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Tiotropium bromide
Chemical compound
IUPAC	(1α,2β,4β,7β)- 7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl- 3-oxa-9-azoniatricyclononane
Gross formula	C₁₉H₂₂NO₄S₂
Molar mass	472.42 g/mol
CAS	186691-13-4
PubChem
drug bank	DB01409
Classification
ATX	R03BB04
Pharmacokinetics
Bioavailable	19.5% (inhalation)
Plasma protein binding	85-90%
Metabolism	liver 25% (CYP2D6, CYP3A4)
Half-life	5–6 hours
Excretion	kidneys
Dosage forms
capsules with powder for inhalation
Other names
Spiriva ®

Tiotropium bromide("Spiriva", "THIOTROPIUM-NATIV") - M-cholinolytic long-acting used to treat chronic obstructive pulmonary disease.

Tiotropium bromide is included in the list of vital and essential drugs.

pharmachologic effect

Contraindications

Hypersensitivity, pregnancy (I trimester), age up to 18 years. With caution. Angle-closure glaucoma, hyperplasia prostate, bladder neck obstruction.

Dosing regimen

Inhalation using a special device, 1 capsule per day at the same time. Elderly patients with renal / hepatic insufficiency dosing adjustment is not required.

Side effects

From the digestive system: dryness of the oral mucosa (usually disappearing during treatment), constipation. From the side respiratory system: . Treatment: symptomatic.

special instructions

The drug should not be used to relieve bronchospasm. Inhalation of the drug can lead to bronchospasm. During the treatment of patients with chronic renal failure, careful monitoring is necessary. Patients should be familiar with the rules for using the inhaler. Avoid getting the powder in your eyes. Should not be used more than once a day.

Interaction

Avoid concomitant use with other anticholinergic drugs. It is possible to use tiotropium in combination with other drugs commonly used to treat COPD: sympathomimetics, methylxanthines, oral and inhaled glucocorticoids.

The combination of olodaterol and tiotropium bromide is effective, as a result of a different mechanism of action. active substances and different localization of target receptors in the lungs, the drug provides complementary bronchodilation. When using olodaterol/tiotropium, a more significant bronchodilating effect was achieved, and the peak expiratory flow rate increased in the morning and evening hours. The combination resulted in a reduced risk of COPD exacerbations and improved tolerability time. physical activity compared to placebo, and also significantly improved inspiratory capacity compared to monotherapy.

At the end of observational studies of real clinical practice OTIVACTO in 83.3% of 7,443 patients, the general condition was assessed as "good to excellent", while at the beginning of the CT only 31.9% of patients received such an assessment. The results were presented at the International Congress of the European Respiratory Society (ERS) 2018 in Paris.

Recipe (international)

Rp: Tiotropii bromidi 0.000018
D.t.d: №30 in caps.
S: For inhalation through an aerolizer, 1 capsule 1 time per day

Prescription form - 107-1/u (Russia)

pharmachologic effect

Cholinolytic, bronchodilatory agent. As a result of inhibition of M3 receptors in respiratory tract is the relaxation of the smooth muscles of the bronchi. High affinity for receptors and slow dissociation from M3 receptors cause a pronounced and prolonged bronchodilatory effect in topical application in patients with COPD.

With the inhalation route of administration, the absolute bioavailability of tiotropium bromide is 19.5%. Due to the chemical structure (quaternary ammonium compound), tiotropium bromide is poorly absorbed from the gastrointestinal tract. For the same reason, food intake does not affect the absorption of tiotropium bromide. The maximum concentration in blood serum after inhalation of the powder at a dose of 18 mcg is reached after 5 minutes and in patients with COPD is 17-19 pg / ml, the equilibrium concentration in blood plasma is 3-4 pg / ml. Plasma protein binding 72%, volume of distribution - 32 l / kg. Does not penetrate the BBB. Biotransformation is insignificant, which is confirmed by the fact that after intravenous administration of the drug to young healthy volunteers, 74% of unchanged tiotropium is found in the urine. Tiotropium is cleaved non-enzymatically to N-methylscopine alcohol and dithienyl glycolic acid, which do not bind to muscarinic receptors. Even at ultra-high doses, tiotropium does not inhibit cytochrome P450, 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in human liver microsomes.

After inhalation, the terminal half-life is 5-6 days, excreted by the kidneys (14% of the dose), the rest, not absorbed in the intestine, is excreted in the feces.
The bronchodilatory effect is a consequence of local rather than systemic action, depends on the dose and persists for at least 24 hours. The use of tiotropium significantly improves function external respiration 30 minutes after a single inhalation for 24 hours. The equilibrium state was achieved during the first week, and a pronounced bronchodilatory effect was observed on the 3rd day.
Evaluation of the bronchodilating effect throughout the year did not reveal manifestations of tolerance. Reduces the number of exacerbations of COPD, increases the period to the first exacerbation compared with placebo, improves quality of life throughout the treatment period, reduces the number of hospitalizations associated with exacerbation of COPD and increases the time until the first hospitalization.

