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

Pharmacotherapeutic group:

Beta-adrenergic agonist in combination

M Cholinolytics in combinations

The 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 bronchodilatory agent (m-holinoblokator + selective beta2-agonists).

Glycopyrrolate (glycopyrronium bromide) - Synthetic quaternary ammonium compound acts as a competitive antagonist of muscarinic acetylcholine receptors. White powder; freely soluble in water and sparingly soluble in absolute alcohol. The molecular weight of 398.33.

Indacaterol maleate, R-enantiomer - selective beta2-adrenergic agonist. Powder from white to light gray or slightly yellow in color; slightly soluble in ethanol, and very slightly soluble in water. The molecular weight of 508.56.

Pharmacology

Pharmacological effect - bronchodilatory.

pharmacodynamics

Glycopyrronium bromide + indacaterol - inhaled long-acting combination drugs. Its constituent glycopyrronium bromide and indacaterol cause relaxation of smooth muscles of the bronchi, mutually reinforcing the bronchodilator effect is due to the different mechanism of action.

Glycopyrronium bromide - is inhaled holinoblokator m-long action, intended for the maintenance treatment of bronchial conduction disturbances in patients with COPD. Its mechanism of action is based on blocking the bronchoconstrictor action of acetylcholine on smooth muscle cells of the airways that leads to a bronchodilatory effect. In humans identified five subtypes of muscarinic receptors (M1-5). It is known that only M1-3 subtypes involved in the physiological function of the respiratory system. Glycopyrronium bromide has 4-5 fold greater selectivity for the M1 and M3 receptor subtypes, as compared to the subtype-m2 receptors. This leads to rapid emergence of therapeutic effect after inhalation drug, as confirmed by clinical studies. Bronchodilator effect of glycopyrronium bromide inhalation after lasting longer than 24 hours. The duration of action after inhalation due to long-term maintenance of therapeutic concentrations of drug in the lungs, which is confirmed by a longer T1 / 2 PM after inhalation application in comparison with / in the introduction.

Indacaterol is a selective beta2-agonists ultradlitelnogo action (within 24 hours after a single admission). The pharmacological action of beta2-agonists, including indacaterol associated with stimulation of intracellular adenylate - an enzyme which catalyzes the conversion of ATP into cyclic 3 ', 5'-cAMP (cyclic AMP). Increasing the content of cyclic AMP leads to relaxation of smooth muscles of the bronchi. Indacaterol is almost full agonist beta2-adrenergic receptors; its stimulating effect on beta2-adrenergic receptors is 24 times stronger than at beta1-adrenergic receptors, and 20 times stronger than beta3-adrenergic receptors. After inhalation of indacaterol has a rapid and long-lasting bronchodilatory effect.

Since the density of m3 and nicotinic acetylcholine receptor beta2 adrenoceptors in the central and peripheral airways differs, beta2-agonists relax better peripheral airways, while the m-holinoblokatory have a significant effect in relation to the central airways. Thus the combination of an M3-anticholinergics and beta2-agonists promotes optimal bronchodilation throughout the system of the lower respiratory tract of man.

The effect of the combination of glycopyrronium bromide + indacaterol occurs within 5 minutes after inhalation and is maintained at a constant level for 24 hours, providing a sustained significant improvement in lung function: increased by an average of 320 in the 26th week of treatment forced expiratory volume in the first second (FEV1) ml compared with patients receiving placebo, and 110 ml compared with patients treated separately glycopyrronium bromide, indacaterol and tiotropium bromide. Also, a decrease of the lungs and residual lung volume of functional residual capacity of 350 and 380 ml (p <0.001) compared with placebo after 60 min after administration on the first day of use, and 520 and 520 ml (p <0.001) compared with placebo after 21 day of therapy, respectively. When using a combination of glycopyrronium bromide + indacaterol marked decrease in dyspnea, improved exercise tolerance. Also observed a significant reduction in the risk of COPD exacerbations (increased time to next exacerbation), reducing the need for inhaled beta2-agonists and short-acting to improve the quality of life of patients (estimated using certified questionnaire St George's Hospital).

On the basis of clinical trials it showed that the combination of indacaterol + glycopyrronium bromide and supraterapevticheskih therapeutic doses has no clinically significant effect on heart rate, QT interval length, and the concentration of potassium in serum glucose.

Electrophysiology heart

QTc interval was investigated in TQT-study (Thorough QT studies, comprehensive clinical trials QT interval) with a combination of indacaterol + glycopyrrolate and each of the components in monotherapy. Research TQT indacaterol with glycopyrrolate and showed that none of these substances had no significant effect on the corrected QT interval at therapeutic doses and supraterapevticheskih (for glycopyrrolate only supraterapevticheskaya tested dose).

In a randomized, partially-blinded, placebo and supraterapevticheskaya dose combination of indacaterol + glycopyrrolate (440 + 499.2 g) was used a positive-controlled crossover TQT-study in 84 healthy subjects. This is respectively 16 and 32 times more than the recommended single dose of the combination of indacaterol glycopyrrolate + 27.5 + 15.6 mg twice a day. Mean maximum change QTcI (individually corrected QT) from baseline was 8.7 msec in comparison with placebo (two-sided 90% CI 7.3; 10.1) at 30 minutes after dosing. Despite the fact that the ultimate effect of the combination of indacaterol + glycopyrrolate on QT interval was observed at a dose supraterapevticheskoy hardly possible clinically significant effect upon exposure to a therapeutic dose.

