Instruction for use: Glycopyrronium bromide + Indacaterol (Glycopyrronii bromidum + Indacaterolum)

Pharmacological group

M Cholinolytics in combinations

Beta-adrenomimetics in combinations

Nosological classification (ICD-10)

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

Characteristics

Combined bronchodilator (m-cholinoblocker + selective beta2-adrenomimetic).

Glycopyrrolate (glycopyrronium bromide), a synthetic quaternary ammonium compound, acts as a competitive antagonist of muscarinic acetylcholine receptors. White powder; Freely soluble in water and moderately soluble in absolute alcohol. Molecular weight 398.33.

Indacaterol maleate, R-enantiomer is a selective beta2-adrenergic receptor agonist. Powder from white to slightly grayish or slightly yellowish in color; Slightly soluble in ethanol and very slightly soluble in water. Molecular weight 508.56.

Pharmacology

Pharmacological action - bronchodilating.

Pharmacodynamics

Glycopyrronium bromide + indacaterol is an inhaled combined long-acting drug. The glycopyrronium bromide and indacaterol included in its composition cause a relaxation of the smooth muscles of the bronchi, mutually strengthening the bronchodilating effect due to a different mechanism of action.

Glycopyrronium bromide is an inhaled m-holinoblokator long-acting, intended for maintenance therapy of bronchial conduction disorders in patients with COPD. The mechanism of its action is based on blocking the bronchoconstrictive action of acetylcholine on smooth muscle cells of the respiratory tract, which leads to a bronchodilating effect. In the human body, five subtypes of muscarinic receptors (m1-5) were identified. It is known that only subtypes m1-3 are involved in the physiological function of the respiratory system. Glycopyrronium bromide has a 4-5-fold greater selectivity for the m1 and m3 receptor subtypes, compared to the receptor m 2 subtype. This leads to a rapid occurrence of therapeutic effect after inhalation of drugs, which is confirmed by clinical studies. The bronchodilating effect of glycopyrronium bromide after inhalation persists for more than 24 hours. The duration of action after inhalation is due to long-term maintenance of the therapeutic concentration of drugs in the lungs, which is confirmed by a longer T1 / 2 LS after inhalation as compared with the intravenous administration.

Indaņaterol is a selective beta2-adrenomimetic of ultra-long-acting action (within 24 hours with a single dose). The pharmacological action of beta2-adrenomimetics, including indacaterol, is associated with the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3 ', 5'-AMP (cyclic AMP). An increase in the content of cyclic AMP leads to a relaxation of the smooth muscles of the bronchi. Indacaterol is an almost complete agonist of beta2-adrenergic receptors; Its stimulating effect on beta2-adrenergic receptors is 24 times stronger than on beta1-adrenergic receptors, and 20 times stronger than β3-adrenergic receptors. After inhalation, indacaterol has a rapid and prolonged bronchodilator effect.

Since the density of m3-cholinergic receptors and beta2-adrenergic receptors in the central and peripheral airways differs, beta2-adrenomimetics better relax the peripheral respiratory tract, while m-holinoblockers have a more significant effect on the central airways. Thus, the combination of m3-holinoblokatora and beta2-adrenomimetic promotes optimal expansion of bronchi throughout the system of the lower respiratory tract of a person.

The effect of the combination glycopyrronium bromide + indacaterol occurs only 5 minutes after inhalation and remains constant for 24 hours, providing a persistent significant improvement in lung function: at the 26th week of therapy, the volume of forced expiration in the first second (FEV1) rises by an average of 320 Ml compared with patients receiving placebo and 110 ml compared to patients receiving separately glycopyrronium bromide, indacaterol or tiotropium bromide. There was also a decrease in functional residual lung capacity and residual lung volume by 350 and 380 ml (p <0.001) compared with placebo 60 min after administration on the first day of use and at 520 and 520 ml (p <0.001) compared with placebo through 21 days of therapy, respectively. When using a combination of glycopyrronium bromide + indacaterol, there is a decrease in dyspnea, an improvement in the tolerance of exercise. There is also a significant decrease in the risk of exacerbations of COPD (an increase in the time until the next exacerbation), a reduction in the need for short-acting inhaled beta2-adrenomimetics, and an improvement in the quality of life of patients (evaluation using the St. George Hospital certified questionnaire).

Based on clinical studies, it has been shown that the combination of glycopyrronium bromide + indacaterol in therapeutic and supra-therapeutic doses does not have a clinically significant effect on heart rate, QT interval length, potassium content and serum glucose concentration.

Electrophysiology of the heart

The QTc interval was studied in TQT studies (Thorough QT studies, exhaustive clinical studies of the QT interval) with a combination of indacaterol + glycopyrrolate and with each component in monotherapy. Studies of TQT with indacaterol and glycopyrrolate showed that none of these substances had a significant effect on the corrected QT interval for supra-therapeutic and therapeutic doses (for the glycopyrrolate, only the supra-therapeutic dose was tested).

In a randomized, partially blind, placebo-controlled and positive-controlled, cross-TQT study, a supra-therapeutic dose of a combination of indacaterol + glycopyrrolate (440 + 499.2 μg) was used in 84 healthy subjects. This is correspondingly 16 and 32 times greater than the single recommended dose of a combination of indacaterol + glycopyrrolate 27.5 + 15.6 μg twice a day. The mean maximum change in QTcI (individually adjusted QT) from baseline versus placebo was 8.7 ms (2-sided 90% CI 7.3, 10.1) 30 minutes after dosing. Despite the fact that the limiting effect of the combination of indacaterol + glycopyrrolate on the QT interval was observed with a supra-therapeutic dose, it is unlikely that a clinically significant effect is possible when exposed to a therapeutic dose.

