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

Pharmacotherapeutic group:

Beta-adrenergic agonist in combination

M Cholinolytics in combinations

The 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

The combined bronchodilator for inhalation use.

Pharmacological action.

bronchodilator.

pharmacodynamics

Olodaterol - beta2-agonists long-acting - and tiotropium bromide - m-holinoblokator - provide complementary bronchodilation resulting from the action of various active ingredients and mechanism of different target receptor localization in the lungs.

Olodaterol has high affinity and selectivity for beta2-adrenergic receptors. Activation of beta2-adrenoceptor airway leading to stimulation of intracellular adenylate cyclase, which is involved in cAMP synthesis. Increased cyclic AMP levels cause bronchodilation by relaxing the smooth muscle cells of the respiratory tract. Olodaterol agonist is a selective beta2-adrenoceptor prolonged action with a rapid onset of action and long-term (at least 24 h) retaining effect. Beta2-adrenergic receptors are present not only in smooth muscle cells, but also in many other cells, including epithelial and endothelial cells of the lung and heart. The precise function of beta2-receptors in the heart is not fully understood, but their presence indicates the possibility of effects on the heart, even highly selective beta2-adrenergic agonists.

Tiotropium bromide - muscarinic antagonist is a long-acting receptors in clinical practice often called m-anticholinergic agent. It has the same affinity for M1-M5 subtypes of muscarinic receptors. The result of inhibition of m3 receptors in the airways is the relaxation of smooth muscle. Bronchodilator effect depends on the dose and lasts for at least 24 hours long duration of action is probably due to the very slow dissociation of tiotropium bromide of m3 receptors:. Poludissotsiatsii period significantly longer than that of ipratropium bromide. Inhalation administration method, tiotropium bromide as N-quaternary ammonium derivative, exerts a selective effect of local (in the bronchi), while in therapeutic doses without causing systemic m-anticholinergic side effects. Dissociation of m2 receptors is faster than that of m3 receptors, suggesting the predominance of selectivity for the M3 receptor subtype of m2 receptors. High affinity receptors and slow dissociation of tiotropium bromide communication receptors cause pronounced and prolonged bronchodilatory effect in patients with COPD.

Bronchodilation, developing after inhalation of tiotropium bromide, due, primarily local effect (on the airways), not a system.

In clinical studies found that the combination of olodaterol + tiotropium bromide, is used 1 time in the morning, led to a rapid (within 5 minutes after the first dose) improve lung function. The effect of the combination of olodaterol + tiotropium bromide exceeds the effect of tiotropium bromide at a dose of 5 mcg and olodaterola at a dose of 5 mg, used as monotherapy (forced expiratory volume in 1 second (FEV1) increased when receiving combination olodaterol + tiotropium bromide to 0,137 liters, with reception only tiotropium bromide - to 0,058 liters, and when receiving only olodaterola - to 0,125 liters).

When using a combination of olodaterol + tiotropium compared with tiotropium bromide and olodaterola as monotherapy achieved a significant bronchodilator effect, as well as increased volume peak expiratory flow in the morning and evening hours.

Use of a combination of tiotropium bromide + olodaterol decreased the risk of COPD exacerbations compared with placebo.

+ Olodaterol combination of tiotropium bromide inhalation significantly improved capacity compared to tiotropium bromide, olodaterolom or placebo, used as monotherapy.

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

Pharmacokinetics

The pharmacokinetics of the combination of tiotropium + olodaterol equivalent pharmacokinetics separately applied olodaterola and tiotropium bromide.

Olodaterolu and tiotropium bromide characterized by linear pharmacokinetics.

Steady state pharmacokinetic olodaterola achieved after 8 days when applying 1 time per day, and the impact of increased compared with a single dose of 1.8 times. The steady state pharmacokinetics of tiotropium bromide when applied 1 time per day was achieved in 7 days.