Pharmacokinetics

Absorption

After inhalation, plasma combination of glycopyrronium bromide + indacaterol average Tmah glycopyrronium bromide and indacaterol were 15 and 5 minutes, respectively. AUC glycopyrronium bromide in equilibrium with the combination of glycopyrronium bromide, + corresponds to that indacaterol inhalation only glycopyrronium bromide.

According to a study in vitro, which studied the efficacy of inhalation, a dose of indacaterol, delivered into the lungs with the combination of glycopyrronium bromide + indacaterol, corresponds to the application only in indacaterol 150 mcg dose. AUC indacaterol in equilibrium with the combination of indacaterol glycopyrronium bromide + meets or can be slightly lower than that indacaterol only inhalation at a dose of 150 micrograms. The absolute bioavailability of indacaterol with the combination of glycopyrronium bromide + indacaterol is from 47 to 66%, glycopyrronium bromide - about 40%.

Glycopyrronium bromide. After inhalation of glycopyrronium bromide is rapidly absorbed, reaching Cmax in the blood plasma after 5 min. About 90% of systemic exposure glycopyrronium bromide accounts for absorption in the lung and 10% of the absorption in the gastrointestinal tract. The absolute bioavailability of glycopyrronium bromide after inhalation is estimated to be 40% of the delivered dose. Against the background of regular inhalations (1 per day) Css glycopyrronium bromide is achieved within 1 week. Glycopyrronium bromide AUC at steady state was 1.4-1.7 times higher than that after the first inhalation. Cmax glycopyrronium bromide in the equilibrium state (at the recommended dose inhalation every day 1) and concentration in blood plasma glycopyrronium bromide in the end of the dosing period are 166 and 8 pg / ml, respectively.

Indacaterol. Mean Tmax indacaterol in serum is about 15 minutes after a single or repeated inhalation. serum concentration of indacaterol increased with its repeated use. Css blood achieved within 12-15 days of application. Inhalation at a dose of 60 to 480 mg (the dose delivered to the lungs) at 1 time a day for 14 days cumulation factor indacaterol estimated from the value of AUC indacaterol on the 1st and 14th and 15th days of from 2.9 to 3.8.

Absorption

After inhalation of indacaterol combination of glycopyrrolate + average Tmah indacaterol and glycopyrrolate in plasma were approximately 15 and 5 minutes, respectively.

Systemic exposure at steady state (AUC0-12, Css) and indacaterol of glycopyrrolate inhalation combination of indacaterol + glycopyrrolate (27.5 + 15.6 mg, 2 times a day) corresponds to that of indacaterol monotherapy (27.5 ug, inhalation 2 times daily) or glycopyrrolate (15.6 mg, 2 times a day), respectively.

Distribution

Glycopyrronium bromide. After the on / in the Vss glycopyrronium bromide was 83 liters and the volume of distribution in the terminal phase (Vz) - 376 liters. The apparent volume of distribution in the terminal phase after inhalation Vz / F amounted to 7310 liters, reflecting slower excretion after inhalation drugs. In vitro glycopyrronium bromide connection with human plasma proteins was 38-41% at a concentration of 1-10 ng / ml.

Indacaterol. After the on / in the Vz indacaterol was 2557 liters, indicating a significant distribution of drugs. Contact with serum proteins and in vitro human plasma is approximately 95%.

Metabolism

Glycopyrronium bromide. In vitro, it was noted that the hydroxylation glycopyrronium bromide leads to the formation of different mono- and bis-hydroxylated metabolites, and the direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). Studies in vitro have shown that CYP enzymes contribute to oxidative biotransformation glycopyrronium bromide. Hydrolysis to M9, apparently catalyzed by a family of enzymes, cholinesterase. Since studies in vitro showed no metabolism of the active substance in the lung, and M9 contributes insignificantly to the circulation (4% of the C max and AUC glycopyrronium bromide) after / in the introduction, it is assumed that M9 formed from absorbable from the gastrointestinal tract (after inhalation) fraction presistemnogo active substance by hydrolysis and / or during the initial passage through the liver. After inhalation, or on / in the M9 minimal amount only been detected in urine (≤0,5% injected dose). Glucuronic and / or sulfate conjugates glycopyrronium bromide was found in human urine following repeated inhalation in an amount of about 3% of the delivered dose.

inhibition in vitro studies demonstrated that glycopyrronium bromide has no significant ability to suppress the activity of isozymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 / 5, transporter proteins MDR1, MRP1 or the MXR, mediating removing drugs from cells, as well as carrier proteins OATR1V1, OATR1VZ, OAT1, OAT3, OST1 or OST2. Studies in vitro enzyme induction is not detected in glycopyrronium bromide clinically significant ability to induce cytochrome P450 isoenzymes, UGT1A1 enzyme and transporter proteins MDR1 and MRP2.