Pharmacokinetics

Absorption

After inhalation of the combination glycopyrronium bromide + indacaterol, the mean Tmax glycopyrronium bromide and indacaterol in blood plasma were 15 and 5 min, respectively. AUC glycopyrronium bromide in equilibrium with the combination glycopyrronium bromide + indacaterol corresponds to that with inhalation only glycopyrronium bromide.

According to the in vitro study, in which the effectiveness of inhalation was studied, the dose of indacaterol delivered to the lungs using a combination of glycopyrronium bromide + indacaterol corresponds to the use of indacaterol alone at a dose of 150 μg. AUC indacaterol in equilibrium with the use of a combination of glycopyrronium bromide + indacaterol corresponds to or may be slightly lower than that for inhaled only indacaterol in a dose of 150 μg. Absolute bioavailability of indacaterol with the combination glycopyrronium bromide + indacaterol is 47 to 66%, glycopyrronium bromide is about 40%.

Glycopyrronium bromide. After inhalation of glycopyrronium, the bromide is rapidly absorbed and reaches C max in the blood plasma after 5 minutes. About 90% of the systemic exposure of glycopyrronium bromide is due to absorption in the lungs and 10% to absorption in the gastrointestinal tract. Absolute bioavailability of glycopyrronium bromide after inhalation is estimated at 40% of the delivered dose. Against the background of regular inhalations (1 time per day), Css glycopyrronium bromide is reached within 1 week. AUC glycopyrronium bromide in the equilibrium state was 1.4-1.7 times higher than after the first inhalation. The cells of glycopyrronium bromide in the equilibrium state (when inhaled the recommended dose once a day) and the glycopyrronium bromide concentration in the blood plasma at the end of the dosing period are 166 and 8 pg / ml, respectively.

Indacaterol. The average Tmax of indacaterol in the serum is about 15 min after a single or repeated inhalation. The concentration of indacaterol in the serum increases when it is repeated. Css in the blood is reached within 12-15 days of use. When inhaled at a dose of 60 to 480 mcg (dose delivered to the lungs) at a frequency of 1 time per day for 14 days, the cumulation index of indacaterol, estimated by the AUC value of indacaterol on days 1, 14 or 15, is From 2.9 to 3.8.

Absorption

After inhalation of the combination of indacaterol + glycopyrrolate, the average Tmax of indacaterol and glycopyrrolate in blood plasma was approximately 15 and 5 minutes, respectively.

Systemic exposure in the equilibrium state (AUC0-12, Css) of indacaterol and glycopyrrolate with inhalations of the combination of indacaterol + glycopyrrolate (27.5 + 15.6 μg, 2 times a day) corresponds to that with indacaterol monotherapy (27.5 μg, inhalation 2 times Per day) or glycopyrrolate (15.6 μg, 2 times a day), respectively.

Distribution

Glycopyrronium bromide. After intravenous administration of Vss, glycopyrronium bromide was 83 liters and the volume of distribution in the terminal phase (Vz) was 376 liters. Apparent volume of distribution in the terminal phase after inhalation of Vz / F was 7310 liters, which reflects a slower elimination of drugs after inhalation. In vitro, the association of glycopyrronium bromide with human plasma proteins was 38-41% at a concentration of 1-10 ng / ml.

Indacaterol. After intravenous administration of Vz, indacaterol was 2557 liters, indicating a significant distribution of drugs. The connection with serum proteins and human blood plasma in vitro is approximately 95%.

Metabolism

Glycopyrronium bromide. In vitro, it was noted that the hydroxylation of glycopyrronium bromide leads to the formation of various mono- and bis-hydroxylated metabolites, and direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). In vitro studies have shown that CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium bromide. Hydrolysis to M9 appears to be catalyzed by enzymes of the cholinesterase family. Since in vitro studies did not reveal the metabolism of the active substance in the lungs, and M9 contributes insignificantly to the circulation (4% of Cmax and AUC of glycopyrronium bromide) after intravenous administration, it is suggested that M9 is formed from the fraction that is absorbed from the digestive tract (after inhalation) Active substance by pre-systemic hydrolysis and / or by primary passage through the liver. After inhalation or with / in administration, only a minimal amount of M9 was detected in urine (≤0.5% of the administered dose). Glucuronic and / or sulfate conjugates of glycopyrronium bromide were detected in human urine after repeated inhalations in an amount of approximately 3% of the delivered dose.

In vitro inhibition studies have shown that glycopyrronium bromide does not have a significant ability to suppress the activity of the isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 / 5, transport proteins MDR1, MRP1 or MXR, mediating the excretion of drugs from cells, and Carrier proteins OATP1B1, OATP1B3, OAT1, OAT3, OST1 or OST2. Studies of induction of enzymes in vitro did not reveal a clinically significant ability in the formation of cytochrome P450 isoenzymes, UGT1A1 enzyme and MDR1 and MRP2 carrier proteins in glycopyrronium bromide.

Indacaterol. When ingestion of radiolabeled indacaterol, unchanged indacaterol is the main component of serum and is approximately 1/3 of the daily AUC of the drug. Of the metabolites of indacaterol in the blood serum, the hydroxylated derivative of indacaterol is determined to the greatest extent. In a smaller amount phenolic O-glucuronide indacaterol and hydroxylated indacaterol are found. In addition, diastereomers of the hydroxylated derivative, indacaterol N-glucuronide and the products of C- and N-dealkylation are detected.