Mode of application

For adults: Inhalation using a special inhaler, 1 capsule per day at the same time. Capsules should not be swallowed. Elderly people, patients with impaired renal or hepatic function can use the drug at recommended doses.

Indications

As maintenance therapy in patients with COPD, including chronic obstructive bronchitis and emphysema (with persistent shortness of breath and to prevent exacerbations).

Contraindications

hypersensitivity to tiotropium bromide, as well as to atropine or its derivatives (for example, ipratropium or oxitropium), I trimester of pregnancy, age up to 18 years.

Side effects

On the part of the digestive tract - dry mouth (usually mild degree severity, often disappears with continued treatment), constipation.
From the side respiratory system: cough, local irritation, possible development of bronchospasm, as well as when taking other inhalants.

Other: tachycardia, difficulty or urinary retention (in men with prostatic hyperplasia), angioedema, blurred vision, acute glaucoma (associated with anticholinergic action).

Release form

Capsules with powder for inhalation 1 caps., tiotropium bromide 18 mcg (corresponding to 22.5 mcg of tiotropium bromide monohydrate), Excipients:
lactose monohydrate
in a blister pack 10 pcs.; in a carton pack 1, 3 or 6 packs complete with HandiHaler inhaler or without inhaler.

ATTENTION!

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Included in medications

Included in the list (Decree of the Government of the Russian Federation No. 2782-r dated December 30, 2014):

VED

ONLS

ATH:

R.03.B.B Anticholinergics

R.03.B.B.04 Tiotropium bromide

Pharmacodynamics:

Blocker of m-cholinergic receptors of long-term action.

It has the same affinity for various subtypes of muscarinic receptors from M1 to M5, however, it interacts with M3 receptors for a longer time. As a result of inhibition of M3 receptors in the airways, smooth muscle relaxation occurs. The bronchodilatory effect is dose-dependent and persists for at least 24 hours.

Pharmacokinetics:

With inhalation, bioavailability is 19.5%. Communication with plasma proteins - 72%. The half-life of inhalation administration is 5-6 days. Biotransformation in the liver is insignificant. Most of the inhaled dose is swallowed and excreted unchanged in the faeces. Elimination of the absorbed part mainly by the kidneys.

Indications:

As maintenance therapy in patients with COPD, including Chronical bronchitis and emphysema (supportive therapy for persistent shortness of breath and to prevent exacerbations).

X.J40-J47.J43 Emphysema

X.J40-J47.J44 Other chronic obstructive pulmonary disease

Contraindications:

Hypersensitivity, pregnancy (I trimester), age up to 18 years.

Carefully:

Angle-closure glaucoma, prostatic hyperplasia, bladder neck obstruction.

Pregnancy and lactation:

The drug is contraindicated for use in the first trimester of pregnancy.

In the II and III trimesters of pregnancy and during lactation, the drug should be prescribed only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus or infant.

Dosage and administration:

Assign 1 capsule / day at the same time.

Side effects:

From the side digestive system: mild dry mouth, often resolving with continued treatment (≥1% and<10%); кандидоз полости рта (≥0.1% и <1%); запор, гастроэзофагеальный рефлюкс (≥0.01% и <1%); в единичных случаях - кишечная непроходимость (включая паралитический илеус), дисфагия.

From the side respiratory system: dysphonia, bronchospasm, cough and local irritation of the pharynx (≥0.1% and<1%); носовое кровотечение (≥0.01% и <1%).

From the side of cardio-vascular system: tachycardia, palpitations (≥0.01% and<1%); в единичных случаях - суправентрикулярная тахикардия, мерцательная аритмия.

From the side CNS: dizziness (≥0.1% and<1%).

From the side urinary system: difficulty urinating and urinary retention in men with predisposing factors, urinary tract infections (≥0.01% and<1%).

Allergic reactions: rash, urticaria, pruritus, hypersensitivity reactions, including immediate-type reactions (≥ 0.01% and< 1%); в единичных случаях - ангионевротический отек.

Others: in isolated cases - blurred vision, increased intraocular pressure (≥0.01% and<1%); глаукома.

Most of the above adverse reactions may be associated with the anticholinergic effect of the drug.

Overdose:

Strengthening of anticholinergic reactions (dry mouth, paresis of accommodation, tachycardia).

Treatment symptomatic.

Interaction:

Anticholinergics or other drugs with anticholinergic activity - increased anticholinergic effects.

Special instructions:

Not intended for the relief of acute attacks of bronchospasm.

After inhalation of tiotropium bromide powder, immediate-type hypersensitivity reactions may develop.

The process of inhalation of tiotropium bromide (as with other inhaled drugs) can cause bronchospasm.

Patients with renal insufficiency (CC ≤ 50 ml / min) should be carefully monitored when prescribing tiotropium bromide.

