Ultibro brizhaler kapslys powder for inhalation 50mkg + 110mkg N30 + breezheiler
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Active ingredients
Glycopyrronium bromide + indacaterol
Composition
1 caps glycopyrronium base 50 mcg, which corresponds to glycopyrronium bromide 63 mcg indacaterol base 110 mcg, which corresponds to indacaterol maleate 143 mcg. Excipients: lactose monohydrate - 24.
Pharmacological effect
Combined long-acting bronchodilatory drug for inhalation use. Its constituent glycopyrronium bromide and indacaterol cause relaxation of the smooth muscles of the bronchi, mutually reinforcing the bronchodilatory effect due to a different mechanism of action. Glycopyrronium bromide is a long-acting inhalation m-cholinoblocker for the maintenance treatment of bronchial conduction disorders in patients with COPD. The mechanism of its action is based on blocking the bronchoconstrictor effect of acetylcholine on the smooth muscle cells of the respiratory tract, which leads to a bronchodilatory effect. In humans, 5 subtypes of muscarinic receptors (M1-5) were detected. It is known that only the M1-3 subtypes are involved in the physiological function of the respiratory system. Glycopyrronium bromide has a 4-5 times greater selectivity for receptors of the M1 and M3 subtypes, as compared to receptors of the M2 mark. This leads to the rapid emergence of a therapeutic effect after inhalation of the drug, which is confirmed by clinical studies. The bronchodilating effect of glycopyrronium bromide is maintained for more than 24 hours after inhalation. The duration of action of the drug after inhalation is due to the prolonged maintenance of the therapeutic concentration of the drug in the lungs, as evidenced by the longer T1 / 2 of the drug after inhalation, compared with iv administration. Indacaterol is a selective beta2-adrenomimetic of ultra-long-acting (for 24 hours in 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 (cAMP). Increasing the content of cAMP leads to relaxation of the smooth muscles of the bronchi. Indacaterol is a nearly complete 2-adrenoreceptor agonist; The stimulating effect of the drug on 2-adrenergic receptors is 24 times stronger than on 1-adrenergic receptors, and 20 times stronger than on 3-adrenergic receptors. After inhalation, indacaterol has a fast and long-lasting bronchodilatory effect.Since the density of M3-cholinergic receptors and 2-adrenergic receptors in the central and peripheral airways is different, beta2-adrenomimetics better relax the peripheral airways, while m-anticholinergic blockers have a more significant effect on the central airways. Thus, the combination of m3-holinoblokator and beta2-adrenergic mimics contributes to the optimal expansion of the bronchi throughout the human respiratory system. The effect of Ultibro Brizhaler comes already 5 minutes after inhalation and remains at a constant level for 24 hours, providing a lasting significant improvement in lung function: at week 26 of therapy, the forced expiratory volume increased by 320 ml on average for the first second (FEV1) compared to patients receiving placebo and 110 ml compared with patients receiving glycopyrronium bromide alone, indacaterol or tiotropium bromide. There was also a decrease in functional residual lung capacity and residual lung volume by 350 ml and 380 ml (less than 0.001) compared with placebo 60 minutes after administration on the first day of use and by 520 ml and 520 ml (smaller than 0.001) compared to placebo after 21 days of therapy, respectively. With the use of the drug, there is a decrease in shortness of breath, an improvement in exercise tolerance. There is also a significant reduction in the risk of COPD exacerbations (an increase in time until the next exacerbation), a decrease in the need for short-acting inhaled beta2-adrenomimetics and an improvement in the quality of life of patients (assessed using a certified questionnaire at St. George's Hospital). Based on the conducted clinical studies, it was shown that the drug Ultibro Brizhaler in therapeutic and supra-therapeutic doses does not have a clinically significant effect on the heart rate, the length of the QT interval, the potassium content and the concentration of glucose in the blood serum.