Suction. Olodaterol rapidly absorbed after inhalation + olodaterol combination of tiotropium bromide Cmax olodaterola usually achieved within 10-20 minutes. In healthy volunteers after inhalation + olodaterol combination of tiotropium bromide olodaterola absolute bioavailability was about 30%, whereas the absolute bioavailability after oral administration olodaterola was <1% in the form of a solution.

Thus, the systemic exposure after inhalation application olodaterola mainly realized by absorption in the lungs, and the contribution to the dose ingested portion negligible systemic exposure.

After inhalation of a solution of tiotropium bromide in the systemic circulation receives about 33% of the inhaled dose. The absolute oral bioavailability of 2-3%. Cmax is observed within 5-7 minutes after inhalation.

Distribution. Olodaterola Binding to plasma proteins is approximately 60%, Vd - 1100 liters.

Tiotropium bromide Binding to plasma proteins is 72%, Vd - 32 l / kg. Preclinical studies have shown that tiotropium bromide does not penetrate the blood-brain barrier.

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

Degree biotransformatspi tiotropium bromide is negligible. This is confirmed by the fact that after the on / in the tiotropium bromide young healthy volunteers 74% excreted by the kidneys unchanged. Tiotropium bromide is an ester which is cleaved in the ethanol-N-metilskopin and ditienilglikolievuyu acid; these compounds do not bind to muscarinic receptors.

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

Withdrawal. Olodaterola total clearance in healthy volunteers was 872 ml / min and the renal clearance - 173 ml / min. The final T1 / 2 after the I / olodaterola application is 22 hours, whereas the final T1 / 2 after inhalation application -. Approximately 45 hours From this it follows that in the latter case, removal is more dependent upon absorption.

The total dose of isotope-labeled olodaterola, excreted through the kidneys (including parent compound and all metabolites) accounted for after the on / in the introduction of 38%, after ingestion - 9%. Total isotope-labeled dose excreted through the kidneys, was unchanged olodaterola after the on / in the 19%. Total isotope-labeled dose is released through the intestines, it was after the on / in 53% after oral administration - 84%.

More than 90% of the dose olodaterola conclusions after the on / in 5 days after ingestion - for 6 days. After inhalation application excretion by the kidneys unchanged olodaterola throughout the dosing interval was in healthy volunteers during the steady-state pharmacokinetics of 5-7% of the dose.

Tiotropium bromide after the on / in the mainly excreted by the kidneys in unchanged form (74%). Total clearance after the on / in the tiotropium bromide young healthy volunteers was 880 ml / min. After inhalation of a solution in patients with COPD, renal excretion is 18.6% (0.93 g), the remaining unabsorbed portion is derived through the intestines. Renal clearance of tiotropium bromide exceeds the creatinine clearance, which indicates its tubular secretion. Terminal T1 / 2 after inhalation of tiotropium bromide is from 27 to 45 hours.

Pharmacokinetics in elderly patients. Clinical studies have shown that despite the effects of age, gender, and body mass olodaterola on systemic exposure, dose adjustment is required.

In old age there is a decrease of tiotropium renal clearance (347 mL / min in COPD patients aged 65 years and 275 ml / min in COPD patients over 65 years). However ego did not increase the value of AUC0-6, ss and Cmax, ss.

Race. Comparison of the pharmacokinetic data obtained in clinical studies olodaterola, shows a trend towards a higher systemic exposure in patients olodaterola from Japan and other Asian race patients compared to Caucasian patients. In clinical studies olodaterola that was used at doses that exceed the therapeutic recommended 2 times in patients Caucasian and Asian races any fears has not been established for safety.

Patients with impaired renal function. In patients with severe renal failure severity (Cl creatinine <30 ml / min) increased systemic exposure olodaterola average 1.4 times. This increase in exposure does not cause safety concerns, taking into account the experience gained in the application of olodaterola in clinical studies.