Patients should be familiarized with the rules for using the inhaler. Do not allow the powder to get into the eyes. Eye pain or discomfort, blurred vision, visual halos, combined with eye redness, conjunctival congestion, and corneal edema may indicate an acute attack of angle-closure glaucoma. With the development of any combination of these symptoms, the patient should immediately consult a doctor. The use of only drugs that cause miosis is not an effective treatment in this case.

One capsule contains 5.5 mg of lactose monohydrate.

Instructions

tiotropium bromide: Spiriva (Boehringer Ingelheim, Germany), Tiotropium bromide.

Spiriva is an innovative m-anticholinergic and bronchodilatory drug for the treatment of chronic obstructive pulmonary diseases, including chronic bronchitis and emphysema.

In accordance with the International Consensus on COPD, a group of experts in 1999 developed the Federal Program, which includes standards for the diagnosis and treatment of COPD. Preparations of the first line of basic therapy - anticholinergics. A new drug in this group, Spiriva (tiotropium bromide), the clinical efficacy and safety of which has been proven by multicenter, randomized, double-blind, placebo-controlled studies.

Innovative bronchodilator - a breakthrough in COPD therapy. Compared with basic therapy, which includes the use of short-acting b2-agonists, derivatives theophylline and inhaled corticosteroids, with salmeterol and ipratropium, its use in COPD of varying severity, as studies have shown, significantly reduces the severity of dyspnea and the frequency of exacerbations. This is an effective drug that can significantly reduce clinical symptoms, increase exercise tolerance, slow down the progression of the disease and undoubtedly improve the quality of life of patients.

Latin name:
Spiriva / Spiriva

Composition and form of release:
capsules of 30 pcs. in a package complete with or without a HandiHaler inhaler.
1 capsule with powder for inhalation contains tiotropium bromide monohydrate 22.5 mcg, which corresponds to 18 mcg of tiotropium bromide.

Pharmachologic effect:
Spiriva - M-anticholinergic, bronchodilator. The result of inhibition of M3 receptors in the airways is the relaxation of smooth muscles. High affinity for receptors and slow dissociation from M3 receptors cause a pronounced and prolonged bronchodilating effect when applied topically in patients with chronic obstructive pulmonary disease (COPD).
The bronchodilatory effect of Spiriva is a consequence of local rather than systemic action, depends on the dose and persists for at least 24 hours. Studies have shown that the drug significantly increases lung function (forced expiratory volume in 1 s) and lung capacity 30 minutes after a single dose. doses over 24 hours. Pharmacodynamic equilibrium was achieved during the first week, and a pronounced bronchodilating effect was observed on the 3rd day. The drug increases the morning and evening peak expiratory flow rate measured by patients. Evaluation of the bronchodilating effect throughout the year did not reveal manifestations of tolerance. The drug reduces the number of exacerbations of COPD, increases the time to the first exacerbation compared with placebo, improves the quality of life throughout the treatment period, reduces the number of hospitalizations associated with an exacerbation of COPD and increases the time to the first hospitalization.

Pharmacokinetics:
With the inhalation route of administration, the absolute bioavailability of tiotropium bromide is 19.5%, indicating that the fraction of the drug that reaches the lungs is highly bioavailable. Based on the chemical structure of the compound (quaternary ammonium compound), tiotropium bromide is poorly absorbed from the gastrointestinal tract. For the same reason, food intake does not affect the absorption of tiotropium bromide. Cmax after inhalation of the powder at a dose of 18 mcg is achieved after 5 minutes and is 17-19 pg / ml in patients with COPD, the equilibrium plasma concentration is -3-4 pg / ml. Plasma protein binding 72%, volume of distribution - 32 l/kg. Does not penetrate the BBB.
Biotransformation is insignificant, which is confirmed by the fact that after intravenous administration of the drug to young healthy volunteers, 74% of unchanged tiotropium is found in the urine. Tiotropium is cleaved non-enzymatically to N-methylscopine alcohol and dithienyl glycolic acid, which do not bind to muscarinic receptors. Even at ultra-high doses, tiotropium does not inhibit cytochrome P450, 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in human liver microsomes.
After inhalation, the terminal T1 / 2 is 5-6 days, excreted by the kidneys (14% of the dose), the remaining (not absorbed in the intestine) part is with feces.

Indications:
As maintenance therapy in patients with COPD, including chronic bronchitis and emphysema (with persistent shortness of breath and to prevent exacerbations).

Dosage and administration:
Inhalation using the HandiHaler or Respimat device, 1 caps. per day at the same time. Spiriva capsules should not be swallowed.
Elderly people, patients with impaired renal or hepatic function can use the drug Spiriva in the recommended doses.

Contraindications:
Hypersensitivity (including to atropine or its derivatives, for example, ipratropium or oxitropium), I trimester of pregnancy, age up to 18 years.

Use during pregnancy and lactation:
Contraindicated in the first trimester of pregnancy. In the rest of the pregnancy and while breastfeeding - only if the expected benefit outweighs any possible risk to the fetus or infant.