The isoenzyme UGT1A1 is the only isoenzyme that metabolizes indacaterol to phenolic O-glucuronide. The hydroxylation of indacaterol mainly occurs with the aid of the CYP3A4 isoenzyme. It was also found that indacaterol is a low-affinity substrate for the membrane transporter of P-gp molecules.

Excretion

Glycopyrronium bromide. Elimination of glycopyrronium bromide by the kidneys reaches 60-70% of the total plasma clearance, 30-40% is excreted in other ways - with bile or due to metabolism. In healthy volunteers and patients with COPD who received glycopyrronium in doses from 50 to 200 μg once a day and once and repeatedly, the average renal clearance of glycopyrronium ranged from 17.4 to 24.4 l / h. Elimination of glycopyrronium bromide through the kidneys is due to active tubular secretion. Up to 23% of the dose is found in the urine in unchanged form. The concentration of glycopyrronium bromide in the blood plasma decreases multiphase. The mean final T1 / 2 is longer after inhalation (33-57 h) than after iv (6.2 h) or oral administration (2.8 h). The nature of elimination suggests long-term absorption in the lungs and / or penetration of glycopyrronium bromide into the systemic circulation during and after 24 hours after inhalation.

Indacaterol. The amount of unchanged indacaterol excreted by the kidneys is less than 2.5% of the delivered dose. Renal clearance of indacaterol - an average of 0.46-1.2 l / h. Given that the serum clearance of indacaterol is 18.8-23.3 l / h, it is obvious that excretion of indacaterol through the kidneys is negligible (approximately 2-5% of system clearance). When ingesting indacaterol was excreted mainly through the intestine: unchanged (54% of the dose) and in the form of hydroxylated metabolites (23% of the dose).

The concentration of indacaterol in the blood serum is reduced multiphase with an average final T1 / 2 value in the range of 45.5 to 126 hours. The effective T1 / 2, calculated on the basis of accumulation of indacaterol after repeated application, varied from 40 to 52 hours, which was consistent with the established time Reaching an equilibrium state (12-15 days).

AUC of indacaterol in the equilibrium state increased in proportion to the delivered dose in the range of 120 to 480 μg.

Linearity / nonlinearity

Glycopyrronium bromide. In patients with COPD, AUC, as well as total excretion by the kidneys of glycopyrronium bromide in an equilibrium state, increased in proportion to the dose in the range of 50 to 200 μg.

Indacaterol. The systemic exposure of indacaterol increases in proportion to the increase in dose (from 150 to 600 μg). Systemic exposure of the drug is due to its absorption in both the lungs and the gastrointestinal tract.

Special patient groups

The combination of glycopyrronium bromide + indacaterol. Age, sex and body weight do not significantly affect the pharmacokinetics of the combination glycopyrronium bromide + indacaterol in patients with COPD. A negative correlation was found between AUC and lean body mass (or body weight), however, since AUC did not change significantly, and the prognostic value of lean body mass is low, it is not recommended to adjust the dose depending on this parameter. Smoking and baseline FEV1 do not have a visible effect on the AUC combination of glycopyrronium bromide + indacaterol.

Glycopyrronium bromide. Age and body weight are factors that influence interindividual differences in AUC. The recommended dose of glycopyrronium bromide can safely be used in any age group and at any body weight. Sex, smoking and baseline FEV1 do not have a visible effect on the glycopyrronium bromide AUC.

Indacaterol. Age (adult patients up to 88 years), sex and body weight (32-168 kg) do not affect the pharmacokinetics of indacaterol in patients with COPD.

Pharmacokinetics in specific patient groups

Population pharmacokinetic analysis revealed no clinically significant effect of age (from 40 to 85 years), body weight (from 45 to 120 kg), sex, smoking status, and initial indices of FEV1 on systemic exposure to indacaterol or glycopyrrolate after inhalation of a combination of indacaterol + glycopyrrolate .

Also, there was no dependence on age, body weight, sex, smoking status and baseline FEV1 values after inhalation of 2 components - indacaterol and glycopyrrolate - separately.

Patients with impaired hepatic function

The combination of glycopyrronium bromide + indacaterol. Based on the pharmacokinetic properties of each of the components used individually, a combination of glycopyrronium bromide + indacaterol can be used at the recommended dose to patients with mild to moderate liver function impairment. Data on use in patients with severe impairment of liver function are absent.

Glycopyrronium bromide. Clinical studies in patients with hepatic insufficiency have not been conducted. Elimination of glycopyrronium bromide occurs mainly through excretion by the kidneys. It is suggested that a deterioration in the metabolism of glycopyrronium bromide in the liver will not result in a clinically significant increase in AUC.

Indacaterol. The pharmacokinetics of indacaterol did not change significantly in patients with mild or moderate severity of hepatic impairment. The use in patients with severe impairment of liver function has not been studied.

Patients with impaired renal function

The combination of glycopyrronium bromide + indacaterol. Based on the pharmacokinetic properties of each of the components used individually, a combination of glycopyrronium bromide + indacaterol can be used at the recommended dose to patients with mild and moderate severity of renal dysfunction. In patients with severe renal dysfunction or with an end-stage CRF requiring hemodialysis, the combination of glycopyrronium bromide + indacaterol should be used only if the expected benefit exceeds the possible risk.

Glycopyrronium bromide. Renal insufficiency affects the glycopyrronium bromide AUC. A moderate increase in AUC up to 1.4 times was observed in patients with mild to moderate renal insufficiency and up to 2.2 times in patients with severe renal insufficiency and terminal stage. The use of population pharmacokinetic analysis led to the conclusion that glycopyrronium bromide can be used in recommended doses in patients with COPD with concomitant renal insufficiency of mild and moderate severity (estimated by GFR ≥30 ml / min / 1.73 m2).