After inhalation use tiotropium bromide 1 time per day during the steady state pharmacokinetics in patients with COPD, renal and mild insufficiency (Cl creatinine 50-80 ml / min) indicated a slight increase AUC0-6, ss on and 1,8-30% Cmax, ss compared with patients with normal renal function (Cl creatinine> 80 ml / min). Patients with COPD and renal failure secondary to severe (Cl creatinine <50 ml / min) / in the use of tiotropium bromide resulted in doubling of the overall impact of tiotropium bromide (AUC0-4 value increased by 82% and Cmax value of the - on the 52%) compared with patients with normal renal function. Similar increases in plasma concentrations observed after dry powder inhalation.

Patients with impaired hepatic function. In patients with mild hepatic impairment, and moderate systemic exposure olodaterola not changed. Systemic exposure olodaterola in patients with severe hepatic impairment has not been studied severity.

It is expected that hepatic impairment did not have a significant effect on the pharmacokinetics of tiotropium bromide, because tiotropium bromide mainly excreted by the kidneys and through enzymatic cleavage of the ester bond to form derivatives that do not possess pharmacological activity.

The use of substances Olodaterol + tiotropium bromide

The combination of olodaterol + tiotropium bromide, used 1 time per day, is indicated for the long-term maintenance therapy in patients with chronic obstructive pulmonary disease, chronic bronchitis and emphysema to reduce airway obstruction and related dyspnea, reduce the frequency of exacerbations, improve exercise tolerance and quality of life.

Contraindications

Hypersensitivity to olodaterolu and tiotropium bromide, prior hypersensitivity to atropine or its derivatives (such as ipratropium bromide and oxitropium bromide), children up to 18 years (due to lack of efficacy and safety data).

Restrictions apply

Sharp-angled glaucoma, prostatic hyperplasia and bladder neck obstruction; cardiovascular diseases, including coronary insufficiency, cardiac arrhythmias, prolongation of the interval QT, hypertrophic obstructive cardiomyopathy, hypertension, hyperthyroidism, spasms; a history of diseases such as myocardial infarction, or hospitalization for heart failure (within the previous year), life-threatening arrhythmia, paroxysmal tachycardia with a heart rate> 100; unusual reactions to sympathomimetic amines.

Pregnancy and breast-feeding

Clinical data on the effect of the combination of tiotropium + olodaterol pregnancy there. In preclinical studies with high doses olodaterola, several times higher than therapeutic, established influence, typical of beta2-agonists. Keep in mind olodaterola inhibitory effect on uterine capacity. The combination of olodaterol + tiotropium bromide should not be used in pregnant women unless the potential benefit to the mother outweighs the potential risk not to the fetus.

Clinical data on the use of the combination of tiotropium + olodaterol in women who are breastfeeding, no. The combination of olodaterol + tiotropium bromide should not be used in breast-feeding women unless the potential benefit to the mother outweighs the potential risk is not a child.

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

Side effects of substances Olodaterol + tiotropium bromide

Adverse reactions have been identified based on the data obtained in clinical trials combination of olodaterol + tiotropium bromide.

Infections and infestations: nasopharyngitis.

On the part of metabolism and nutrition: dehydration.

From the nervous system: dizziness, insomnia.

From a sight organ: increased IOP, glaucoma, blurred vision.

From the CCC: atrial fibrillation, palpitations, tachycardia, supraventricular tachycardia, increased blood pressure.

From the side of respiratory, thoracic and mediastinal disorders: cough, epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.

On the part of the digestive tract: small dry mouth, constipation, oral candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction including paralytic ileus.

For the skin: skin infections and sores on the skin, dry skin.

Allergic reactions: rash, pruritus, angioedema, urticaria, hypersensitivity, including immediate type reactions.

On the part of the musculoskeletal system and connective tissue disorders: arthralgia, swelling in the joints, pain in the back (this side effect is related to the dosage form, rather than the combination of the components).

On the part of the kidney and urinary system: dysuria, urinary retention (usually in men with the presence of predisposing factors), urinary tract infection.