Side effects:
From the digestive tract: dry mouth (usually mild, often disappears with continued treatment), constipation.
From the respiratory system: cough, local irritation, possible development of bronchospasm, as well as when taking other inhalants.
Other: tachycardia, difficulty or urinary retention (in men with predisposing factors), angioedema, blurred vision, acute glaucoma (associated with anticholinergic action).

Precautions and special instructions:
Careful monitoring of patients with moderate or severe renal insufficiency, receiving the drug in combination with other drugs, excreted mainly by the kidneys, is necessary.
Be wary appoint patients with narrow-angle glaucoma, prostatic hyperplasia or obstruction of the bladder neck.
The drug should not be used as an initial therapy for acute attacks of bronchospasm (that is, in emergency cases).
After inhalation, immediate hypersensitivity reactions may develop.
Do not allow the powder to get into the eyes.
The drug should only be used with the HandiHaler device.

Drug interaction:
The simultaneous use of Spiriva with other anticholinergics is not recommended.

Estimated price(cost) of the drug - 85-90 US dollars

Russian name

Olodaterol + Tiotropium bromide

Latin name of substances Olodaterol + Tiotropium bromide

Olodaterolum + Tiotropii bromidum ( genus. Olodateroli + Tiotropii bromidi)

Pharmacological group of substances Olodaterol + Tiotropium bromide

Nosological classification (ICD-10)

Characteristics of substances Olodaterol + Tiotropium bromide

Combined bronchodilator for inhalation use.

Pharmacology

pharmachologic effect- bronchodilator.

Pharmacodynamics

Olodaterol, a long-acting beta2-agonist, and tiotropium bromide, an m-cholinergic blocker, provide complementary bronchodilation as a result of a different mechanism of action of active substances and different localization of target receptors in the lungs.

Olodaterol has a high affinity and selectivity for beta2-adrenergic receptors. Activation of beta 2 -adrenergic receptors in the respiratory tract leads to stimulation of intracellular adenylate cyclase, which is involved in the synthesis of cAMP. An increase in cAMP causes bronchodilation by relaxing the smooth muscle cells of the airways. Olodaterol is a selective long-acting beta2-adrenergic agonist with a rapid onset of action and long-term (at least 24 hours) retention of the effect. Beta 2-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 beta 2 receptors in the heart is not fully understood, but their presence points to the possibility of even highly selective beta 2 -adrenergic agonists affecting the heart.

Tiotropium bromide is a long-acting muscarinic receptor antagonist, often called an m-anticholinergic agent in clinical practice. It has the same affinity for the m 1 -m 5 subtypes of muscarinic receptors. The result of inhibition of m 3 receptors in the respiratory tract is the relaxation of smooth muscles. The bronchodilating effect depends on the dose and lasts for at least 24 hours. A significant duration of action is probably associated with a very slow dissociation of tiotropium bromide from m 3 receptors: the half-dissociation period is significantly longer than that of ipratropium bromide. With the inhalation method of administering tiotropium bromide, as an N-quaternary ammonium derivative, it has a local selective effect (on the bronchi), while at therapeutic doses it does not cause systemic m-anticholinergic side effects. Dissociation from m 2 receptors occurs faster than from m 3 receptors, which indicates the predominance of selectivity for the m 3 receptor subtype over m 2 receptors. The high affinity for receptors and the slow dissociation of tiotropium bromide from its association with receptors cause a pronounced and prolonged bronchodilatory effect in patients with COPD.

Bronchodilation that develops after inhalation of tiotropium bromide is primarily due to local action (on the respiratory tract), and not systemic.

In clinical studies, it was found 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 mcg and olodaterol at a dose of 5 mcg, used as monotherapy (forced expiratory volume in 1 second (FEV1) increased when taking the combination of olodaterol + tiotropium bromide by 0.137 l; with taking only tiotropium bromide - by 0.058 l and when taking only olodaterol - by 0.125 l).

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

The combination of olodaterol + tiotropium bromide resulted in a reduced risk of COPD exacerbations compared with placebo.

The combination of olodaterol + tiotropium bromide significantly improved inspiratory capacity compared to tiotropium bromide, olodaterol, or placebo alone.

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

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 pharmacokinetics of olodaterol was achieved after 8 days when administered once daily, and the degree of exposure increased compared with a single dose by 1.8 times. Steady state pharmacokinetics of tiotropium bromide when applied once a day was achieved after 7 days.

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

Thus, the systemic exposure of olodaterol after inhalation is mainly realized through absorption in the lungs, and the contribution of the ingested part of the dose to the systemic exposure is negligible.

After inhalation of a solution of tiotropium bromide, about 33% of the inhalation dose enters the systemic circulation. Absolute oral bioavailability is 2-3%. C max is observed 5–7 minutes after inhalation.