Pharmacokinetics
Absorption: Ultibro Brizhaler: After inhalation of Ultibro Brizhaler, the average time to reach Cmax of glycopyrronium bromide and indacaterol in the blood plasma was 15 min and 5 min, respectively. AUC of glycopyrronium bromide in an equilibrium state when using the drug Ultibro Bryzhaler corresponds to that during inhalation of glycopyrronium bromide separately.According to an in vitro study, in which the effectiveness of inhalation was studied, the dose of indacaterol delivered to the lungs when using the drug Ultibro Bryzhaler corresponds to the use of indacaterol separately at a dose of 150 mcg. AUC of indacaterol in the equilibrium state with the use of the drug Ultibro Brizhaler corresponds or may be slightly lower than inhalation of indacaterol alone at a dose of 150 mg. The absolute bioavailability of indacaterol when using the drug Ultibro Brizhaler is from 47% to 66%, glycopyrronium bromide - about 40%. Glycopyrronium bromide: After inhalation, glycopyrronium is rapidly absorbed and reaches Cmax in the blood plasma after 5 min. About 90% of the systemic exposure of glycopyrronium bromide occurs to absorption in the lungs, and 10% to absorption in the gastrointestinal tract. The absolute bioavailability of glycopyrronium bromide after inhalation is estimated at 40% of the delivered dose. Against the background of regular inhalations (1 time / day), Css glycopyrronium bromide is reached within 1 week. AUC of glycopyrronium bromide in the equilibrium state was 1.4–1.7 times higher than after the first inhalation. Cmax of glycopyrronium bromide in the equilibrium state (during inhalation at the recommended dose of 1 time / day) and the concentration of glycopyrronium bromide in the blood plasma at the end of the dosing period are 166 pg / ml and 8 pg / ml, respectively. Indacaterol: The average time to Cmax of indacaterol in serum is about 15 minutes after a single or repeated inhalation. The concentration of indacaterol in the serum increases with repeated use of the drug. Css substances in the blood is achieved within 12-15 days of the drug. With inhalation of the drug in a dose of 60 to 480 mcg (dose delivered to the lungs) with a frequency of 1 time / day for 14 days, the coefficient of cumulation of indacaterol, estimated by the AUC value of the drug on the 1st and 14th or 15th days, ranges from 2.9 to 3.8. Glycopyrronium bromide distribution After iv administration, the volume of distribution in the equilibrium state (Vss) of glycopyrronium bromide was 83 l, the volume of distribution in the terminal phase (Vz) was 376 l. The apparent volume of distribution in the terminal phase after inhalation (Vz / F) was 7310 liters, which reflects a slower elimination of the drug after inhalation. In vitro, the binding of glycopyrronium bromide to human plasma proteins is 38-41% at a concentration of 1-10 ng / ml. Indacaterol After intravenous injection, Vz of indacaterol was 2557 l, which indicates a significant distribution of the drug. Binding to human plasma proteins in vitro is approximately 95%.Metabolism: Glycopyrronium bromide: In vitro, it was noted that 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 cholinesterase enzymes. Since In vitro studies have not revealed metabolism of the active substance in the lungs, and M9 makes a minor contribution to the circulation (4% of Cmax and AUC glycopyrronium bromide) after intravenous administration, it is assumed that M9 is formed from the fraction of the active substance absorbed from the gastrointestinal tract by presystemic hydrolysis and / or "first pass" through the liver. After inhalation or iv administration, only a minimal amount of M9 was detected in the urine (less than 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 inhibit the activity of the isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 / 5, MDR1, MRP1 or MXR transport proteins, as well as other, they can be used, but they can also be used, as to be used by the article, and it should be used in the case of the study, in particular, it should be used in the study, but it should be used in the study, but it should be used in the study, but it can also be used in the study. also OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2 carrier proteins. In vitro enzyme induction studies in glycopyrronium bromide did not reveal a clinically significant ability to induce cytochrome P450 isoenzymes, UGT1A1 enzyme, and MDR1 and MRP2 carrier proteins. Indacaterol: When administered labeled with a radioactive isotope of indacaterol, unchanged indacaterol is the main component of the serum and is approximately 1/3 of the daily AUC of the drug. Of the metabolites of indacaterol in the serum to the greatest extent determined hydroxidated derivative of indacaterol. In smaller quantities, phenolic O-glucuronide indacaterol and hydroxylated indacaterol are found. In addition, diastereomers of the hydroxylated derivative, indacaterol N-glucuronide and C- and N-dealkylation products are detected. The UGT1A1 isoenzyme is the only isoenzyme metabolizing indacaterol to phenolic O-glucuronide. Hydroxylation of indacaterol