Indacaterol. Since indacaterol is excreted by the kidneys to an insignificant degree, pharmacokinetics in patients with impaired renal function has not been studied.

Ethnicity

The combination of glycopyrronium bromide + indacaterol. There was no statistically significant effect of ethnicity on the AUC of both components.

Glycopyrronium bromide. There were no differences between ethnic subgroups.

Indacaterol. There were no differences between ethnic subgroups. The experience of using indacaterol in the Negroid race is limited.

Pharmacogenomics

Indacaterol. The pharmacokinetics of indacaterol was prospectively studied in patients with the UGT1A1 (TA) 7 / (TA) 7 genotype (low expression of UGT1A1, also designated as * 28) and (TA) 6 / (TA) 6 by genotype. In the equilibrium state, AUC and Cmax of indacaterol were 1.2 times higher with the genotype [(TA) 7, (TA) 7], which indicates that the effect of the UGT1A1 genotype is insignificant when exposed to indacaterol.

Glycopyrrolate. Effects of pharmacogenomic variants on the pharmacokinetics of glycopyrrolate have not been investigated.

Indications

Long-term maintenance therapy of bronchial obstruction disorders in patients with chronic obstructive pulmonary disease, relieving symptoms and reducing the number of exacerbations.

Contraindications

Increased sensitivity to glycopyrronium bromide and indacaterol; Age under 18 years (effectiveness and safety not established); Intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption (the preparation contains lactose).

It is not recommended simultaneous reception with drugs containing other long-acting beta2-adrenomimetics or long-acting m-holinoblokatory.

Restrictions on the use

Although there is no clinically significant effect on the CAS of the glycopyrronium bromide + indacaterol combination at the therapeutic dose, caution should be exercised in its administration to patients with concomitant cardiovascular diseases (coronary heart disease (including unstable angina), acute myocardial infarction (Including history), arterial hypertension, cardiac arrhythmias, QTc interval prolongation (QT corrected> 0.44 s), convulsive disorders, thyrotoxicosis, diabetes mellitus, congenital QT interval prolongation, caution should be exercised with the combination of glycopyrronium Bromide + indacaterol in patients concomitantly taking drugs, prolonging the QT interval (antiarrhythmic preparations of IA and III classes, tricyclic and tetracyclic antidepressants, neuroleptics, macrolides, antifungal drugs, imidazole derivatives, some antihistamines, including astemizole, terfenadine, ebastin), Drugs for general anesthesia from the barbiturate group, as well as in patients who have a history of inadequate response to the action of beta2-adrenomimetics.

Caution should also be exercised when using glycopyrronium bromide + indacaterol in patients with angle-closure glaucoma, severe impaired hepatic function, urinary retention, severe renal insufficiency (GFR below 30 mL / min / 1.73 m2), including terminal renal disease Deficiency requiring hemodialysis (a combination of glycopyrronium bromide + indacaterol should only be used if the expected benefit exceeds the potential risk).

In the presence of one of the listed diseases, before taking a combination of glycopyrronium bromide + indacaterol, you should consult a doctor.

pregnancy and lactation

Data on the use of a combination of glycopyrronium bromide + indacaterol in pregnant women is not available. Data on the use of pregnant women glycopyrronium bromide or indacaterol are also absent.

In the study of early and late embryogenesis in rats, no effects of glycopyrronium bromide + indacaterol combination used in different doses on the embryo or fetus were detected. In rats and rabbits receiving inhalation of glycopyrronium bromide, no teratogenic effect was detected. A low concentration of glycopyrronium bromide in the umbilical cord plasma was observed 86 minutes after a single intravenous injection of glycopyrronium bromide at a dose of 0.006 mg / kg to women who had a cesarean section. Indacaterol had no teratogenic effect in rats and rabbits with n / to administration. However, indacaterol had a toxic effect on the reproductive system, which was manifested in an increase in the frequency of changes in the skeleton in rabbits.

Due to the lack of clinical data on the use of glycopyrronium bromide + indacaterol in pregnant women, drugs can be used during pregnancy only if the intended use for the mother exceeds the potential risk to the fetus.

It is not known whether glycopyrronium bromide and / or indacaterol penetrate breast milk in women. However, both indacaterol and glycopyrronium bromide (including its metabolites) were found in the milk of lactating rats. Given this circumstance, the use of a combination of glycopyrronium bromide + indacaterol in breast-feeding women is allowed only if the intended benefit to the mother exceeds the possible risk to the child.

Indacaterol can slow down the process of labor due to the relaxing effect on the smooth muscles of the uterus.

Fertility

Neither reproductive toxicity studies nor other animal studies suggest that the combination of glycopyrronium bromide + indacaterol can affect fertility in men or women.

Adequate and strictly controlled studies of the combination of indacaterol + glycopyrrolate or individual components - indacaterol and glycopyrrolate - in pregnant women have not been carried out. The combination of indacaterol + glycopyrrolate should be used during pregnancy only if the expected effect of therapy exceeds the potential risk to the fetus. Women should be advised to consult their doctor if pregnancy is determined during treatment with a combination of indacaterol + glycopyrrolate.

It is not known whether the combination of indacaterol + glycopyrrolate penetrates the breast milk of women. Since many drugs are excreted into human milk, caution should be exercised when using a combination of indacaterol + glycopyrrolate with nursing mothers. Since there are no strictly controlled clinical trials using the combination of indacaterol + glycopyrrolate in nursing mothers, based on the data for the individual components, a decision should be made whether to stop breastfeeding or stop using the combination of indacaterol + glycopyrrolate, taking into account the importance of using it for the mother.