Indacaterol. When administered radiolabelled indacaterol unchanged indacaterol is a major component of serum and is approximately 1/3 of the daily AUC PM. Indacaterol metabolites from blood serum is determined to the greatest degree indacaterol hydroxylated derivative. In a smaller number of detected phenolic O-glucuronide of indacaterol and hydroxylated indacaterol. Furthermore, the hydroxylated derivative identified diastereomers, N-glucuronide and indacaterol products C- and N- dealkylation.

Isozyme UGT1A1 is the only isoenzyme metabolized indacaterol to the phenolic O-glucuronide. Indacaterol hydroxylation occurs mainly via isoenzyme CYP3A4. Also it found that indacaterol nizkoafinnym is a substrate for a membrane transporter molecules of P-gp.

breeding

Glycopyrronium bromide. Withdrawal glycopyrronium bromide kidneys 60-70% of total plasma clearance, 30-40% is excreted in other ways - in the bile or by metabolism. In healthy volunteers and patients with COPD, glycopyrronium treated at doses of 50 to 200 mg 1 time per day and once and repeatedly glycopyrronium mean renal clearance ranged from 17.4 to 24.4 l / h. Withdrawal glycopyrronium bromide through the kidneys due to active tubular secretion. Up to 23% of the dose is found in the urine in unchanged form. plasma concentration of glycopyrronium bromide is reduced polyphase. Average final T1 / 2 after inhalation is longer (33-57 h) than after / in (6.2 h) or oral administration (2.8 hours). Nature suggests elimination prolonged absorption in the lungs and / or penetration of glycopyrronium bromide in the systemic circulation during and after 24 h 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 of 18,8-23,3 l / h, it is obvious that indacaterol excretion through the kidneys small (about 2-5% of systemic clearance). When administered indacaterol is derived mainly through the intestine: in unchanged form (54% of the dose) and in the form of hydroxylated metabolites (23% of the dose).

Indacaterol concentration in serum decreases with mean polyphase finite T1 / 2 in the range from 45.5 to 126 hours. Effective T1 / 2, based on the calculated accumulation after repeated use indacaterol ranged from 40 to 52 hours, which is consistent with the set time reach equilibrium (12-15 days).

Indacaterol AUC at steady state increased in proportion to the delivered dose in the range of 120 to 480 micrograms.

Linearity / non-linearity

Glycopyrronium bromide. Patients with COPD AUC, and total renal excretion glycopyrronium bromide in equilibrium increased proportionally with dose in the range of 50 to 200 micrograms.

Indacaterol. Systemic exposure increases in proportion to the increase of indacaterol doses (150 to 600 g). Systemic exposure of the drug due to its absorption in the lungs, and the digestive tract.

Special patient groups

The combination of glycopyrronium bromide + indacaterol. Age, gender, and body mass does not have a significant effect on the pharmacokinetics of the combination of glycopyrronium bromide + indacaterol in patients with COPD. There was a negative correlation between the AUC and lean body mass (or weight), however, as the AUC changed slightly, and the predictive value of lean body mass is small, 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 weight are factors that influence the interindividual differences in AUC. The recommended dose of glycopyrronium bromide can be used safely at any age and at any body weight. Sex, smoking, baseline FEV1 do not have a visible effect on the AUC glycopyrronium bromide.

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

Pharmacokinetics in special patient groups

Population pharmacokinetic analysis revealed no evidence of clinically significant effect of age (from 40 to 85 years), body weight (45 to 120 kg), gender, smoking status and baseline FEV1 in the systemic exposure of indacaterol or glycopyrrolate after inhalation combination of indacaterol + glycopyrrolate .

Also not observed depending on the age, body weight, sex, smoking status and baseline FEV1 after inhalation of 2 components - indacaterol and glycopyrrolate - alone.

Patients with impaired hepatic function

The combination of glycopyrronium bromide + indacaterol. Based on the pharmacokinetic properties of each of the components used alone, the combination of glycopyrronium bromide + indacaterol can be used at the recommended dose in patients with mild to moderate hepatic impairment. Data for use in patients with severe hepatic impairment are not available.

Glycopyrronium bromide. Clinical studies have not been conducted in patients with hepatic insufficiency. Excretion of glycopyrronium bromide is mainly due to excretion by the kidneys. It is assumed that the deterioration of 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 to moderate hepatic impairment. Use in patients with severe hepatic impairment 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 alone, the combination of glycopyrronium bromide + indacaterol can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severely impaired renal function or with end-stage renal disease requiring hemodialysis, a combination of glycopyrronium bromide + indacaterol should be used only if the expected benefits outweigh the potential risk.

Glycopyrronium bromide. Kidney failure affects AUC glycopyrronium bromide. A moderate increase in AUC and 1.4 fold was observed in patients with renal insufficiency of mild to moderate severity and up to 2.2-fold in patients with severe renal insufficiency and end stage. Using population pharmacokinetic analysis led to the conclusion that patients with COPD with associated renal insufficiency of mild to moderate severity (assessed by eGFR ≥30 ml / min / 1.73 m2) glycopyrronium bromide can be used in recommended doses.

Indacaterol. Since indacaterol excreted by the kidneys to a small extent, the pharmacokinetics in patients with impaired renal function has not been studied.

Ethnicity

The combination of glycopyrronium bromide + indacaterol. No statistically significant effect of ethnicity on the AUC of both components have been identified.

Glycopyrronium bromide. No differences between ethnic subgroups have been identified.