Many of the adverse effects caused by anticholinergic tiotropium bromide and beta2-adrenomimeticheskim olodaterola action. Therefore, you should take into consideration the possibility of adverse effects characteristic of the entire class of beta-agonists, such as arrhythmia, myocardial ischemia, angina, hypotension, tremor, headache, nervousness, nausea, muscle cramps, fatigue, and malaise, hypokalemia, hyperglycemia and metabolic acidosis.

Agonists beta2-adrenoceptor long-acting, such as olodaterol, - one of the active components of the combination of tiotropium bromide + olodaterol - increase the risk of accidents with fatalities associated with asthma. The combination of olodaterol + tiotropium bromide is not indicated for the treatment of asthma (see. "Precautions").

The following adverse reactions are discussed in greater detail elsewhere in this description:

- Immediate hypersensitivity reactions (see "Precautions.");

- Paradoxical bronchospasm (see "Precautions.");

- The deterioration of visual function with angle-closure glaucoma (see "Precautions.");

- Strengthening of urinary retention (see "Safety precautions.").

Clinical trials in COPD

Because clinical trials are conducted with a different set of conditions, the incidence of adverse reactions observed in these studies may not coincide with that obtained in other studies, and observed in clinical practice.

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

The primary safety database consisted of a pool of data obtained during two 52-week, double-blind trials to confirm the active and control groups in parallel. In these trials involved 4162 adult patients with COPD (72.9% men and 27.1% women) aged 40 years and older. Of these, 1029 patients were treated with a combination of tiotropium + olodaterol 1 per day. This group consisted mostly of Caucasians (71.1%) with a mean age of 63.8 years and an average calculated baseline in FEV1 of 43.2%. In these two studies as an active control used 5 micrograms tiotropium bromide and 5 g olodaterola, placebo was not used.

In the above two clinical trials, adverse reactions were observed in 74% of patients treated with the combination of tiotropium bromide olodaterol +, compared to 76.6 and 73.3% of patients in the group receiving 5 ug and 5 ug olodaterola tiotropium bromide respectively. The proportion of patients who discontinued treatment due to adverse reactions was 7.4% in the group receiving a combination of olodaterol + tiotropium bromide, compared to 9.9 and 9% for the group of patients treated with 5 mcg olodaterola and 5 micrograms tiotropium bromide. The most common cause of failure of treatment was exacerbation of COPD.

The most common serious adverse events were COPD exacerbation and pneumonia.

Below are the combined data on the number and frequency of adverse reactions that occurred in> 3% of COPD patients aged 40 years or more (and more often than any of the comparison groups using tiotropium bromide and / or olodaterola) in two 52-week double blind confirming trials with active controls, and parallel groups. The first group of numbers - the data for the group receiving the combination of olodaterol + tiotropium bromide 1 per day (N = 1029, in brackets in percentage), the second - for the control group, treated with tiotropium bromide at a dose of 5 mg 1 time per day (N = 1033 in brackets in percentage), and the third - control group receiving a dose of 5 olodaterol 1 mg once a day (N = 1038, the percentage in parentheses).

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

From the side of respiratory, thoracic and mediastinal disorders: cough, 40 (3.9%); 45 (4.4%) and 31 (3%).

On the part of the musculoskeletal system and connective tissue disorders: pain in the back 37 (3.6%); 19 (1.8%) and 35 (3.4%).

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

On the part 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, palpitations, supraventricular tachycardia, tachycardia, hypertension.

From the side of respiratory, thoracic and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.

On the part of the digestive tract: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, GERD, gingivitis, glossitis, stomatitis, intestinal obstruction including paralytic ileus.

On the part of the skin subcutaneous tissue disorders: rash, pruritus, angioedema, urticaria, skin infection, skin ulceration, skin dryness, hypersensitivity reactions (including immediate type reactions).

On the part of the skin subcutaneous tissue disorders: rash, pruritus, angioedema, urticaria, skin infection, skin ulceration, skin dryness, hypersensitivity reactions (including immediate type reactions).