occurs mainly with the isoenzyme CYP3A4.It is also established that indacaterol is a low affinity substrate for the membrane carrier of P-glycoprotein molecules (P-gp). Excretion of glycopyrronium bromide The excretion of glycopyrronium by the bromide by the kidneys reaches 60-70% of the total plasma clearance, 30-40% is excreted by other means - with bile or through metabolism. In healthy volunteers and patients with COPD who received glycopyrronium in doses of 50 to 200 mcg 1 time / day once and repeatedly, the average renal clearance of glycopyrronium ranged from 17.4 to 24.4 l / h. The excretion of glycopyrronium bromide through the kidneys is due to active tubular secretion. Up to 23% of the dose is detected in the urine unchanged. The concentration of glycopyrronium bromide in the blood plasma decreases multiphase. The average 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 the 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. The average renal clearance of indacaterol was 0.46-1.2 l / h. Given that the serum clearance of indacaterol is 18.8-23.3 l / h, it is obvious that the drug excretion through the kidneys is insignificant (approximately 2-5% of systemic clearance). When ingestion, indacaterol was eliminated mainly through the intestines: unchanged (54% of the dose) and in the form of hydroxylated metabolites (23% of the dose). Serum indacaterol concentration decreases multiphase with an average final T1 / 2 in the range from 45.5 to 126 h. Effective T1 / 2, calculated on the basis of indacaterol cumulation after repeated use, ranged from 40 to 52 h, which is consistent with the established time to reach equilibrium states (12-15 days). The equilibrium AUC of indacaterol increased in proportion to the delivered dose in the range from 120 μg to 480 μg. Linearity / non-linearity of glycopyrronium bromide In patients with COPD, AUC, as well as the total excretion of glycopyrronium bromide by the kidneys in an equilibrium state, increased proportionally to the dose in the range from 50 μg to 200 μg. Indacaterol: Systemic exposure to indacaterol increases in proportion to the dose increase (from 150 to 600 μg). Systemic exposure of the drug due to its absorption in the lungs and in the digestive tract.Pharmacokinetics in special groups of patients: Ultibro Brizhaler: Age, sex and body weight do not have a significant effect on the pharmacokinetics of Ultibro Brizhaler in patients with COPD. A negative correlation was found between AUC and lean body mass (or body weight), however, since the AUC did not change much and the predictive value of lean body mass was 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 of Ultibro Bryzhaler. Based on the pharmacokinetic properties of each of the components used separately, Ultibro Bryzhaler can be used in the recommended dose for patients with mild or moderately impaired liver function. Data on the use of the drug in patients with severely impaired liver function are not available. Based on the pharmacokinetic properties of each of the components used separately, Ultibro Bryzhaler can be used in the recommended dose for patients with impaired renal function of mild to moderate severity. In patients with severely impaired renal function or end-stage chronic renal failure (CRF) requiring hemodialysis, Ultibro Bryzhaler should be used only if the expected benefit outweighs the possible risk. There is no statistically significant effect of ethnicity on the AUC of both components. Glycopyrronium bromide: Age and body weight are factors affecting interindividual differences in the AUC of a drug. The recommended dose of glycopyrronium bromide can be safely applied in any age group and for any body weight. Gender, smoking, and baseline FEV1 do not have a visible effect on the AUC of glycopyrronium bromide. Clinical studies in patients with liver failure have not been conducted. Excretion of glycopyrronium bromide occurs mainly due to excretion by the kidneys. It is assumed that the deterioration of glycopyrronium bromide metabolism in the liver will not lead to a clinically significant increase in AUC. Renal failure affects the AUC of glycopyrronium bromide. 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 in patients with COPD with concomitant renal insufficiency of mild and moderate severity (estimated by GFR> 30 ml / min / 1.73 m2), glycopyrronium bromide can be used in recommended doses. No differences between ethnic subgroups were found. Indacaterol: Age (adult patients up to 88 years old), gender and body weight (32-168 kg) do not affect the pharmacokinetics of indacaterol in patients with COPD. The pharmacokinetics of indacaterol did not change significantly in patients with mild or moderately impaired liver function. The use of the drug in patients with severely impaired liver function has not been studied. Since indacaterol is excreted by the kidneys to a small extent, the pharmacokinetics of the drug in patients with impaired renal function has not been studied. No differences between ethnic subgroups were found. Experience with the use of the drug in persons of the Negroid race is limited.