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

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

Biotransformation. Olodaterol is extensively metabolized by direct glucuronidation and O-demethylation followed by conjugation. Of the six identified metabolites, only one unconjugated demethylated derivative binds to beta 2 receptors ( SOM 1522), however, this metabolite is not detected in plasma after prolonged inhalation use at the recommended therapeutic dose or at doses greater than 4 times the therapeutic dose. O-demethylation of olodaterol involves cytochrome P450 (isoenzymes CYP2C9, CYP2C8 and to a minor extent CYP3A4). Uridine diphosphate glycosyltransferase isoforms are involved in the formation of olodaterol glucuronides 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 young healthy volunteers, 74% is excreted by the kidneys unchanged. Tiotropium bromide is an ester that breaks down into ethanol-N-methylscopine and dithienylglycolic acid; these compounds do not bind to muscarinic receptors.

In research in vitro it was shown that some part of the preparation (<20% дозы после в/в введения) метаболизируется путем окисления цитохромом Р450 (CYP2D6 и 3А4) с последующей конъюгацией с глутатионом и образованием различных метаболитов.

Withdrawal. The total clearance of olodaterol in healthy volunteers is 872 ml/min, and the renal clearance is 173 ml/min. The final T 1/2 after intravenous use of olodaterol is 22 hours, while the final T 1/2 after inhalation is approximately 45 hours. It follows that in the latter case, excretion is more dependent on absorption.

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

More than 90% of the dose of olodaterol was eliminated after intravenous administration for 5 days and after oral administration for 6 days. After inhalation, the excretion of unchanged olodaterol by the kidneys during the dosing interval in healthy volunteers during the period of steady state pharmacokinetics was 5-7% of the dose.

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 of the solution in patients with COPD, renal excretion is 18.6% (0.93 mcg), the remaining unabsorbed part is excreted through the intestines. The renal clearance of tiotropium bromide exceeds the clearance of creatinine, which indicates its tubular secretion. The terminal T 1/2 of tiotropium bromide after inhalation is from 27 to 45 hours.

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

In the elderly, there is a decrease in the renal clearance of tiotropium (347 ml / min in patients with COPD under the age of 65 and 275 ml / min in patients with COPD over 65 years of age). However, this did not lead to an increase in AUC 0-6,ss and C max,ss.

Race. Comparison of pharmacokinetic data obtained in clinical studies of olodaterol revealed a trend towards higher systemic exposure of olodaterol in patients from Japan and other Asian patients compared with Caucasian patients. In clinical studies of olodaterol, used at doses that exceeded the recommended therapeutic dose by 2 times, no safety concerns were found in Caucasian and Asian patients.

In patients with severe renal insufficiency (Cl creatinine<30 мл/мин) системное воздействие олодатерола увеличивалось в среднем в 1,4 раза. Такое повышение воздействия не вызывает опасений в отношении безопасности, учитывая опыт, полученный в ходе применения олодатерола в клинических исследованиях.

After inhalation use of tiotropium bromide 1 time per day during the steady state of pharmacokinetics in patients with COPD and mild renal insufficiency (Cl creatinine 50-80 ml / min), there was a slight increase in AUC 0-6,ss by 1.8-30% and C max,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 мл/мин) в/в применение тиотропия бромида приводило к двукратному увеличению общего воздействия тиотропия бромида (значение AUC 0–4 увеличивалось на 82%, а величина С max - на 52%) по сравнению с пациентами с нормальной функцией почек. Аналогичное повышение концентрации в плазме отмечалось и после ингаляции сухого порошка.

Patients with impaired liver function. In patients with mild to moderate hepatic insufficiency, systemic exposure to olodaterol did not change. Systemic exposure to olodaterol in patients with severe hepatic impairment has not been studied.

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

Application of substances Olodaterol + Tiotropium bromide

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

Contraindications

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

Application restrictions

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

Use during pregnancy and lactation

There are no clinical data on the effect of the combination of olodaterol + tiotropium bromide on pregnancy. In preclinical studies, when using high doses of olodaterol, several times higher than therapeutic, effects typical of beta 2-adrenergic agonists were established. The inhibitory effect of olodaterol on uterine contractility should be taken into account. The combination of olodaterol + tiotropium bromide should not be used in pregnant women unless the potential benefit to the mother outweighs the potential risk to the fetus.

Clinical data on the use of the combination of olodaterol + tiotropium bromide in women who are breastfeeding are not available. The combination of olodaterol + tiotropium bromide should not be used in breastfeeding women unless the potential benefit to the mother outweighs the potential risk to the baby.

For the period of application of the combination of olodaterol + tiotropium bromide, it is necessary to stop breastfeeding.

Side effects of substances Olodaterol + Tiotropium bromide

Adverse reactions were identified on the basis of data obtained from clinical studies of the combination of olodaterol + tiotropium bromide.

Infections and infestations: nasopharyngitis.

dehydration.

From the nervous system: dizziness, insomnia.

From the side of the organ of vision: increased IOP, glaucoma, blurred vision.

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

cough, epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.

From the gastrointestinal tract: mild dry mouth, constipation, oral candidiasis, dysphagia, gastroesophageal reflux, gingivitis, glossitis, stomatitis, intestinal obstruction including paralytic ileus.