Indacaterol. It is not known whether indacaterol is excreted into the breast milk of women. Indacaterol (including its metabolites) was found in the milk of lactating rats.

Glycopyrrolate. It is not known whether glycopyrrolate is excreted into breast milk of women. Glycopyrrolate (including its metabolites) was detected in the milk of lactating rats at concentrations up to 10 times the concentration in the blood of animals.

The action category for fetus by FDA is C.

Side effects

Adverse events (AEs) with the combination glycopyrronium bromide + indacaterol are characterized by symptoms typical for m-cholinoblockers and beta2-adrenomimetics used in monotherapy. Among the other most frequent AEs associated with this drug (which occurred in at least 3% of patients taking a combination of glycopyrronium bromide + indacaterol and whose frequency was higher than in the placebo trial) include cough and pain in the oropharynx (including perforation in the throat).

In patients with COPD with inhalation at the recommended doses, the combination of glycopyrronium bromide + indacaterol does not have a clinically significant systemic beta2-adrenergic effect. The heart rate changes by no more than 1 bpm on average, and tachycardia develops rarely and at a lower frequency than in the placebo group. The frequency of significant prolongation of the QTc interval (> 450 ms) and hypokalemia is similar to that in the placebo group.

Clinical research experience

Because clinical studies are conducted with a different set of conditions, the incidence of adverse reactions observed in these studies can not be directly compared with the frequency in other clinical trials and predict the occurrence of side effects in clinical practice.

The safety database for the combination of indacaterol + glycopyrrolate included 2,654 patients with COPD who participated in two 12-week lung tests and one 52-week long-term safety study. A total of 712 people received treatment with a combination of indacaterol + glycopyrrolate 27.5 + / 15.6 μg twice a day. The safety data presented below is based on the results of two 12-week trials and one 52-week study.

12-week trial

The incidence of adverse reactions associated with the combination of indacaterol + glycopyrrolate is based on data from two 12-week placebo-controlled trials (trials 1 and 2, N = 1001 and N = 1042, respectively). Out of 2040 people, 63% were men and 91% were Caucasians. The average age was 63 years, smoking averaged 47 packs of cigarettes per year, 52% of people were identified at the beginning of the study as smokers. In screening, the median percentage of the predicted FEV1 after taking the bronchodilator was 55% (range: 29 to 79%), the average FEV1 / FVC (forced vital capacity) ratio after taking the bronchodilator was 50% (range: 19 to 71% The percentage of reversibility of bronchial obstruction was 23% (range: 0 to 144%).

The most common adverse reactions (frequency greater than or equal to 2% or higher compared with placebo) were nasopharyngitis and hypertension.

The proportion of patients who discontinued treatment due to adverse reactions was 2.95% when treated with a combination of indacaterol + glycopyrrolate and 4.13% in patients receiving placebo.

Patients received 1 dose twice daily in the following variants: a combination of indacaterol + glycopyrrolate 27.5 μg / 15.6 μg; Indacaterol 27.5 μg; Glycopyrrolate 15.6 μg or placebo.

Adverse reactions associated with a combination of indacaterol + glycopyrrolate (greater than or equal to 1% of cases and higher than in the placebo group) in COPD patients

The results are presented as follows: next to the name of the side effect, the number of patients who had this effect recorded (in parentheses the frequency of occurrence of the side effect in percent is indicated everywhere). The results obtained with the combination of indacaterol + glycopyrrolate 27.5 + 15.6 μg twice a day (N = 508) are shown through a semicolon; When using indacaterol, 27.5 μg twice daily (N = 511); When glycopyrronium bromide is used twice a day (N = 513); Placebo (N = 508).

Nasopharyngitis: 21 (4.1%); 13 (2.5%); 12 (2.3%); 9 (1.8%).

Hypertension: 10 (2%); 5 (1%); 3 (0.6%); 7 (1.4%).

Back pain: 9 (1.8%); 7 (1.4%); 2 (0.4%); 3 (0.6%).

Pain in the oropharynx: 8 (1.6%); 4 (0.8%); 8 (1.6%); 6 (1.2%).

Other adverse events observed more often with the combination of indacaterol + glycopyrrolate than placebo but less than 1% include dyspepsia, gastroenteritis, chest pain, fatigue, peripheral edema, rash / itching, insomnia, dizziness, urinary obstruction Bladder / urine retention, atrial fibrillation, palpitations, tachycardia.

52-week trial

In a long-term safety study, 614 patients received a combination of indacaterol + glycopyrrolate at a dose of 27.5 + 15.6 μg twice daily for 52 weeks or at a dose of 27.5 + 31.2 μg twice daily or indacaterol 75 μg once in a day. Demographic and baseline characteristics in a long-term safety study were similar to those of the placebo-controlled efficacy trials described above. The adverse reactions noted in the long-term safety study corresponded to those observed in placebo-controlled 12-week trials.

Additional adverse reactions that occurred with a frequency greater than or equal to 2% in the group receiving indacaterol + glycopyrrolate 27.5 + 15.6 μg twice a day, which is higher than the frequency of taking indacaterol 75 μg once a day in this The tests were: infection of the upper and lower respiratory tract, pneumonia, diarrhea, headache, GERD, hyperglycemia, rhinitis.

Post-marketing experience

In the postmarketing observation period, when using a combination of indacaterol + glycopyrrolate at a higher than recommended dose, angioedema was recorded. Since messages are received voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship with the effect of drugs.