Indications
- long-term maintenance therapy of bronchial obstruction in patients with chronic obstructive pulmonary disease, which alleviates the symptoms and reduces the number of exacerbations.
Contraindications
- hypersensitivity to glycopyrronium bromide, indacaterol or any other components that make up the drug - age up to 18 years (efficacy and safety not established) - galactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose). Concurrent use with drugs containing other long-acting beta2-adrenomimetics or long-acting m-cholinoblockers is not recommended. With caution Although there was no clinically significant effect on the cardiovascular system of Ultibro Bryzhaler at the therapeutic dose, care should be taken when prescribing it to patients with concomitant cardiovascular diseases (coronary artery disease (including unstable angina), acute myocardial infarction (including history), arterial hypertension, cardiac arrhythmias, prolongation of the QTc interval (QT corrected> 0.44 s)), convulsive disorders, thyrotoxicosis, diabetes mellitus, and dennogo lengthening QT interval.It is necessary to use the drug Ultibro Brizhaler with caution in patients who are simultaneously taking drugs that prolong the QT interval (antiarrhythmic drugs IA and Class III, tricyclic and tetracyclic antidepressants, neuroleptics, macrolide antibiotics, 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 an inadequate response to the action of beta2-adrenum. homimetics. You should also be careful when using the drug in patients with angle-closure glaucoma, severe liver dysfunction, diseases accompanied by urinary retention, severe renal failure (GFR below 30 ml / min / 1.73 m2), including end-stage renal failure requiring hemodialysis ( Ultibro Brizhaler should be used only if the expected benefit outweighs the potential risk).
Use during pregnancy and lactation
Data on the use of the drug Ultibro Brizhaler in pregnant women is not available. Data on the use of glycopyrronium bromide or indacaterol in pregnant women are also not available. In the study of early and late embryogenesis in rats, no effects of Ultibro Bryzhaler, used in different doses, on the embryo or fetus were revealed. In rats and rabbits treated with inhaled glycopyrronium bromide, no teratogenic effect was detected. A low concentration of glycopyrronium bromide in cord blood plasma was noted 86 minutes after a single intramuscular injection of glycopyrronium bromide at a dose of 0.006 mg / kg in women undergoing caesarean section. Indacaterol did not have a teratogenic effect in rats and rabbits when s / c administration. However, indacaterol had a toxic effect on the reproductive system, which was manifested in an increase in the frequency of skeletal changes in rabbits. Due to the lack of clinical data on the use of the drug Ultibro Brizhaler in pregnant women, the drug can be used during pregnancy only if the intended use of the drug for the mother outweighs the potential risk to the fetus. Indacaterol may slow down the process of childbirth due to the relaxing effect on the smooth muscles of the uterus.It is not known whether glycopyrronium bromide and / or indacaterol is excreted in 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 the drug Ultibro Brizhaler in breastfeeding women is allowed only if the intended benefit to the mother outweighs the possible risk to the baby. Neither reproductive toxicity studies nor other animal studies suggest that the drug may affect fertility in men or women.
