Composition, form of production and packaging
Capsules with powder for inhalation, solid, size 3, transparent, colorless, labeled "Novartis logo" black on the lid and "IGP110.50" in blue ink over the double blue stripe on the body; the contents of the capsules are white or almost white powder.
1 caps.
glycopyrronium base 50 Ојg,
which corresponds to glycopyrronium bromide 63 Ојg
indacaterol base of 110 Ојg,
which corresponds to indacaterol maleate 143 Ојg
Excipients: lactose monohydrate - 24.757 mg, magnesium stearate - 37 mcg.
The composition of the capsule: hypromellose - 45.7 mg, water - 2.7 mg, carrageenan - 420 Ојg, sodium chloride - 180 Ојg.
Composition of black ink: shellac, iron dye oxide black (E172), propylene glycol, potassium hydroxide, water.
Composition of blue ink: shellac, indigocarmine (E132), propylene glycol, titanium dioxide.
6 pcs. - blisters of PA / Al / PVC and aluminum foil (1) complete with device for inhalation (breezhaler) - packs of cardboard.
6 pcs. - blisters of PA / Al / PVC and aluminum foil (2) complete with device for inhalation (breezhaler) - packs of cardboard.
6 pcs. - blisters of PA / Al / PVC and aluminum foil (5) complete with device for inhalation (breeze) - packs of cardboard.
Multi-pack.
6 pcs. - blisters from PA / Al / PVC and aluminum foil (1) - packs cardboard (25) complete with device for inhalation (breezhaler) - boxes.
6 pcs. - blisters from PA / Al / PVC and aluminum foil (2) - packs of cardboard (4) complete with device for inhalation (breezhaler) - boxes.
6 pcs. - blisters of PA / Al / PVC and aluminum foil (5) - packs of cardboard (3) complete with device for inhalation (breezhaler) - boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Combined long-acting bronchodilator for inhalation. 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, 5 subtypes of muscarinic receptors (M 1-5 ) were detected. It is known that only subtypes M 1-3 are involved in the physiological function of the respiratory system. Glycopyrronium bromide has a 4-5-fold greater selectivity for the receptors of the subtypes M 1 and M 3 , compared with the M 2 receptors. This leads to a rapid occurrence of therapeutic effect after inhalation of the drug, which is confirmed by clinical studies.
The bronchodilating effect of glycopyrronium bromide after inhalation persists for more than 24 hours. The duration of action of the drug after inhalation is due to long-term maintenance of the therapeutic concentration of the drug in the lungs, which is confirmed by a longer T 1/2 of the drug after inhalation, compared with the intravenous administration.
Indacaterol - selective beta 2 -adrenomimetic ultra-long-acting (within 24 hours with a single dose). The pharmacological action of beta 2 -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). An increase in the content of cAMP results in relaxation of the smooth muscles of the bronchi. Is indacaterol an almost complete agonist? 2- adrenoreceptors; stimulating effect of the drug on? 2- adrenoreceptors are 24 times stronger than on? 1- adrenoreceptors, and 20 times stronger than on? 3- adrenoreceptors. After inhalation, indacaterol has a rapid and prolonged bronchodilator effect.
Since the density of M 3 -cholinoreceptors and? 2- adrenoreceptors in the central and peripheral airways is different, beta 2 -adrenomimetics better relax the peripheral respiratory tract, while m-cholinoblockers have a more significant effect on the central airway. Thus, the combination of m 3 -cholinoblocker and beta 2 -adrenomimetic promotes optimal bronchial dilatation throughout the lower respiratory system of a person.
The effect of the drug UltibroВ® Brizhaler В® comes only 5 minutes after inhalation and remains constant for 24 hours, providing a persistent significant improvement in lung function: at 26 weeks of therapy, an increase in the volume of forced expiration in the first second (FEV1) by an average of 320 ml by compared with patients receiving placebo and 110 ml compared with patients receiving separately glycopyrronium bromide, indacaterol or tiotropium bromide. There was also a decrease in the functional residual capacity of the lungs and the residual volume of the lungs by 350 ml and 380 ml (p <0.001) compared with placebo 60 min after administration on the first day of use and at 520 ml and 520 ml (p <0.001) compared to placebo after 21 days of therapy, respectively. When using the drug, there is a decrease in dyspnea, an improvement in the tolerability of physical exertion. There is also a significant reduction 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 beta 2 -adrenomimetics, and an improvement in the quality of life of patients (evaluation using the St. George Hospital certified questionnaire).