Indacaterol. No differences between ethnic subgroups have been identified. Experience in the use of indacaterol in blacks persons is limited.

pharmacogenomics

Indacaterol. Pharmacokinetics indacaterol was prospectively studied in patients with UGT1A1 (TA) 7 / (TA) 7 genotype (low expression of UGT1A1, also referred to as 28 *) and the (TA) 6 / (TA) 6 genotype. In equilibrium, the AUC and Cmax indacaterol were 1.2 times higher for genotype [(TA) 7, (TA) 7], indicating that the insignificance of UGT1A1 genotype effect under exposure indacaterol.

Glycopyrrolate. The effects on the pharmacokinetics of pharmacogenomic variants glycopyrrolate has not been investigated.

The use of substances glycopyrronium bromide + indacaterol

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

The use of substances glycopyrronium bromide + indacaterol

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

Contraindications

Hypersensitivity to glycopyrronium bromide and indacaterol; age of 18 years (effectiveness and safety have been established); galactose intolerance, lactase deficiency or glucose-galactose malabsorption (product contains lactose).

Not recommended simultaneous reception of a drug containing other beta2-agonists long-acting, or m-long holinoblokatory action.

Restrictions apply

Despite the fact that a clinically significant effect on the cardiovascular combination of glycopyrronium bromide + indacaterol in a therapeutic dose have been identified, caution should be exercised when administered to patients with underlying cardiovascular disease (coronary heart disease (including unstable angina), acute myocardial infarction (including in history), hypertension, cardiac arrhythmias, prolongation of QTc (corrected QT> 0.44), convulsive disorders, thyrotoxicosis, diabetes, syndrome of congenital prolongation of the QT interval. It should be used with caution in combination of glycopyrronium bromide + indacaterol in patients concurrently taking drugs, lengthening the interval QT (antiarrhythmics class IA and III, tricyclic and tetracyclic antidepressants, antipsychotics, macrolides, antifungal drugs, imidazole derivatives, some antihistamines, including astemizole, terfenadine, ebastine) , drugs for general anesthesia from the group of barbiturates, as well as in patients with a history of inadequate response to beta2-agonists.

Also, caution should be exercised when using a combination of glycopyrronium bromide + indacaterol in patients with narrow-angle glaucoma, severe liver dysfunction, diseases accompanied by urinary retention, severe renal insufficiency (glomerular filtration rate below 30 mL / min / 1.73 m2), including end-stage renal failure requiring hemodialysis (a combination of glycopyrronium bromide + indacaterol should be used only if the expected benefit outweighs the potential risk).

If you have one of these diseases before taking a combination of glycopyrronium bromide + indacaterol should consult with a physician.

Pregnancy and breast-feeding

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

In a study of early and late embryogenesis in rats no effects of the combination of glycopyrronium bromide + indacaterol used in different doses, on the embryo or fetus is revealed. In rats and rabbits treated with inhalation of glycopyrronium bromide, no teratogenic effects were found. There was a low concentration of glycopyrronium bromide in plasma of umbilical cord blood after 86 minutes after a single i / m injection glycopyrronium bromide at a dose of 0.006 mg / kg for women who underwent cesarean section. Indacaterol not teratogenic in rats and rabbits at n / to the introduction. However, indacaterol has a toxic effect on the reproductive system, which was manifested in an increase in the frequency of skeletal changes in rabbits.

In the absence of clinical studies on the use of a combination of glycopyrronium bromide + data indacaterol in pregnant women, drugs can be used during pregnancy only if the intended use of the benefit to the mother outweighs the potential risk to the fetus.

It is not known whether penetrate glycopyrronium bromide and / or indacaterol passes into breast milk in women. However, indacaterol and glycopyrronium bromide (including metabolites) were detected in the milk of lactating rats. With this in mind, the combination of glycopyrronium bromide + indacaterol breastfeeding women are allowed only if the expected benefit to the mother outweighs the potential risk to the child.

Indacaterol may inhibit the birth process as a result of a relaxing effect on the smooth muscles of the uterus.

fertility

No reproductive toxicity studies, no other studies on animals do not suggest that the combination of glycopyrronium bromide + indacaterol may affect fertility in men or women.

Adequate and well-controlled studies of the combination of indacaterol + glycopyrrolate or individual components - indacaterol and glycopyrrolate - are not carried out in pregnant women. The combination of indacaterol + glycopyrrolate should be used during pregnancy only if the expected effect of therapy outweighs the potential risk to the fetus. Women should be advised to consult your doctor in case a pregnancy during treatment with the combination of indacaterol + glycopyrrolate.

It is unknown whether the combination of indacaterol + glycopyrrolate in the breast milk of women through. Because many drugs are excreted in human milk, caution should be exercised when using a combination of indacaterol + glycopyrrolate nursing mothers. Since no data is strictly controlled clinical trials of the combination of indacaterol + glycopyrrolate in nursing mothers, based on the data for the individual components should decide to discontinue breastfeeding or discontinue the use of the combination of indacaterol + glycopyrrolate, taking into account the importance of the use of her mother.

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

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

Category effects on the fetus by FDA - C.