On the part of the musculoskeletal system and connective tissue disorders: arthralgia, swelling of the joints.

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

Interaction

Although specific drug interactions studies have not been conducted, tiotropium bromide is used in conjunction with other drugs for the treatment of COPD, including methylxanthines, steroids for oral and inhalation application, with clinical signs of drug-drug interactions were observed.

Long-term concomitant use of tiotropium bromide with other m-holinoblokatorami has not been studied. Therefore, long-term joint use of a combination of tiotropium bromide + olodaterol other m-anticholinergic drugs is not recommended.

Concomitant use of other adrenergic drugs may enhance the adverse effects of the combination of olodaterol + tiotropium bromide.

Concomitant use of xanthine derivatives, steroids or diuretics (non-potassium-sparing group) may enhance the effect of gipokaliemichesky agonists.

Beta-blockers may weaken the effect of olodaterola or counteract this effect. In this case, preferably use beta1-adrenoceptor antagonists, although they should be used with caution.

MAO inhibitors, tricyclic antidepressants, or other drugs that can lengthen the QTc interval, may enhance the effect of the combination of tiotropium bromide olodaterol + to CCC.

The combined use of olodaterola with ketoconazole resulted in an increase in systemic exposure olodaterola 1.7 times that had no effect on safety. Changing the dose is not required.

Adrenergic drugs. Use caution when assigning additional adrenergic drugs with any route of administration, as may increase sympathomimetic action olodaterola - one of the components of the combination of tiotropium bromide + olodaterol (see "Safety precautions.").

Sympathomimetics, xanthine derivatives, steroids or diuretics. Tiotropium bromide was used in conjunction with sympathomimetic (beta agonist) Short and long-acting bronchodilators, methylxanthines, and oral or inhaled steroids without increased adverse events. The combined use of xanthine derivatives, steroids or diuretics may enhance the effect of any gipokaliemicheskoe olodaterola (see. "Precautions").

Nekaliysberegayuschie diuretics. Beta-agonists can greatly degrade the ECG changes and / or hypokalemia, resulting from the reception nekaliysberegayuschih diuretics (such as loop or thiazide diuretics), especially when the recommended dose is exceeded beta-agonist. The clinical significance of these effects is unknown, however caution should be exercised when used together the combination of tiotropium + olodaterol nekaliysberegayuschimi with diuretics.

MAO inhibitors, tricyclic antidepressants, drugs prolonging the QTc interval. With extreme caution should be used a combination of olodaterol + tiotropium bromide, as well as other drugs containing beta2-agonists in patients receiving MAO inhibitors or tricyclic antidepressants, or other drugs with known ability to lengthen the QTc interval, because These drugs may enhance the action of agonists on the cardiovascular system. Drugs with a known ability to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.

Beta-blockers. Antagonists of beta-adrenergic receptors (beta-blockers) and olodaterol - combinations of the components olodaterol + tiotropium bromide - when used together can mutually adversely affect the validity of each of these drugs. Beta-blockers not only block the effects of beta-agonists, but also can cause severe bronchospasm in patients with COPD. Therefore patients with COPD are generally should not receive treatment for beta blockers. Nevertheless, under certain conditions (eg prevention after myocardial infarction) at the beta-blockers are no acceptable alternatives for use in patients with COPD. In such cases it is necessary to apply cardioselective beta blockers, although they should be used with caution.

Anticholinergic drugs. There is the possibility of an additive interaction with the co-anticholinergic drugs. In this regard, should avoid joint use of a combination of olodaterol + tiotropium bromide with other drugs containing an anticholinergic component, as this may lead to increased anticholinergic side effects (see., "Precautions").

Inhibitors of cytochrome P450 and the transport protein P-gp. The study of drug interaction with ketoconazole, a potent inhibitor of CYP and P-gp, there was a 1.7-fold increase in Cmax and AUC olodaterola. Olodaterol evaluated in clinical trials lasting up to 1 year, at doses higher than the recommended therapeutic 2 times. Correction dose combination of tiotropium + olodaterol not required.