Dosage and administration
The drug is a capsule with powder for inhalation, which should be used only for inhalation through the mouth using a special device for inhalation (Brizhaler), included in the kit. The drug can not be taken orally. Capsules with powder for inhalation should be stored in a blister and removed from it immediately before use. The recommended dose of Ultibro Brizhaler is 110 mcg + 50 mcg (contents of 1 capsule) 1 time / day. Inhalation of the drug is carried out daily at the same time. If a dose is missed, it should be taken as soon as possible. You should not take more than 1 dose of the drug per day. When prescribing the drug Ultibro Brizhaler patient should be instructed on the proper use of the device for inhalation. In the absence of an improvement in respiratory function, you should ensure that the patient is using the drug correctly. The drug should be inhaled, not swallowed. Dose adjustment of the drug in patients aged 75 years is not required. In patients with impaired mild or moderate renal function, dose adjustment is not required. In patients with severe renal failure or terminal stage requiring hemodialysis, Ultibro Bryzhaler should be used at the recommended dose only if the intended benefit outweighs the potential risk. In patients with impaired liver function of mild and moderate severity, no dose adjustment is required. The use of the drug in patients with severe violations of the liver has not been studied. Instructions for use of the device for inhalation Each package of the drug Ultibro Brizhaler contains one device for inhalation (brizhaler) and blisters with capsules with powder for inhalation. Capsules with powder for inhalation should not be taken orally. A device for inhalation in the package is intended for use only with the capsules of the drug.For the inhalation of capsules that are in the package, only the bricaler is used. Do not use the capsules of the drug with any other device for inhalation and, in turn, should not use the brizhaler for inhalation of other drugs. After 30 days of use, the brichaler should be discarded. Instructions for use of the device for inhalation 1. Remove the cap. 2. Open the device for inhalation, for which you should firmly take it by the base and tilt the mouthpiece. 3. Separate one blister from the blister pack, tearing it off by perforation. Take one blister and remove the protective film from it to release the capsule. 4. Wipe hands dry and remove the capsule from the blister. Do not swallow the capsule. 5. Place the capsule in the capsule chamber. Do not put the capsule directly into the mouthpiece. 6. Tightly close the brichaler. When it closes to the end, it should click. 7. Keep the bree-chaler in a vertical position with the mouthpiece pointing upwards. Simultaneously push all buttons to the end. When piercing the capsule should be heard click. Do not press the buttons to pierce the capsule more than once. 8. Fully loosen the buttons on the brighter on both sides. 9. Before you insert the mouthpiece into your mouth, you should take a full breath. Do not blow into the mouthpiece. 10. Put the mouthpiece of the brizhalera into the mouth and tightly squeeze the lips around it. Holding the bree-chaler with your hand, take a quick, uniform, maximum deep breath. Do not press the buttons of the piercing device. 11. When the patient inhales through the inhalation device, a characteristic rattling sound created by rotating the capsule in the chamber and spraying the powder should be heard. The patient can feel the sweet taste of the drug in the mouth. If the rattling sound is not audible, it may mean that the capsule is stuck in the brizhalera chamber. In this case, open the brichaler and gently release the capsule by tapping the base of the device. To release the capsule, do not press the buttons to pierce the capsule. If necessary, repeat steps 9 and 10. 12. If the patient heard a characteristic sound when inhaled, you should hold your breath as long as possible (so as not to experience any unpleasant sensations), and at the same time remove the mouthpiece from the mouth. After that, exhale.Then you should open the brichaler and see if there is any powder remaining in the capsule. If a powder remains in the capsule, it is necessary to close the brighter and repeat steps 9-12. Most people can empty the capsule in 1 or 2 inhalations. Some people have a cough for a short time after the drug is inhaled. If a cough occurs, do not worry. If no powder remains in the capsule, it means that the patient received a full dose of the drug. 13. After the daily dose of Ultibro Brizhaler is taken, reject the mouthpiece, remove the empty capsule, tapping the device for inhalation, and discard it. Lower the mouthpiece of the briquhaler and close it with a lid. Do not store capsules in the breezegamer. Memo for the patient Do not ingest capsules with powder for inhalation. It is necessary to use only the brizhaler which is in packaging. Capsules should be stored in a blister and removed immediately before use. You should never put the capsule in the mouthpiece holder. Do not press the piercing device more than once. You should never blow into the mouthpiece of the brighaler. You should always pierce the capsule before inhalation. Do not wash the brichaler, you must keep it dry. Do not disassemble the brizhaler. When starting a new package of drugs, for inhalation of the capsules, you should always use a new brizhaler, which is in the package. Do not store capsules in the breezegamer. It is always necessary to store blisters with capsules and a brizhaler in a dry place. Additional Information In very rare cases, a small amount of capsule contents may get into the mouth. The patient should not be worried if he inhaled the contents of the capsules or swallowed them. If the patient has punctured the capsule more than once, the risk of breaking it increases. How to clean the brizhaler It is necessary to clean the brizhaler 1 time per week. The mouthpiece is wiped inside and out with a clean, dry cloth. You should never use water to clean the briqualera, you must keep it dry.