Side effects

Adverse events (AEs) with the combination of glycopyrronium bromide + indacaterol is characterized by symptoms that are typical for m-beta2- agonists and anticholinergics used in monotherapy. Other most frequent adverse events associated with the drug (which were marked at least 3% of patients treated with a combination of glycopyrronium bromide + indacaterol and whose frequency is higher than on placebo application) relates cough and pain in the oropharynx (including pershenie in the throat).

In patients with COPD, inhalation at recommended doses of the combination of glycopyrronium bromide + indacaterol has no clinically significant systemic effects of beta2-adrenomimeticheskoe. Average heart rate changes by no more than 1 u. / Min, and the tachycardia is rare and less frequent than in the placebo treatment group. The incidence of significant QTc prolongation (> 450 ms) and hypokalemia is similar to that in the placebo treatment group.

The following are adverse events, notes with the combination of glycopyrronium bromide + indacaterol during the registration of clinical trials (duration of 6 and 12 months), the drug is used 1 time per day in patients with COPD. AEs are distributed in accordance with the frequency of occurrence. The following criteria are used to assess frequency: very common (≥1 / 10); commonly (≥1 / 100, <1/10); uncommon (≥1 / 1000, <1/100); rare (≥1 / 10,000, <1/1000); very rare (<1/10000), including isolated reports.

Infectious and parasitic diseases: very often - upper respiratory tract infection; often - nasopharyngitis, urinary tract infection, sinusitis, rhinitis.

Immune system: rarely - hypersensitivity.

On the part of metabolism and nutrition: seldom - diabetes mellitus and hyperglycemia.

Mental disorders: rarely - insomnia.

From the nervous system: often - dizziness, headache; rarely - paresthesia.

From a sight organ: seldom - glaukoma1.

From the heart: Infrequent - ischemic heart disease, atrial fibrillation, tachycardia, palpitations.

The respiratory system, organs, thoracic and mediastinal disorders: often - cough, pain in the oropharynx, sore throat; rarely - nosebleeds.

From the digestive system: often - indigestion, tooth decay; rare - dryness of the oral mucosa.

Skin and subcutaneous tissue disorders: rare - skin rash / pruritus.

On the part of the musculoskeletal system and connective tissue disorders: often - pain in the muscles and bones; rarely - muscle spasm, myalgia.

On the part of the kidney and urinary tract: rarely - obstruction of the bladder, urinary retention.

General disorders and administration in place: often - lihoradka1, chest pain; rarely - peripheral edema, fatigue.

1 New AEs observed on the background using a combination of glycopyrronium bromide and indacaterol + is not marked in the application of each of the components separately.

Against the background of glycopyrronium bromide and indacaterol monotherapy were also observed following adverse events.

The respiratory system, organs, thoracic and mediastinal disorders: rarely - paradoxical bronchospasm.

From the digestive system: often - gastroenteritis.

On the part of the musculoskeletal system and connective tissue disorders: rarely - pain in the limbs.

Description of the individual adverse drug reactions

Of the adverse events typical of m-anticholinergics, the most frequently observed dry mouth (0.6% in the use of a combination of glycopyrronium bromide, indacaterol versus + 0.3% in the placebo treatment group); At the same time, against the background of the use of a combination of glycopyrronium bromide + indacaterol it is rarely observed adverse events than treatment with glycopyrronium bromide as a monotherapy. In most cases, xerostomia has been associated with the drug and the severity was mild; dryness was not observed in the mouth severe degree.

The cough is often celebrated, but as a rule, had a mild degree.

Some serious adverse events, including ischemic heart disease and hypersensitivity reactions have been observed during treatment with indacaterol as monotherapy. Patients in the group using a combination of glycopyrronium bromide + indacaterol hypersensitivity reactions and coronary artery disease were observed with a frequency of 0.1% (0% in the placebo treatment group) and 0.4% (0.3% in the placebo treatment group), respectively.

In patients aged ≥75 years who received a combination of glycopyrronium bromide + indacaterol, urinary tract infection was observed with a frequency of 3.5% (2.8% in the placebo treatment group). Below are AEs identified among patients, according to spontaneous reports and the cases described in the literature in the post-registration period: the frequency is unknown - angioedema.

If any of the above instructions or side effects were exacerbated by any other side effects not mentioned in the instructions, you should inform your doctor.

Experience in clinical research

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

Base Safety Data + glycopyrrolate combination of indacaterol included 2654 patients with COPD who took part in two 12-week trials in lung function and a 52-week long-term safety study. A total of 712 people were treated with a combination of indacaterol glycopyrrolate + 27.5 + / 15.6 mg twice a day. Safety data presented below are based on the results of two trials of 12-week and one 52 week study.

12-week trial

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

The most common adverse events (greater than or equal to the frequency of 2% and above in comparison with placebo) were nasopharyngitis and hypertension.

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

Patients received one dose twice a day for the following variants: indacaterol combination glycopyrrolate + 27.5 g / 15.6 g; indacaterol of 27.5 g; glycopyrrolate 15.6 mcg or placebo.

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

The results are as follows: next to the side effect indicated the number of patients in whom this effect was observed (shown in brackets everywhere incidence of side effect in percentage). A semicolon shows the results obtained with the combination of indacaterol glycopyrrolate + 27.5 + 15.6 micrograms twice per day (N = 508); when applying indacaterol 27.5 micrograms twice per day (N = 511); glycopyrronium bromide when applied 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%).