Overdose

Symptoms: an overdose olodaterola can lead to severe effects typical of beta2-agonists, such as myocardial ischemia, an increase or decrease in blood pressure, tachycardia, arrhythmia, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, spasm muscles, nausea, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.

When using high doses of tiotropium bromide may be manifestations of m-anticholinergic action. After 14-day administration by inhalation in doses of tiotropium bromide, up to 40 mg in healthy individuals were no significant adverse events, besides a sense of dryness and nasal mucous membranes of the oropharynx, the frequency of which depended on the dose quantities (10-40 mg per day). The exception was a distinct decrease in salivation, starting from the 7th day of application.

Treatment: + olodaterol reception combination of tiotropium bromide should be discontinued. Displaying supportive and symptomatic treatment. In severe cases, hospitalization is necessary. It may recommend the use of beta1-adrenergic blockers, but only under special care, because the use of these drugs can cause bronchospasm.

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

Tiotropium bromide. The use of high doses of tiotropium bromide may cause anticholinergic signs and symptoms. However, there were no systemic anticholinergic side effects after administration of a single dose to 282 ug of tiotropium bromide in 6 healthy volunteers. In studies involving 12 healthy volunteers after a single inhalation of 141 micrograms tiotropium bromide have been cases of bilateral conjunctivitis and dry mouth. Dryness of the mouth / throat and dryness of the nasal mucous membranes were observed in healthy volunteers after the 14-day inhalation of a solution of tiotropium bromide in a dose of 40 mcg dose-dependent study (10-40 mg daily).

Olodaterol. Expected signs and symptoms of an overdose olodaterola same as when excessive beta-adrenergic stimulation and include cases of myocardial ischaemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmia, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry in the mouth, muscle cramps, nausea, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis. As with other sympathomimetic drugs overdose olodaterola may be associated cases of cardiac arrest and death.

Treatment of overdose include the abolition of the use of a combination of tiotropium bromide + olodaterol and assigning the appropriate symptomatic and supportive therapy. The use of cardioselective beta-blockers may be considered only on the basis of the fact that these drugs can cause bronchospasm. There are no sufficient grounds to assert that effective dialysis in overdose + olodaterol combination of tiotropium bromide. In case of overdose, monitoring of cardiac function is recommended.

Routes of administration

Inhalation.

Precautions substances Olodaterol + tiotropium bromide

The combination of olodaterol + tiotropium bromide should not be used in asthma. Efficacy and safety of the combination of olodaterol + tiotropium in asthma has not been studied.

Acute bronchospasm. The combination of olodaterol + tiotropium bromide is not indicated for the treatment of acute episodes of bronchospasm, ie as a means of emergency.

Hypersensitivity. After application of a combination of olodaterol + tiotropium bromide may develop hypersensitivity reactions of immediate type.

Paradoxical bronchospasm. Use of a combination olodaterol + tiotropium bromide, like other inhaled medicines, may cause paradoxical bronchospasm, sometimes life-threatening. In the case of paradoxical bronchospasm + olodaterol the combination of tiotropium bromide should be discontinued immediately and alternative therapy is appointed.

Patients with impaired renal function. Since tiotropium bromide is derived primarily by the kidneys, patients with renal failure secondary to severe (Cl creatinine <50 ml / min), applying a combination of olodaterol + tiotropium bromide should be under close medical supervision.

Violations of the organ of vision. Patients should be aware of the correct application of the combination of olodaterol + tiotropium bromide. Do not allow product to reach a solution or spray into the eyes. Pain or discomfort in the eyes, blurred vision, visual halos around light sources combined with redness of the eyes, caused by swelling of the conjunctiva and cornea, can be symptoms of acute angle-closure glaucoma. With the development of any combination of these symptoms should immediately see a specialist. Eye drops having mitotic activity, are not considered effective treatment.