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

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

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

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

Many of these undesirable effects are due to the anticholinergic effect of tiotropium bromide or the beta 2-adrenomimetic effect of olodaterol. Therefore, the possibility of undesirable effects characteristic of the entire class of beta-agonists, such as arrhythmia, myocardial ischemia, angina pectoris, hypotension, tremor, headache, nervousness, nausea, muscle spasms, fatigue, malaise, hypokalemia, hyperglycemia and metabolic disorders, should be taken into account. acidosis.

RxList.com

Long-acting beta2-adrenergic agonists such as olodaterol, one of the active ingredients in the combination 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 elsewhere in this specification:

Immediate type hypersensitivity reactions (see "Precautions");

Paradoxical bronchospasm (see "Precautions");

Deterioration of visual functions in angle-closure glaucoma (see "Precautions");

Increased urinary retention (see "Precautions").

Results of clinical trials in COPD

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

The primary safety database consisted of a pool of data from two 52-week double-blind confirmation trials with active controls and parallel groups. These trials included 4162 adult patients with COPD (72.9% men and 27.1% women) aged 40 years and older. Of these, 1029 patients received the combination of olodaterol + tiotropium bromide once a day. This cohort was predominantly Caucasian (71.1%) with a mean age of 63.8 years and a mean FEV1 estimated at baseline of 43.2%. In these two studies, tiotropium bromide 5 μg and olodaterol 5 μg were used as active controls; no placebo was used.

In the above two clinical trials, adverse reactions were observed in 74% of patients treated with the combination of olodaterol + tiotropium bromide, compared with 76.6 and 73.3% in the groups of patients treated with olodaterol 5 mcg and tiotropium bromide 5 mcg, respectively. The proportion of patients who discontinued treatment due to adverse reactions was 7.4% in the olodaterol + tiotropium bromide combination group, compared with 9.9 and 9% for the olodaterol 5 µg and tiotropium bromide 5 µg groups. The most common reason for not treating was an exacerbation of COPD.

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

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

From the side of the respiratory system, chest and mediastinum: cough 40 (3.9%); 45 (4.4%) and 31 (3%).

back pain 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% during clinical studies, are listed below.

From the side of metabolism and nutrition: dehydration.

From the nervous system: dizziness, insomnia.

From the side of the organ of vision: glaucoma, increased IOP, blurred vision.

From the CCC: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension.

From the side of the respiratory system, chest and mediastinum: 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, urticaria, skin infection, skin ulceration, dry skin, hypersensitivity reactions (including immediate type reactions).

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

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

Interaction

Although no specific drug interaction studies have been conducted, tiotropium bromide has been co-administered with other drugs for the treatment of COPD, including methylxanthines, oral and inhaled steroids, with no clinical evidence of drug interactions.

Long-term co-administration of tiotropium bromide with other m-anticholinergics has not been studied. Therefore, the long-term combined use of the combination of olodaterol + tiotropium bromide with other m-anticholinergic 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 potassium-sparing group) may enhance the hypokalemic effect of adrenomimetics.

Beta-blockers 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 that can prolong the QTc interval may increase the effect of the combination of olodaterol + tiotropium bromide on CCC.

The combined use of olodaterol with ketoconazole resulted in a 1.7-fold increase in systemic exposure to olodaterol, which did not affect safety. Dose change is not required.

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

Sympathomimetics, xanthine derivatives, steroids or diuretics. Tiotropium bromide has been co-administered with short-acting and long-acting sympathomimetics (beta-agonists), bronchodilators, methylxanthines, and oral or inhaled steroids without increasing adverse reactions. The combined use of xanthine derivatives, steroids or diuretics may enhance any hypokalemic effect of olodaterol (see "Precautions").

Non-potassium-sparing diuretics. Beta-agonists can greatly worsen 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 a beta-agonist is exceeded. The clinical significance of these effects is unknown, however, caution should be exercised when using the combination of olodaterol + tiotropium bromide with non-potassium-sparing diuretics.

MAO inhibitors, tricyclic antidepressants, drugs that prolong the QTc interval. With extreme caution, the combination of olodaterol + tiotropium bromide, as well as other drugs containing beta 2 agonists, should be used in patients receiving MAO inhibitors or tricyclic antidepressants, or other drugs with a known ability to prolong the QTc interval, tk. these drugs can enhance the effect of adrenomimetics on the CCC. Drugs known 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 - a component of the combination of olodaterol + tiotropium bromide - when used together, can mutually negatively affect the action of each of these drugs. Beta-blockers not only block the effects of beta-agonists, but can also cause severe bronchospasm in patients with COPD. Because of this, COPD patients generally should not be treated with beta-blockers. However, under certain conditions (for example, 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 a possibility of additive interaction with concomitantly used anticholinergic drugs. In this regard, the combined use of a combination of olodaterol + tiotropium bromide with other drugs containing an anticholinergic component should be avoided, because. this may lead to an increase in anticholinergic side effects (see "Precautions").