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

Other adverse reactions were observed more frequently with the combination of indacaterol + glycopyrrolate than placebo, but with a frequency of less than 1%, include the following: dyspepsia, gastroenteritis, chest pain, fatigue, peripheral edema, rash / pruritus, insomnia, dizziness, urinary obstruction bladder / urinary retention, atrial fibrillation, palpitations, tachycardia.

52-week trial

In the long-term safety study

Interaction

Inhalation combined use of glycopyrronium bromide and indacaterol in equilibrium pharmacokinetics of both drugs remained unchanged.

Specific interaction studies combined glycopyrronium bromide + indacaterol with other drugs have not performed. Information on the potential interactions of combinations of glycopyrronium bromide + indacaterol is based on data on possible interactions of each of its components.

Drug interactions associated with glycopyrronium bromide

Studies in vitro have demonstrated that glycopyrronium bromide, probably does not affect the metabolism of other drugs. Inhibition of metabolism or induction of glycopyrronium bromide does not lead to significant changes in AUC of the drug. Metabolic transformation taking place with the participation of various enzymes in the removal of glycopyrronium bromide do not play a significant role.

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

m-Anticholinergics. Specific interaction studies combined glycopyrronium bromide + indacaterol with other drugs containing m-holinoblokatory not conducted. Not recommended simultaneous with drugs containing m-long holinoblokatory action.

Anticholinergic drugs. There is a possibility of an additive interaction with the simultaneous use of anticholinergic drugs. Therefore, you should avoid joint use of a combination of indacaterol + glycopyrrolate with other anticholinergic drugs, because this may lead to increased anticholinergic side effects.

Drug interactions associated with indacaterol

Beta-blockers. Because beta-blockers can weaken or inhibit the effect of the action of beta2-agonists, combination of glycopyrronium bromide + indacaterol is not recommended to be used in conjunction with beta-blockers (including eye drops) unless there are strong reasons for their joint application.

Beta-blockers. Beta-adrenoceptor antagonists and the combination of indacaterol + glycopyrrolate may affect the action of each other, while the application. Beta blockers inhibit not only the therapeutic effect of beta-agonists, but can lead to a marked bronchospasm in patients with COPD. Therefore, patients in the treatment of COPD should not normally be used beta-blockers. However, under certain circumstances, such as the prevention of myocardial infarction in the absence of acceptable alternatives to the use of beta-blockers in patients with COPD could be considered cardioselective beta blockers, although they should be used with caution.

If necessary, use both classes of drugs is preferable to use selective beta-blockers, but they should be used with caution.

Drugs prolonging the QT interval. As with other beta2-agonists, caution should be exercised when using a combination of glycopyrronium bromide + indacaterol in patients receiving MAO inhibitors, tricyclic antidepressants, or other drugs that can lengthen the QT interval, as they can enhance their effect on QT interval length. When using drugs that can lengthen the QT interval, increased risk of ventricular arrhythmias.

Sympathomimetic drugs. Concomitant use of indacaterol with sympathomimetics (both separately and as part of combination therapy) may increase the risk of adverse events. Not recommended simultaneous reception of a drug containing other beta2-agonists long-acting.

Gipokaliemicheskoe PM. The simultaneous use of methylxanthine derivatives, corticosteroids or diuretics that cause hypokalemia, hypokalemia may enhance the potential caused by beta2-agonists.

The interaction at the level of CYP3A4 and membrane transporter P-gp. It was studied the interaction of indacaterol with specific inhibitors of CYP3A4 and P-gp, such as ketoconazole, erythromycin, verapamil and ritonavir. The simultaneous use of verapamil indacaterol resulted 1.4-2-fold increase in AUC and 1.5-fold increase in Cmax. When using indacaterol with erythromycin was an increase in AUC by 1.4-1.6 times and Cmax 1.2-fold. Combination therapy with indacaterol and ketoconazole caused 2- and 1.4-fold increase in AUC and Cmax, respectively. With simultaneous use of indacaterol with ritonavir (an inhibitor of CYP3A4 and P-gp) was an increase in AUC by 1.6-1.8 times, however, Cmax remains unchanged. This increase in AUC as a result of drug interactions does not lead to a change in the safety profile.

When applied with other LC indacaterol drug interactions were observed. Studies in vitro have shown that indacaterol has negligible potential to interact with drugs on the enzymes of metabolism level or at the level of membrane transporters with the AUC, achieved in the appointment of the therapeutic dose.

Indacaterol. Studies in vitro indicated that indacaterol has little potential for drug interactions with the metabolic (by inhibition or induction of cytochrome P450 enzymes or UGT1A1 induction) in systemic exposure levels achieved in clinical practice. in vitro studies have shown that in vivo indacaterol is unlikely to significantly inhibit transport proteins such as P-gp, MRP2, BCRP, OCT1 and OCT2, MATE1 and MATE2K and indacaterol has negligible potential for induction of P-gp or MRP2.

Adrenergic drugs. If necessary, use additional adrenergic drugs for any route of administration should be used with caution, because sympathetic effects of indacaterol - a combination of indacaterol component glycopyrrolate + - can be amplified.

