintenance therapy. The use of cardioselective beta-blockers can be considered only in view of the fact that these drugs can cause bronchospasm. There is insufficient evidence to suggest that dialysis is effective in overdosing a combination of olodaterol + tiotropium bromide. In case of an overdose it is recommended to monitor cardiac functions.

Routes of administration

Inhalation.

Precautions

The combination of olodaterol + tiotropium bromide should not be used for bronchial asthma. The efficacy and safety of the combination of olodaterol + tiotropium bromide in bronchial asthma have not been studied.

Acute bronchospasm. The combination of olodaterol + tiotropium bromide is not indicated for the treatment of acute episodes of bronchospasm, i.e. As an ambulance.

Hypersensitivity. After the application of a combination of olodaterol + tiotropium bromide, the development of immediate-type hypersensitivity reactions is possible.

Paradoxical bronchospasm. The use of a combination of olodaterol + tiotropium bromide, as well as other inhaled drugs, can lead to a paradoxical bronchospasm, sometimes life-threatening. In the case of paradoxical bronchospasm, the combination of olodaterol + tiotropium bromide should be immediately discontinued and alternative therapy should be prescribed.

Patients with impaired renal function. Since tiotropium bromide is excreted mainly by the kidneys, patients with moderate and severe renal insufficiency (Cl creatinine <50 ml / min), using a combination of olodaterol + tiotropium bromide, should be carefully monitored by a physician.

Disorders from the side of the organ of sight. Patients should be familiar with the correct use of a combination of olodaterol + tiotropium bromide. Do not allow solution or aerosol to enter the eyes. Pain or discomfort in the eyes, fuzzy vision, visual halos around the light sources combined with reddening of the eyes caused by edema of the conjunctiva and the cornea, may be symptoms of acute closed-angle glaucoma. When developing any combination of these symptoms, you should immediately contact a specialist. Eye drops that have a miotic effect are not considered effective treatment.

Cardiovascular effects. Olodaterol, like other beta2-adrenomimetics, can have a clinically significant effect on CCC in some patients (increased heart rate, increased blood pressure and / or the appearance of the corresponding symptoms). If these symptoms occur, treatment may need to be discontinued. In addition, it was reported that beta2-adrenomimetics led to ECG changes such as flattening of the T wave and ST segment depression, although the clinical significance of these changes is unknown.

Hypokalemia. Beta-2-adrenomimetics in some patients can lead to the development of hypokalemia, which creates the prerequisites for the occurrence of undesirable effects on CAS. Reducing the concentration of potassium in the blood serum is usually short-term and does not require its replenishment. In patients with severe COPD, hypokalemia may increase due to hypoxia and concomitant treatment and increase the risk of arrhythmias.

Hyperglycemia. Inhaled use of large doses of beta2-adrenomimetics may lead to an increase in the concentration of glucose in the blood plasma.

The combination of olodaterol + tiotropium bromide should not be used in combination with any other drugs containing long-acting beta2-adrenomimetics.

Influence on the ability to drive vehicles and mechanisms. Studies to study the effect on the ability to drive vehicles and mechanisms have not been carried out. Care should be taken when performing these types of activities; May develop dizziness or blurred vision.

The risk of death associated with asthma. Data from large placebo-controlled studies with asthma patients indicated that beta2-adrenomimetics may increase the risk of death associated with asthma. There are no data to establish whether long-acting beta2-adrenomimetics affect the increase in mortality in patients with COPD.

In a 28-week placebo-controlled study in the United States, an increase in mortality in patients treated with salmeterol was shown when comparing the safety of another long-acting beta2-adrenomimetic (salmeterol) with placebo with each addition to standard anti-asthmatic therapy. The increased risk of death associated with asthma is considered a classic effect of long-acting beta2-adrenomimetics, including olodaterol, one of the active components of a combination of olodaterol + tiotropium bromide. Studies sufficient to establish the relationship between the increase in asthma-related mortality in patients receiving the combination of olodaterol + tiotropium bromide were not performed. The efficacy and safety of the combination of olodaterol + tiotropium bromide in patients with asthma have not been established. The combination of olodaterol + tiotropium bromide is not indicated for the treatment of asthma.

Exacerbation of the disease and acute episodes. Treatment with a combination of olodaterol + tiotropium bromide should not be started in patients with exacerbation of COPD, which can be a life-threatening condition. The combination of olodaterol + tiotropium bromide has not been studied in patients with exacerbation of COPD. The use of a combination of olodaterol + tiotropium bromide in such a state is inappropriate.

The combination of olodaterol + tiotropium bromide should not be used to relieve acute symptoms, i.e. In the form of emergency therapy for the treatment of acute episodes of bronchospasm. The use of a combination of olodaterol + tiotropium bromide to alleviate acute symptoms has not been studied, and elevated doses of this combination for such purposes should not be used. Acute symptoms should be treated with short-acting inhaled beta2-adrenergics.