Interaction

When inhaled combined use of glycopyrronium bromide and indacaterol under equilibrium conditions, the pharmacokinetic properties of both drugs did not change.

Special studies of the interaction of glycopyrronium bromide + indacaterol with other drugs have not been conducted. Information on the potential interactions of glycopyrronium bromide + indacaterol combination is based on data on possible interactions of each of its components.

Drug interactions associated with glycopyrronium bromide

In vitro studies have shown that glycopyrronium bromide probably does not affect the metabolism of other drugs. Inhibition or induction of glycopyrronium bromide metabolism does not lead to significant changes in the AUC of the drug. Metabolic transformations taking place with the participation of various enzymes in the removal of glycopyrronium bromide play no significant role.

Cimetidine or other inhibitors of cation transporters. In clinical studies in healthy volunteers, cimetidine, an inhibitor of organic cation transporters, affecting the renal clearance of glycopyrronium bromide, increased the glycopyrronium bromide AUC by 22% and reduced renal clearance by 23%. Based on these indicators, no clinically significant interaction is contemplated with simultaneous use of glycopyrronium bromide with cimetidine or other inhibitors of cation transporters.

M-holinoblokatory. Special studies of the interaction of glycopyrronium bromide + indacaterol with other drugs containing m-cholinoblockers have not been carried out. It is not recommended simultaneous reception with drugs containing long-acting m-holinoblokatory.

Anticholinergic drugs. There is a possibility of additive interaction with simultaneous use of anticholinergic drugs. Therefore, the combined use of a combination of indacaterol + glycopyrrolate with other anticholinergic drugs should be avoided. This can lead to increased anticholinergic side effects.

Drug interactions associated with indacaterol

Beta-blockers. Since beta-blockers can weaken the effect or interfere with the action of beta2-adrenomimetics, the combination of glycopyrronium bromide + indacaterol is not recommended to be used simultaneously with beta-blockers (including eye drops) in the absence of valid reasons for their joint use.

Beta-blockers. Beta-adrenoreceptor antagonists and a combination of indacaterol + glycopyrrolate can influence the effects of each other when used simultaneously. Beta-adrenoblockers not only block the therapeutic effect of beta-agonists, but can lead to severe bronchospasm in patients with COPD. Therefore, patients with COPD treatment should not usually use beta-blockers. Nevertheless, under certain circumstances, for example, as a prophylaxis after myocardial infarction, in the absence of acceptable alternatives to the use of beta-blockers in patients with COPD, cardioselective beta-blockers can be considered, although they should be used with caution.

If it is necessary to use both classes of drugs, it is preferable to use selective beta-blockers, but use them with caution.

LS, extending the interval QT. As with the use of other beta2-adrenomimetics, caution should be exercised when using a combination of glycopyrronium bromide + indacaterol in patients receiving MAO inhibitors, tricyclic antidepressants, or other drugs capable of prolonging the QT interval, They can enhance their effect on the length of the QT interval. When using drugs that can extend the QT interval, the risk of ventricular arrhythmia increases.

Sympathomimetic drugs. The simultaneous use of indacaterol with sympathomimetics (both separately and as part of combination therapy) can increase the risk of developing adverse events. It is not recommended simultaneous reception with drugs containing other long-acting beta2-adrenomimetics.

Hypokalemic drugs. Simultaneous use with methylxanthine derivatives, GCS or diuretics, causing hypokalemia, may enhance the possible hypokalemia caused by beta2-adrenomimetics.

Interaction at the level of the isoenzyme CYP3A4 and membrane transporter P-gp. The interaction of indacaterol with specific inhibitors of the isoenzyme CYP3A4 and P-gp, such as ketoconazole, erythromycin, verapamil and ritonavir was studied. Simultaneous use of indacaterol with verapamil led to a 1.4-2-fold increase in AUC and a 1.5-fold increase in Cmax. When using indacaterol with erythromycin, AUC increased by 1.4-1.6 times and Cmax by 1.2 times. Combination therapy with indacaterol and ketoconazole caused a 2- and 1.4-fold increase in AUC and Cmax, respectively. With the simultaneous use of indacaterol with ritonavir (inhibitor of the isoenzyme CYP3A4 and P-gp), the AUC increased 1.6-1.8 times, but Cmax remained unchanged. This increase in AUC due to drug interactions did not lead to a change in the safety profile.

Indacaterol. In vitro studies have shown that indacaterol has little potential for metabolic interaction with drugs (by inhibiting or inducing cytochrome P450 enzymes or induction of UGT1A1) at systemic exposure levels attained in clinical practice. In vitro studies show that in vivo indacaterol is unlikely to substantially inhibit transport proteins such as P-gp, MRP2, BCRP, OCT1 and OCT2, MATE1 and MATE2K, and indacaterol has little potential for induction of P-gp or MRP2.

Adrenergic drugs. If it is necessary to use additional adrenergic drugs for any route of administration, they should be used with caution. The sympathetic effects of indacaterol - a component of the combination of indacaterol + glycopyrrolate - can be enhanced.

Non-potassium-sparing diuretics. Changes in the ECG and / or hypokalemia that may result from the use of non-potassium-sparing diuretics (eg loop or thiazide) can be aggravated by beta-agonists such as indacaterol, a component of the combination of indacaterol + glycopyrrolate - especially if the recommended dose of beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution should be exercised when combined combination of indacaterol + glycopyrrolate with non-potassium-sparing diuretics.

Overdose

In patients with COPD, after 14 days of administration of a combination of glycopyrronium bromide + indacaterol in doses several times higher than therapeutic, there was an increase in the incidence of ventricular extrasystole. In general, unstable ventricular tachycardia was noted in four patients, with the duration of the longest episode being 4 seconds (9 abbreviations).