Nekaliysberegayuschie diuretics. ECG changes and / or hypokalemia that may result from the application of nekaliysberegayuschih diuretics (such as loop or thiazide) may dramatically worsened by beta-agonists, such as indacaterol - component combination indacaterol + glycopyrrolate - especially beta-agonist, the recommended dose is exceeded. Although the clinical significance of these effects is not known, caution is advised when used together the combination of indacaterol with glycopyrrolate + nekaliysberegayuschimi diuretics.

Overdose

COPD patients after 14 days using a combination of indacaterol + glycopyrronium bromide in doses several times higher than therapeutic, there was an increase in the incidence of ventricular arrhythmia. In general, unstable ventricular tachycardia was observed in four patients with the longest duration was 4 episodes (9 cuts).

It is expected that an overdose of a combination of glycopyrronium bromide + indacaterol is characterized by symptoms typical of an overdose of beta 2-agonists such as tachycardia, tremors, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalemia and hyperglycemia, as well as symptoms typical of an overdose of m-cholinergic antagonists such as increased IOP (accompanied by pain in the eyes, blurred vision, or redness of the eye), constipation or difficulty urinating.

Information on overdose glycopyrronium bromide. Patients with COPD, regular inhalation administration glycopyrronium bromide in a total dose of 100 or 200 mg 1 time per day for 4 weeks was well tolerated.

Acute intoxication if accidentally swallowed the capsule glycopyrronium bromide is unlikely because of the low bioavailability of glycopyrronium bromide ingestion (about 5%).

Cmax and AUC after the on / in the 150 micrograms glycopyrronium bromide in healthy volunteers were approximately 50 and 6 times higher, respectively, than the Cmax and AUC at steady state to be achieved in the application of glycopyrronium bromide inhalation at recommended doses. Signs of overdose is not detected.

Information on overdose of indacaterol. After a single application of indacaterol in COPD patients at a dose greater than the maximum therapeutic factor of 10, observed a moderate increase in heart rate, increased blood pressure, and QTc interval elongation.

Treatment. It shows the supported and symptomatic therapy. In severe cases, patients need to be hospitalized. If necessary, possible to use selective beta-blockers. Use selective beta-blockers should be cautious, only under strict medical supervision, since their use may provoke the development of bronchospasm.

Routes of administration

Inhalation.

Precautions substances glycopyrronium bromide + indacaterol

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

The combination of glycopyrronium bromide + indacaterol is intended for the maintenance treatment of patients with COPD. Due to the fact that in the general population of COPD patients significantly prevail over the age of 40 years, the appointment of drugs to patients under 40 years is required spirometric confirmation of the diagnosis of COPD.

Hypersensitivity reactions. Against the background of glycopyrronium bromide and indacaterol, glycopyrronium bromide combination of components + indacaterol, have been reported cases of immediate hypersensitivity reactions. If there are signs that the development of an allergic reaction (such as difficulty breathing or swallowing, swelling of the tongue, lips and face, hives, skin rash), a combination of glycopyrronium bromide + indacaterol you want to cancel and choose an alternative therapy.

Bronchial asthma. In the absence of data on the use of a combination of glycopyrronium bromide + indacaterol in patients with asthma, medicines should not be used for the treatment of bronchial asthma.

When using beta2-agonists long-acting for the treatment of asthma increases the risk of serious adverse events associated with asthma, including death.

Mortality from asthma

Long-acting beta2-adrenergic agonists, including indacaterol - a combination of the active ingredient indacaterol + glycopyrrolate, - increase the risk of mortality associated with asthma.

These large-scale, placebo-controlled studies in the US in patients with asthma showed that beta2-adrenoceptor agonists of long action may increase the risk of death related to asthma. There are no data to determine whether the risk of death increases with the use of drugs of this group of patients with COPD.

28-week, placebo-controlled trial in the US to evaluate the safety of other beta2-agonists long-acting (salmeterol) in patients with asthma showed that the addition of salmeterol to standard asthma therapy led to an increase in mortality associated with asthma (13 of 13176 patients additionally received salmeterol versus 3 of 13 179 patients receiving placebo; hazard ratio 4.37, 95% CI 1.25, 15.34). Astmaassotsiirovannoy Increased risk of mortality is considered to be a class-effect of long-acting beta2-agonists, including indacaterol - one of the components of the combination of indacaterol + glycopyrrolate.

No adequate studies conducted to determine whether the increased risk of mortality associated with asthma, patients with the combination of indacaterol + glycopyrrolate. Safety and efficacy of the combination of indacaterol + glycopyrrolate not established in patients with asthma. The combination of indacaterol + glycopyrrolate is not indicated for the treatment of asthma.

The aggravation of the disease, and acute episodes

Do not start the combination of glycopyrrolate + indacaterol in patients with acute worsening of COPD or potentially life-threatening attacks. The combination of indacaterol + glycopyrrolate has not been studied in patients with acute 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, ie, as emergency aid for the treatment of acute episodes of bronchospasm. The combination of indacaterol + glycopyrrolate has not been studied as a means of assistance in case of acute symptoms and higher doses should not be used for this purpose. For the relief of acute symptoms should use inhaled beta2-agonists of short action.