Before starting treatment with a combination of olodaterol + tiotropium bromide, patients who previously used short-acting inhaled beta2-adrenomimetics on a regular basis (for example, 4 times a day) should be warned about the need to refuse the regular use of these drugs and use them only for the symptomatic relief of acute respiratory symptoms . When appointing a combination of olodaterol + tiotropium bromide, the attending physician should also prescribe a short-acting inhaled beta2-adrenomimetic and instruct the patient on how to use the drug. An increase in the dose of short-acting inhaled beta2-adrenomimetic is a sign of an exacerbation of the disease requiring immediate medical intervention.

Exacerbation of COPD can be acute for several hours or chronic for several days or longer. Signs of an exacerbation of the disease are the lack of control over the symptoms of bronchoconstriction with the use of a combination of olodaterol + tiotropium bromide, a decrease in the effectiveness of short-acting beta2-adrenergic inhalations, or the need for a more frequent use of beta2-adrenomimetics of a shorter action than usual. In such cases, the patient's condition should be immediately reassessed and the treatment strategy of COPD revised. An increase in the daily dose of a combination of olodaterol + tiotropium bromide above recommended in such a situation is unacceptable.

Excessive use of a combination of olodaterol + tiotropium bromide and application together with other long-acting beta2-adrenomimetics. The combination of olodaterol + tiotropium bromide, as well as other inhaled drugs containing beta2-adrenomimetics, should not be used more often than recommended in a dose exceeding recommended or in combination with other drugs containing long-acting beta2-adrenomimetics, This can lead to an overdose. There are data on clinically significant cardiovascular effects and deaths associated with excessive use of inhaled sympathomimetic drugs.

Reactions of immediate type hypersensitivity. After applying the combination of olodaterol + tiotropium bromide, immediate-type hypersensitivity reactions such as urticaria, angioedema (including swelling of the lips, tongue, larynx), rash, bronchospasm, anaphylaxis, or pruritus may develop. If such reactions occur, immediately stop the therapy with a combination of olodaterol + tiotropium bromide and consider alternative therapies. Patients with a known history of hypersensitivity to atropine and its derivatives, when administering tiotropium bromide structurally close to atropine, should be carefully observed when using a combination of olodaterol + tiotropium bromide for the occurrence of similar hypersensitivity reactions.

Paradoxical bronchospasm. Like other inhaled drugs, the combination of olodaterol + tiotropium bromide can cause a paradoxical bronchospasm, incl. Threatening to life. If a paradoxical bronchospasm occurs, the combination of olodaterol + tiotropium bromide should be stopped immediately and an alternative therapy is prescribed.

Cardiovascular effects. Olodaterol, like other beta2-adrenomimetics, can cause clinically significant cardiovascular effects in some patients, manifested by increased heart rate, SAD or DAD, and / or the appearance of the corresponding symptoms. When these effects occur, the use of a combination of olodaterol + tiotropium bromide should be suspended. In addition, it is known that beta-adrenomimetics cause ECG changes, such as flattening of the T wave, prolongation of the QTc interval and depression of the ST segment. The clinical significance of these observations is unknown. Long-acting beta2-adrenomimetics should be used with caution in patients with cardiovascular disease, especially with heart failure, cardiac arrhythmia, hypertrophic obstructive cardiomyopathy, and hypertension.

Accompanying illnesses. Olodaterol, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, a known or suspected prolongation of the QT interval and an unusual response to treatment with sympathomimetic amines. There is evidence that IV injection of albuterol-related beta2-adrenomimetic-led to an exacerbation of existing diabetes mellitus and ketoacidosis.

Deterioration of visual functions in closed-angle glaucoma. The combination of olodaterol + tiotropium bromide should be used with caution in patients with closed-angle glaucoma. The attending physician and patient should take into account the signs and symptoms of acute angle-closure glaucoma (eg, pain and discomfort in the eye, blurred vision, visual aureoles or color images combined with redness of the eyes caused by conjunctival hyperemia and corneal edema). It should be instructed the patient about the need for immediate consultation of a doctor in the development of any of these signs or symptoms.

Deterioration of the condition associated with urinary retention. The combination of olodaterol + tiotropium bromide should be used with caution in patients with a delay in urine. The attending physician and patient should take into account the signs and symptoms of prostatic hyperplasia and obstruction of the bladder neck (eg difficulty urinating, painful urination), especially in patients with prostatic hyperplasia and bladder neck obstruction. It should be instructed the patient about the need for immediate consultation of a doctor in the development of any of these signs or symptoms.

Impaired renal function. Since tiotropium bromide is excreted mainly by the kidneys, careful monitoring of anticholinergic side effects in patients with moderate or severe renal impairment (Cl creatinine less than or equal to 60 ml / min) receiving a combination of olodaterol + tiotropium bromide should be undertaken.

Hypokalemia and hyperglycemia. Beta-adrenomimetics can cause significant hypokalemia in some patients, which can lead to adverse cardiovascular effects. The decrease in serum potassium levels is usually transient and does not require replenishment. Inhaling high doses of beta2-adrenomimetics can cause an increase in the level of glucose in the blood plasma.

In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant medication (see "Interaction"), which may increase sensitivity to cardiac arrhythmias.

In clinical studies with prolonged use of olodaterol, clinically significant decreases in potassium levels in the blood serum or changes in blood glucose levels were infrequent and comparable to those observed with placebo. The use of olodaterol was not studied in patients with insufficient control of diabetes mellitus.

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