Cardiovascular Effects. Olodaterol, like other beta2-adrenergic agonists may provide a clinically significant effect on the cardiovascular system in some patients (increased heart rate, increased blood pressure and / or the appearance of the relevant symptoms). In the event of such symptoms may require discontinuation of treatment. In addition, it was reported that the beta 2-agonists leads to the ECG changes, as the flattening of the T wave and depression of segment ST, although the clinical significance of these changes is unknown.

Hypokalemia. Beta2-agonists in some patients may lead to the development of hypokalemia, which creates prerequisites for the emergence of adverse effects on the cardiovascular system. Reducing the concentration of potassium in serum is usually short and it does not require replenishment. In patients with severe COPD, hypokalaemia may be aggravated due to hypoxia and concomitant treatment and increase the risk of arrhythmias.

Hyperglycemia. Inhaler large doses of beta 2 agonists may lead to increased concentrations of glucose in plasma.

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

Patients frequently use inhaled beta2-adrenoceptor agonists short-acting (e.g. 4 times a day), it is necessary to instruct that these preparations are used only for acute relief of symptoms of bronchospasm.

The combination of olodaterol + tiotropium bromide is used for the maintenance treatment of patients with COPD. Due to the fact that in the general population of COPD patients significantly prevail over the age of 40 years, in the appointment of this combination in patients younger than 40 years need spirometric confirmation of the diagnosis of COPD.

Effects on ability to drive and use machines. Studies on the effect on the ability to drive and use machinery have not been conducted. Use caution when performing these activities, because may develop dizziness or blurred vision.

The risk of death associated with asthma. Data obtained in large placebo-controlled studies in patients with asthma showed that beta2-adrenergic agonists may increase the risk of death related to asthma. There are no data to determine whether beta2-agonists long-acting effect on the increase in mortality in patients with COPD.

In the 28-week placebo-controlled study conducted in the United States, when compared to the safety of other beta2-agonists long-acting (salmeterol) with placebo, with the addition of each of them to the standard anti-asthmatic therapy showed an increase in mortality in patients treated with salmeterol. The increased risk of death associated with asthma, is regarded as a classic effect of beta2-agonists long-acting, including olodaterol - one of the active components of the combination of tiotropium bromide + olodaterol. Research sufficient to establish a link between the increase in mortality associated with asthma, patients receiving the combination of olodaterol + tiotropium bromide, were not carried out. Efficacy and safety of the combination of tiotropium + olodaterol in patients with asthma have not been established. The combination of olodaterol + tiotropium bromide is not indicated for the treatment of asthma.

The aggravation of the disease, and acute episodes. Treatment combination of olodaterol + tiotropium bromide should not be initiated in patients with acute exacerbation of COPD, which may be life-threatening condition. The combination of olodaterol + tiotropium bromide has not been studied in patients with acute exacerbation of COPD. The use of a combination of tiotropium + olodaterol in this condition is inappropriate.

The combination of olodaterol + tiotropium bromide should not be used to relieve acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. The use of a combination of tiotropium + olodaterol to relieve acute symptoms has not been studied, and higher doses of this combination for such purposes should not be used. Acute symptoms should be treated with the use of inhaled beta2-agonists of short action.

Before starting treatment with a combination of olodaterol + tiotropium patients who previously used an inhaled beta2-agonists short action on a regular basis (for example, 4 times a day) should be alerted about the need to abandon the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms . When you assign a combination of tiotropium + olodaterol doctor should also prescribe inhaled beta2-agonists of short action and instruct the patient how he should use the drug. Increasing the dose of inhaled beta2-agonists short-acting is a sign of acute illness requiring immediate medical intervention.

An exacerbation of COPD can be acute for several hours or chronic over several days or longer. Symptoms of acute disease is the lack of control the symptoms of bronchoconstriction with the combination of tiotropium bromide + olodaterol, reducing the effectiveness of inhaled beta2-agonists short-acting or the need for more frequent use of beta2-agonists short-acting than usual. In such cases, you should immediately overestimate the patient's condition and to revise the tactics of treatment of COPD. Increasing the daily dose combination of tiotropium + olodaterol above recommended in this situation is unacceptable.