It is suggested that an overdose of a combination of glycopyrronium bromide + indacaterol is characterized by symptoms typical of an overdose of beta2-adrenomimetics, such as tachycardia, tremor, palpitation, headache, nausea, vomiting, drowsiness, ventricular arrhythmia, metabolic acidosis, hypokalemia and hyperglycemia, , Typical of an overdose of m-holinoblokatorov, such as an increase in IOP (accompanied by pain in the eyes, visual impairment or reddening of the eyes), constipation or difficulty urinating.

Information about an overdose of glycopyrronium bromide. In patients with COPD, the regular inhalation administration of glycopyrronium bromide in a total dose of 100 and 200 μg once a day for 4 weeks was well tolerated.

Acute intoxication with accidental ingestion of glycopyrronium bromide capsule is unlikely due to low bioavailability of glycopyrronium bromide when ingested (about 5%).

Cmax and AUC after iv introduction of 150 μg glycopyrronium bromide in healthy volunteers were approximately 50 and 6 times higher, respectively, than Cmax and AUC in equilibrium, achieved with glycopyrronium bromide inhalation at the recommended doses. Signs of an overdose were not detected.

Information on the overdose of indacaterol. After a single application of indacaterol in patients with COPD at a dose exceeding the maximum therapeutic dose by 10 times, there was a moderate increase in heart rate, an increase in blood pressure, and an extension of the QTc interval.

Treatment. Supportive and symptomatic therapy is indicated. In severe cases, patients should be hospitalized. If necessary, the use of selective beta-blockers is possible. Use selective beta-blockers with caution, only under strict medical supervision, since their use can provoke the development of bronchospasm.

Routes of administration

Inhalation.

Precautions of substances Glycopyrronium bromide + Indacaterol

The combination of glycopyrronium bromide + indacaterol is not recommended for relief of acute episodes of bronchospasm.

The combination of glycopyrronium bromide + indacaterol is intended for maintenance treatment of patients with COPD. Due to the fact that patients in the general population of COPD are significantly older than 40, the prescription of drugs for patients under 40 years of age requires spirometric confirmation of the diagnosis of COPD.

Hypersensitivity reactions. Against the background of the use of glycopyrronium bromide or indacaterol, components of the combination glycopyrronium bromide + indacaterol, cases of the development of immediate-type hypersensitivity reactions have been reported. If there are signs indicating the development of an allergic reaction (in particular, difficulty breathing or swallowing, swelling of the tongue, lips and face, urticaria, skin rash), the combination of glycopyrronium bromide + indacaterol should be abolished and alternative therapy should be selected.

Bronchial asthma. In connection with the lack of data on the use of glycopyrronium bromide + indacaterol combination in patients with bronchial asthma, drugs should not be used to treat bronchial asthma.

When using long-acting beta2-adrenomimetics for the treatment of bronchial asthma, the risk of serious AE associated with bronchial asthma increases, including. Lethal outcome.

Mortality from asthma

Long-acting agonists of beta2-adrenergic receptors, incl. Indacaterol - an active component of the combination of indacaterol + glycopyrrolate, - increase the risk of mortality associated with asthma.

Data from a large-scale placebo-controlled study in the US in patients with asthma have shown that long-acting beta2-adrenomimetics can increase the risk of death associated with asthma. There is no data available to determine whether the risk of mortality increases with the use of drugs of this group in patients with COPD.

A 28-week, placebo-controlled study in the United States to evaluate the safety of long-acting beta2-adrenomimetic (salmeterol) in asthmatic patients showed that the addition of salmeterol to standard asthma therapy resulted in an increase in asthma-related deaths (13 of 13,176 patients additionally receiving Salmeterol, versus 3 of the 13179 patients receiving placebo, the risk ratio was 4.37, 95% CI 1.25, 15.34). An increased risk of asthma-associated mortality is considered a class effect of long-acting beta2-agonists, including indacaterol, one of the components of a combination of indacaterol + glycopyrrolate.

There have not been adequate studies to determine whether the risk of asthma-related mortality increases in patients using the combination of indacaterol + glycopyrrolate. The safety and effectiveness of the combination of indacaterol + glycopyrrolate in patients with asthma have not been established. The combination of indacaterol + glycopyrrolate is not indicated for the treatment of asthma.

Exacerbation of the disease and acute episodes

Do not start the use of a combination of indacaterol + glycopyrrolate in patients with acute worsening of COPD or potentially life-threatening seizures. The combination of indacaterol + glycopyrrolate has not been studied in patients with exacerbation of COPD and is not intended for use in this situation.

The combination of indacaterol + glycopyrrolate should not be used to relieve acute symptoms, i.e. As an emergency aid for the treatment of acute episodes of bronchospasm. The combination of indacaterol + glycopyrrolate has not been studied as an aid for acute symptoms and elevated doses should not be used for this purpose. To stop acute symptoms should be used inhaled beta2-agonists of short action.

At the beginning of the use of the combination of indacaterol + glycopyrrolate, patients who regularly took short-acting oral or inhaled beta2-agonists (for example, 4 times a day) should stop the ongoing treatment with these drugs and use them only for the symptomatic relief of acute respiratory symptoms. When appointing a combination of indacaterol + glycopyrrolate, the doctor should also prescribe a short-acting inhaled beta2-agonist and instruct the patient how it should be used. An increase in the dose of inhaled beta2-agonist is a sign of an exacerbation of the disease, which requires immediate medical attention.