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

Overdose

Symptoms: an overdose of olodaterol can lead to pronounced effects typical of beta 2-agonists, such as myocardial ischemia, increased or decreased blood pressure, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasm , nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.

When using high doses of tiotropium bromide, manifestations of m-anticholinergic action are possible. After 14 days of inhaled use of tiotropium bromide at doses up to 40 mcg, no significant adverse events were observed in healthy individuals, except for a feeling of dryness of the mucous membranes of the nose and oropharynx, the frequency of which depended on the dose (10–40 mcg per day). The exception was a distinct decrease in salivation, starting from the 7th day of application.

Treatment: the combination of olodaterol + tiotropium bromide should be discontinued. Supportive and symptomatic treatment is indicated. In severe cases, hospitalization is necessary. The use of beta 1 -blockers may be recommended, but only with special care, because. the use of these drugs can cause bronchospasm.

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

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

Olodaterol. Expected signs and symptoms of olodaterol overdose are the same as for excessive beta-adrenergic stimulation and include cases of myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmia, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dryness in the mouth, muscle cramps, 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 overdose includes the abolition of the combination of olodaterol + tiotropium bromide and the appointment of appropriate symptomatic and supportive therapy. The use of cardioselective beta-blockers can only be considered taking into account the fact that these drugs can cause bronchospasm. There is no sufficient evidence to suggest that dialysis is effective in overdose of the combination of olodaterol + tiotropium bromide. In case of overdose, monitoring of cardiac functions is recommended.

Routes of administration

Inhalation.

Substance Precautions Olodaterol + Tiotropium Bromide

The combination of olodaterol + tiotropium bromide should not be used in 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 using the combination of olodaterol + tiotropium bromide, immediate type hypersensitivity reactions may develop.

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

Patients with impaired renal function. Since tiotropium bromide is excreted primarily by the kidneys, patients with moderate to severe renal insufficiency (Cl creatinine<50 мл/мин), применяющие комбинацию олодатерол + тиотропия бромид, должны находиться под тщательным наблюдением врача.

Violations of the organ of vision. Patients should be familiarized with the correct use of the combination of olodaterol + tiotropium bromide. Do not allow the solution or aerosol to get 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, may be symptoms of acute angle-closure glaucoma. With the development of any combination of these symptoms, you should immediately consult a specialist. Miotic eye drops are not considered an effective treatment.

cardiovascular effects. Olodaterol, like other beta2-adrenomimetics, may have a clinically significant effect on the cardiovascular system in some patients (increased heart rate, increased blood pressure and / or the appearance of related symptoms). If such symptoms occur, treatment may need to be discontinued. In addition, beta2-adrenergic agonists have been reported to cause ECG changes such as T-wave flattening and ST-segment depression, although the clinical significance of these changes is unknown.

Hypokalemia. Beta 2-agonists in some patients can lead to the development of hypokalemia, which creates the prerequisites for the occurrence of undesirable effects on the cardiovascular system. A decrease in 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 be exacerbated by hypoxia and concomitant treatment and increase the risk of arrhythmias.

Hyperglycemia. Inhalation use of large doses of beta 2-adrenergic agonists can 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-agonists.

Patients who frequently use short-acting inhaled beta2-adrenergic agonists (eg 4 times a day) should be instructed that these drugs are used only to relieve acute symptoms of bronchospasm.

The combination of olodaterol + tiotropium bromide is indicated for the maintenance treatment of patients with COPD. Due to the fact that patients over the age of 40 years significantly predominate in the general COPD population, when prescribing this combination to patients younger than 40 years old, spirometric confirmation of the diagnosis of COPD is required.

Influence on the ability to drive vehicles and mechanisms. Studies on the effect on the ability to drive vehicles and mechanisms have not been conducted. Care must be taken when performing these activities, as may develop dizziness or blurred vision.

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Risk of death associated with asthma. Data from large placebo-controlled trials in patients with asthma suggested that beta2-adrenergic agonists may increase the risk of asthma-related death. There are no data to establish whether long-acting beta2-adrenergic agonists increase mortality in patients with COPD.

In a 28-week placebo-controlled study conducted in the United States, comparing the safety of another long-acting beta2-agonist (salmeterol) with placebo when each was added to standard asthma therapy, an increase in mortality was shown in patients treated with salmeterol. An increased risk of asthma-related death is seen as a classic effect of long-acting beta2-adrenergic agonists, including olodaterol, one of the active ingredients in the olodaterol + tiotropium bromide combination. Studies sufficient to establish a correlation between an increase in asthma-related mortality in patients receiving the combination of olodaterol + tiotropium bromide have not been conducted. 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 olodaterol + tiotropium bromide should not be started in patients with a COPD exacerbation, which can be life-threatening. The combination of olodaterol + tiotropium bromide has not been studied in patients with exacerbations of COPD. The combination of olodaterol + tiotropium bromide in this condition is inappropriate.