At the beginning of the use of a combination of indacaterol + glycopyrrolate patients who regularly took oral or inhaled beta2-agonists, short-acting (eg 4 times a day), discontinue treatment with these drugs constantly and use them only for symptomatic relief of acute respiratory symptoms. When you assign a combination of indacaterol + glycopyrrolate doctor should also prescribe inhaled beta2-agonist short action and instruct the patient how it should be used. Increasing the dose of inhaled beta2-agonist is a sign of acute illness, which requires immediate medical attention.

An exacerbation of COPD may develop acute for several hours or chronically over several days or longer. If the combination of indacaterol + glycopyrrolate longer controls symptoms of bronchoconstriction, inhaled beta2-agonists short-acting patient become less effective, or the patient needs more inhaled short-acting beta2-agonists than normal - it may be signs of acute illness. In these cases, you should immediately re-evaluate the patient and revise the scheme of treatment of COPD. Increasing the daily dose combination of indacaterol + glycopyrrolate above recommended not recommended in this situation.

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

Like other inhaled drugs containing beta 2-agonists, the combination of indacaterol + glycopyrrolate should not be used more than recommended, at higher doses than recommended, or in combination with other drugs containing beta 2-agonists, long-acting, because this may lead to an overdose. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic. Patients using a combination of indacaterol + glycopyrrolate should not use other drugs containing beta2-agonist long-acting, regardless of the cause.

Paradoxical bronchospasm. In clinical studies with the combination of glycopyrronium bromide + indacaterol no cases paradoxical bronchospasm. However, the use of other inhaled drugs were cases paradoxical bronchospasm, potentially life-threatening. In the case of paradoxical bronchospasm the combination of glycopyrronium bromide + indacaterol should be discontinued immediately and alternative therapy is appointed.

m-anticholinergic effect. In the absence of data on the use of a combination of glycopyrronium bromide + indacaterol in patients with angle-closure glaucoma in 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 halt the use of a combination of glycopyrronium bromide + indacaterol, and immediately inform your doctor if any of these signs or symptoms.

Diseases accompanied by urinary retention. In the absence of data on the use of a combination of glycopyrronium bromide + indacaterol in patients with diseases accompanied by urinary retention, caution should be exercised in this group of patients.

Urinary retention (aggravation). The combination of indacaterol + glycopyrrolate should be used with caution in patients with urinary retention. It is necessary to be attentive to the signs and symptoms of urinary retention (eg difficulty with urination, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. It is necessary to instruct patients on the immediate treatment to the doctor, if you develop any of these signs or symptoms.

Influence of beta2-agonists on the cardiovascular system. Beta2-adrenergic receptors are mainly represented in the smooth muscle of the bronchi, and the human heart contains predominantly beta1-adrenergic receptors. However, the share of beta2-adrenoceptor human heart falls from 10 to 50% of adrenoceptors. It is not clearly determined what function is performed by beta2-adrenergic receptors in the heart, but their presence in the heart suggests that even highly selective beta2-adrenoceptor agonists may have effects on the heart. Beta2-adrenergic agonists may have a clinically significant effect on the cardiovascular system, including increase in heart rate, increased blood pressure. In case of adverse events with the combination of glycopyrronium bromide + indacaterol may require discontinuation of therapy. In addition, the application of beta2-agonists the following ECG changes may occur: the flattening of the T wave, prolongation of the QT interval and depression of segment ST (however, the clinical significance of these changes has not been established). In clinical studies in the application of drugs in recommended therapeutic doses significant lengthening QT interval versus placebo were observed.

kaliopenia

In some patients, the application of beta2-agonists may experience significant hypokalemia, leading to the development of adverse events with the CCC. Reducing the concentration of potassium in serum is usually transient and do not require correction. Patients with severe COPD hypokalemia may be caused by hypoxia and concomitant therapy, which in turn may increase the likelihood of arrhythmias. In clinical studies, when the use of drugs at the recommended therapeutic doses, no clinically significant effects of hypokalemia.

Hyperglycemia. Inhalation of high doses of beta2-agonists may increase the level of glucose in the blood plasma. When applied in patients with diabetes must regularly monitor the concentration of glucose in blood plasma. In clinical studies in patients treated with drugs (at 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. No dose adjustment is required in patients aged ≥75 years.

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

Of the total number of participating in clinical studies combination indacaterol glycopyrrolate + 45% of patients were aged ≥65 years, while 11% - the age ≥75 years. There were no differences in efficacy or safety between these patients and younger subjects, as well as other reports of clinical practice. But we can not exclude a greater sensitivity of some older individuals.

Patients with impaired renal function. No dosage adjustment is required when used in patients with impaired renal function mild or moderate. In patients with severe renal impairment or end-stage, requiring dialysis, the combination of glycopyrronium bromide + indacaterol should be used at the recommended dose only if the expected benefit outweighs the potential risk.

Patients with impaired liver function. No dosage adjustment is required when used in patients with impaired liver function mild to moderate severity. Use in patients with severe hepatic impairment has not been studied.

Effects on ability to perform potentially hazardous activities that require attention and fast reactions (driving and working with moving machinery, etc.). The combination of glycopyrronium bromide + indacaterol has no or negligible influence on the ability to drive and perform potentially hazardous activities that require high concentration and speed of psychomotor reactions.