Exacerbation of COPD can develop acute within a few hours or chronically for several days or longer. If the combination of indacaterol + glycopyrrolate no longer controls bronchoconstriction symptoms, short-acting inhaled beta2-agonists in the patient become less effective or the patient needs more short-acting inhaled beta2-agonists than usual-these may be signs of exacerbation of the disease. In these cases, a reassessment of the patient's condition should be undertaken immediately and the treatment regimen of COPD revised. An increase in the daily dose of a combination of indacaterol + glycopyrrolate above recommended in this situation is not recommended.

Excessive use of a combination of indacaterol + glycopyrrolate and use with other long-acting beta2-adrenergic agonists

Like other inhaled drugs containing beta2-adrenomimetics, the combination of indacaterol + glycopyrrolate should not be used more often than recommended, at higher doses than recommended, or in combination with other drugs containing long-acting beta2-agonists, This can lead to an overdose. Clinically significant cardiovascular effects and fatal outcomes have been reported due to the excessive use of inhaled sympathomimetics. Patients using the combination of indacaterol + glycopyrrolate should not use other drugs containing a long-acting beta2-agonist, regardless of the cause.

Paradoxical bronchospasm. In clinical studies using a combination of glycopyrronium bromide + indacaterol, there were no cases of paradoxical bronchospasm. However, when using other inhaled drugs, there were cases of paradoxical bronchospasm, potentially a threat to life. In the case of paradoxical bronchospasm, the combination of glycopyrronium bromide + indacaterol should be immediately discontinued and alternative therapy should be prescribed.

M-Holin-blocking effect. Due to the lack of data on the use of glycopyrronium bromide + indacaterol combination in patients with angle-closure glaucoma, these patients should be careful.

Patients should be informed of the signs and symptoms of an acute attack of angle-closure glaucoma and the need to discontinue the use of a combination of glycopyrronium bromide + indacaterol and also to inform their physician immediately if any of these signs or symptoms occur.

Diseases accompanied by a delay in urine. Due to the lack of data on the use of glycopyrronium bromide + indacaterol combination in patients with urinary retention, caution should be exercised in this group of patients.

Urinary retention (exacerbation). The combination of indacaterol + glycopyrrolate should be used with caution in patients with a delay in urine. One should be attentive to the signs and symptoms of urinary retention (for example, difficulty urinating, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction. Patients should be instructed to seek immediate medical attention if any of these signs or symptoms develop.

Effect of beta2-adrenomimetics on CCC. Beta2-adrenergic receptors are mainly represented in the smooth muscles of the bronchi, and the human heart contains predominantly beta1-adrenergic receptors. However, the proportion of beta2-adrenoreceptors in the human heart accounts for 10 to 50% of all adrenergic receptors. It has not been established exactly what function beta2-adrenoceptors in the heart perform, but their presence in the heart suggests that even highly selective beta2-adrenomimetics can affect the heart. Beta-2-adrenomimetics can have a clinically significant effect on CAS, incl. Increased heart rate, increased blood pressure. In the case of AE when using a combination of glycopyrronium bromide + indacaterol, treatment may be discontinued. In addition, with the use of beta2-adrenomimetics, the following ECG changes can be noted: flattening of the T wave, prolongation of the QT interval and depression of the ST segment (however, the clinical significance of these changes has not been established). In clinical trials with the use of drugs at recommended therapeutic doses, there was no significant prolongation of the QT interval compared with placebo.

Hypokalemia

In some patients, with the use of beta2-adrenomimetics, significant hypokalemia can occur, leading to the development of AEs from the CCC. Reducing the concentration of potassium in the blood serum is usually transient and does not require correction. In patients with COPD severe hypokalaemia can be caused by hypoxia and concomitant therapy, which, in turn, can increase the likelihood of arrhythmias. In clinical trials with the use of drugs in the recommended therapeutic doses, there were no clinically significant effects of hypokalemia.

Hyperglycemia. With inhalation of high doses of beta2-adrenomimetics, an increase in the level of glucose in the blood plasma is possible. When used in patients with diabetes should regularly monitor the concentration of glucose in the blood plasma. In clinical trials in patients receiving drugs (in recommended doses), there was an increase in the incidence of clinically significant hyperglycemia, 4.1%, compared with the placebo group, 2.3%. Efficacy and safety of use in patients with uncompensated diabetes mellitus have not been studied.

Special patient groups

Patients older than 75 years. Do not require dose adjustment in patients ≥75 years of age.

Use in geriatrics. Based on the available data, dose adjustment of the combination of indacaterol + glycopyrrolate in geriatric patients is not required. Combinations of indacaterol + glycopyrrolate can be used in the recommended dose in patients ≥75 years of age.

Of the total number of indacaterol + glycopyrrolate combinations participating in clinical trials, 45% of patients were ≥65 years of age, while 11% were ≥75 years of age. There was no difference in safety or efficacy between these patients and younger subjects, as well as in other reports from clinical practice. But one can not rule out the greater sensitivity of some older people.

Patients with impaired renal function. Do not require dose adjustment when used in patients with impaired renal function of mild or moderate. In patients with severe renal insufficiency or terminal stage requiring hemodialysis, the combination glycopyrronium bromide + indacaterol should be used at the recommended dose only if the intended benefit exceeds the potential risk.

Patients with impaired liver function. Do not require dose adjustment when used in patients with impaired liver function of mild and moderate severity. The use in patients with severe impairment of liver function has not been studied.

Impact on the ability to carry out potentially hazardous activities requiring special attention and quick reactions (vehicle management, working with moving mechanisms, etc.). The combination of glycopyrronium bromide + indacaterol does not or has little effect on the ability to drive vehicles and carry out potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.