The combination of olodaterol + tiotropium bromide should not be used to relieve acute symptoms, i.e. as emergency therapy for the treatment of acute episodes of bronchospasm. The use of the combination of olodaterol + tiotropium bromide for the relief of 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 short-acting inhaled beta2-agonists.

Before starting treatment with olodaterol + tiotropium bromide, patients who have previously used short-acting inhaled beta2-adrenergic agonists on a regular basis (for example, 4 times a day) should be warned about the need to abandon the regular use of these drugs and use them only for the symptomatic relief of acute respiratory infections. symptoms. When prescribing a combination of olodaterol + tiotropium bromide, the attending physician should also prescribe a short-acting inhaled beta 2-agonist and instruct the patient how he should use the drug. An increase in the dose of an inhaled short-acting beta 2-agonist is a sign of an exacerbation of the disease, requiring immediate medical attention.

A COPD exacerbation can be acute over hours or chronic over days or longer. Signs of an exacerbation of the disease are the lack of control of symptoms of bronchoconstriction when using a combination of olodaterol + tiotropium bromide, a decrease in the effectiveness of inhaled short-acting beta 2-agonists, or the need for more frequent use of short-acting beta 2 -agonists than usual. In such cases, the patient's condition should be immediately reassessed and the tactics of treating COPD should be reviewed. An increase in the daily dose of the combination of olodaterol + tiotropium bromide above the recommended one in such a situation is unacceptable.

Excessive use of the combination of olodaterol + tiotropium bromide and use in conjunction with other long-acting beta2-agonists. The combination of olodaterol + tiotropium bromide, like other inhaled drugs containing beta 2-adrenomimetics, should not be used more often than recommended, at a dose exceeding the recommended one, or in combination with other drugs containing long-acting beta 2-adrenergic agonists, because. this may lead to an overdose. There are data on clinically significant cardiovascular effects and deaths associated with the excessive use of inhaled sympathomimetic drugs.

Hypersensitivity reactions of immediate type. After the combination of olodaterol + tiotropium bromide, immediate hypersensitivity reactions such as urticaria, angioedema (including swelling of the lips, tongue, larynx), rash, bronchospasm, anaphylaxis or pruritus may develop. If such reactions occur, olodaterol + tiotropium bromide combination therapy should be discontinued immediately and alternative therapies considered. Patients with a known history of hypersensitivity to atropine and its derivatives treated with tiotropium bromide, which is structurally related to atropine, should be carefully observed when using the combination of olodaterol + tiotropium bromide for the occurrence of such hypersensitivity reactions.

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

cardiovascular effects. Olodaterol, like other beta2-adrenergic agonists, can cause clinically significant cardiovascular effects in some patients, manifested by an increase in heart rate, SBP or DBP and / or the appearance of corresponding symptoms. If such effects occur, the combination of olodaterol + tiotropium bromide should be suspended. In addition, beta-adrenergic agonists are known to cause ECG changes, such as T-wave flattening, QTc prolongation, and ST-segment depression. The clinical significance of these observations is unknown. Long-acting beta2-agonists should be used with caution in patients with cardiovascular disease, especially in heart failure, cardiac arrhythmia, hypertrophic obstructive cardiomyopathy and hypertension.

Accompanying illnesses. Olodaterol, like other sympathomimetic amines, should be used with caution in patients with seizure disorders or thyrotoxicosis, known or suspected QT prolongation, and an unusual response to sympathomimetic amine treatment. There is evidence that the / in the introduction of albuterol - a related beta 2 -agonist - led to an exacerbation of existing diabetes mellitus and ketoacidosis.

Deterioration of visual functions in angle-closure glaucoma. The combination of olodaterol + tiotropium bromide should be used with caution in patients with angle-closure glaucoma. The attending physician and patient should be aware of the signs and symptoms of acute angle-closure glaucoma (eg, pain and discomfort in the eye, blurred vision, visual halos or color images in combination with redness of the eyes caused by conjunctival hyperemia and corneal edema). The patient should be instructed to consult a physician immediately if any of these signs or symptoms develop.

Worse 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 patient should be aware of the signs and symptoms of prostatic hyperplasia and bladder neck obstruction (eg, difficulty urinating, painful urination), especially in patients with prostatic hyperplasia and bladder neck obstruction. The patient should be instructed to consult a physician immediately if any of these signs or symptoms develop.

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

Hypokalemia and hyperglycemia. Beta-agonists can cause significant hypokalemia in some patients, which may lead to adverse cardiovascular effects. The decrease in serum potassium levels is usually transient and does not require replenishment. Inhalation of high doses of beta 2-agonists can cause an increase in plasma glucose levels.

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

In clinical studies with long-term use of olodaterol, clinically significant decreases in serum potassium levels or changes in blood glucose levels were infrequent and comparable to those observed with placebo control. Olodaterol has not been studied in patients with inadequately controlled diabetes mellitus.