Excessive use of the combination of tiotropium + olodaterol and use in conjunction with other beta2-agonists long-acting. The combination of olodaterol + tiotropium bromide, like other inhaled drugs containing beta2-agonists, should not be applied more frequently than is recommended at a dose greater than the recommended or in combination with other drugs containing beta2-agonists long-acting, because this may lead to an overdose. There is evidence of clinically significant cardiovascular effects and deaths associated with excessive use of inhaled sympathomimetic drugs.

Immediate type hypersensitivity reactions. After application of a combination of olodaterol + tiotropium bromide may develop reactions of immediate hypersensitivity, such as urticaria, angioedema (including swelling of the lips, tongue, throat), rash, bronchospasm, anaphylaxis, or itching. In the event of such reactions, you should immediately discontinue therapy combination olodaterol + tiotropium bromide, and consider alternative treatments. Patients with a known history of hypersensitivity to atropine and derivatives thereof, for administration of tiotropium bromide, atropine structurally close should carefully be observed with the combination of tiotropium bromide + olodaterol for such occurrence of hypersensitivity reactions.

Paradoxical bronchospasm. As with other inhaled drugs, the combination of olodaterol + tiotropium bromide may cause paradoxical bronchospasm, including life-threatening. If you have the combination of paradoxical bronchospasm olodaterol + tiotropium bromide should be stopped and to appoint an alternative therapy immediately.

Cardiovascular Effects. Olodaterol, like other beta2-agonists may cause a clinically significant cardiovascular effect in some patients manifesting an increase in pulse rate, Garden or Dad and / or the appearance of the relevant symptoms. When the effects of the combination of olodaterol + tiotropium bromide should be suspended. In addition, it is known that beta-agonists cause ECG changes, such as flattening of the tooth T, prolongation of the QTc interval and segment depression ST. The clinical significance of these observations is unknown. Beta2-adrenoceptor agonists of long action should be used with caution in patients with cardiovascular disease, especially heart failure, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy and hypertension.

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

The deterioration of visual function with angle-closure glaucoma. The combination of olodaterol + tiotropium bromide should be used with caution in patients with narrow-angle glaucoma. The attending physician and the patient should take into account the signs and symptoms of acute angle-closure glaucoma (such as pain and discomfort in the eye, blurred vision, visual halos or colored images in conjunction with redness of the eyes, caused by hyperemia of the conjunctiva and corneal edema). Patients should be instructed on the need to immediately consult a doctor in the development of any of these signs or symptoms.

Deterioration of a condition associated with urinary retention. The combination of olodaterol + tiotropium bromide should be used with caution in patients with urinary retention. The attending physician and the patient should take into account the signs and symptoms of benign prostatic hyperplasia and bladder outlet obstruction (such as difficulty urinating, painful urination), especially in patients with benign prostatic hyperplasia and bladder neck obstruction. Patients should be instructed on the need to immediately consult a doctor in the development of any of these signs or symptoms.

Impaired renal function. Since tiotropium bromide is excreted primarily by the kidneys, should organize a thorough monitornig for anticholinergic side effects in patients with moderate or severe renal impairment (Cl creatinine less than or equal to 60 ml / min) receiving combination olodaterol + tiotropium bromide.

Hypokalemia and hyperglycemia. Beta-adrenergic agonist can cause significant hypokalemia in some patients, which may lead to cardiovascular side effects. Reducing the level of potassium in the blood serum is usually transient and did not require his fill. Inhalation of high doses of beta 2-agonists may cause an increase in glucose level in plasma.

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

In clinical studies with long-term use olodaterola clinically significant decrease in the level of potassium in the blood serum, or changes in blood glucose levels were infrequent and comparable to those observed in the placebo control group. Application olodaterola has not been studied in patients with an inadequate level of diabetes control.