Side effects
Undesirable effects when using the drug Ultibro Brizhaler are characterized by symptoms typical for m-anticholinergics and beta2-adrenergic mimetic drugs used in monotherapy.Other common adverse events associated with this drug (which were observed in at least 3% of patients taking Ultibro Bryzhaler, and whose frequency was higher than during placebo) include cough and oropharyngeal pain (including in the throat). In patients with COPD during inhalation at recommended doses, the drug does not have a clinically significant systemic beta2-adrenomimetic action. The average heart rate did not change by more than 1 beats per minute, and tachycardia developed rarely and with less frequency than in the placebo group. The incidence of significant lengthening of the QTc interval (> 450 ms) and hypokalemia was similar to that in the placebo group. The following are undesirable effects observed during the use of the drug during registration clinical trials (lasting 6 and 12 months), the drug was used 1 time / day in patients with COPD. The adverse events are distributed according to the frequency of occurrence. The following criteria were used to estimate the frequency: very often (1/10); often (1/100, less than 1/10); infrequently (1/1000, less than 1/100); rarely (1/10 000, less than 1/100); very rarely (less than 1/10 000), including individual messages. Infectious and parasitic diseases: very often - an infection of the upper respiratory tract; often - nasopharyngitis, urinary tract infection, sinusitis, rhinitis. On the part of the immune system: infrequently - hypersensitivity. Metabolism: infrequently - diabetes mellitus and hyperglycemia. Mental disorders: infrequently - insomnia. The nervous system: often - dizziness, headache; infrequently - paresthesia. On the part of the organ of vision: infrequently - glaucoma1. Since the cardiovascular system: infrequently - ischemic heart disease, atrial fibrillation, tachycardia, palpitations. On the part of the respiratory system: often - cough, pain in the oropharynx, sore throat; infrequently - nosebleeds. On the part of the digestive system: often - dyspepsia, dental caries; infrequently - dryness of the oral mucosa. On the part of the skin and subcutaneous tissues: infrequently - rash, pruritus. From the musculoskeletal system: often - pain in muscles and bones; infrequently - muscle spasm, myalgia. On the part of the urinary system: infrequently - bladder obstruction, urinary retention.Others: often - fever1, chest pain; infrequently - peripheral edema, fatigue. 1 - new undesirable effects, observed on the background of the use of the combined drug Ultibro Brizhaler and not observed when using each of the components separately. Against the background of the use of glycopyrronium bromide or indacaterol as monotherapy, the following adverse events were also noted. On the part of the respiratory system: infrequently - paradoxical bronchospasm. On the part of the digestive system: often - gastroenteritis. From the musculoskeletal system: infrequently - pain in the limbs. Description of individual adverse reactions Of the adverse events typical of m-cholinoblockers, dry mouth was most often observed (0.6% in the group of the drug Ultibro Bryzhaler versus 0.3% in the placebo group); at the same time, against the background of the use of the drug Ultibro Brizhaler, this undesirable phenomenon was noted less frequently than against the background of the use of glycopyrronium bromide as monotherapy. In most cases, dry mouth was associated with the use of the drug and was mild; dry mouth severe severity was not observed. Cough was noted often, but, as a rule, was mild. Some serious adverse events, including hypersensitivity reactions and coronary artery disease, have been noted as adverse events with indacaterol as monotherapy. In patients in the group using the drug Ultibro Brizhaler, hypersensitivity reactions and CHD were observed with a frequency of 0.1%, (0% in the placebo group) and 0.4% (0.3% in the placebo group), respectively. In patients aged 75 years who took Ultibro Bryzhaler, urinary tract infection was observed with a frequency of 3.5% (2.8% in the placebo group). Adverse events detected in patients according to spontaneous reports and cases described in the literature in the post-registration period: the frequency is unknown - angioedema. If any of the side effects indicated in the instructions are aggravated or any other side effects that are not indicated in the instructions are noted, the patient should inform the physician.
Overdose
Symptoms In patients with COPD, after 14 days of treatment with Ultibro Bryzhaler in doses several times higher than therapeutic, an increase in the incidence of ventricular extrasystoles was observed. In general, unstable ventricular tachycardia was observed in 4 patients, while the duration of the longest episode was 4 seconds (9 contractions). It is expected that an overdose of the drug Ultibro Brizhaler characterized by symptoms typical of an overdose of beta2-agonists such as tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalemia and hyperglycemia, as well as symptoms, typical for an overdose of m-anticholinergics, such as an increase in intraocular pressure (accompanying