Based on the clinical studies, it was shown that the drug UltibroВ® BreezhalerВ® in therapeutic and supra-therapeutic doses had no clinically significant effect on heart rate, QT interval length, potassium content, and serum glucose concentration.
PHARMACOKINETICS
Suction
UltibroВ® BrizhalerВ®
After the inhalation of the drug UltibroВ® BrizhalerВ®, the mean time to reach C max glycopyrronium bromide and indacaterol in blood plasma was 15 min and 5 min, respectively. AUC glycopyrronium bromide in equilibrium with the use of the drug UltibroВ® Breezhaler В® corresponds to that with the inhalation of glycopyrronium bromide alone.
According to the in vitro study, in which the effectiveness of inhalation was studied, the dose of indacaterol delivered to the lungs with the use of the drug UltibroВ® BreezhalerВ® corresponds to the use of indacaterol alone at a dose of 150 Ојg. AUC of indacaterol in equilibrium with the use of the drug UltibroВ® BreezhalerВ® meets or may be slightly lower than that of inhaled indacaterol alone at a dose of 150 Ојg. Absolute bioavailability of indacaterol with the use of the drug ULTRIBRICAВ® BrizhalerВ® ranges from 47% to 66%, glycopyrronium bromide is about 40%.
Glycopyrronium bromide
After inhalation of glycopyrronium, the bromide is rapidly absorbed and reaches C max in blood plasma after 5 minutes. About 90% of the systemic exposure of glycopyrronium bromide is accounted for by absorption in the lungs, and 10% by absorption in the digestive tract. Absolute bioavailability of glycopyrronium bromide after inhalation is estimated at 40% of the delivered dose. Against the background of regular inhalations (1 time / day) C ss 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. Cmax glycopyrronium bromide in equilibrium (with inhalation at the recommended dose 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 mean time to reach C max of indacaterol in the blood serum is about 15 minutes after a single or repeated inhalation. The concentration of indacaterol in the blood serum increases with repeated use of the drug. C ss of the substance in the blood is reached within 12-15 days of application of the drug. When inhaled drug at a dose of 60 to 480 mcg (dose delivered to the lungs) at a frequency of 1 times / day for 14 days, the cumulation index of indacaterol, estimated by the AUC value of the drug on the 1 st and 14 th or 15 th days, is from 2.9 to 3.8.
Distribution
Glycopyrronium bromide
After IV introduction, the volume of distribution in the equilibrium state (V ss ) of glycopyrronium bromide was 83 liters, the volume of distribution in the terminal phase (V z ) was 376 liters. Apparent volume of distribution in the terminal phase after inhalation (V z / F) was 7310 liters, which reflects a slower elimination of the drug after inhalation. In vitro binding of glycopyrronium bromide to human plasma proteins is 38-41% at a concentration of 1-10 ng / ml.
Indacaterol
After intravenous administration of V z indacaterol was 2557 liters, indicating a significant distribution of the drug. The binding to human plasma proteins in vitro is approximately 95%.
Metabolism
Glycopyrronium bromide
In vitro, it has been observed 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 enzymes of the cholinesterase family. Because In vitro studies did not reveal the metabolism of the active substance in the lungs, and M9 contributes insignificantly to the circulation (4% of C max and AUC glycopyrronium bromide) after iv administration, it is suggested that M9 is formed from the fraction of the active (from the digestive) absorbed substance by pre-systemic hydrolysis and / or by "first passage" through the liver. After inhalation or with / in administration, only a minimal amount of M9 was detected in the 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 also OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2 carrier proteins. 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 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 help of the CYP3A4 isoenzyme. It was also found that indacaterol is a low-affinity substrate for the membrane transporter of P-glycoprotein molecules (P-gp).
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 Ојg 1 time / day 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 intravenous (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. The renal clearance of indacaterol averaged 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 excretion of the drug through the kidneys is insignificant (approximately 2-5% of the system clearance). When ingesting indacaterol was excreted mainly through the intestine: in unchanged form (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 T 1/2 value in the range from 45.5 to 126 hours. The effective T 1/2 , calculated on the basis of accumulation of indacaterol after repeated application, varied from 40 to 52 hours, which was consistent with the established time achievement of the equilibrium state (12-15 days).
AUC of indacaterol in the equilibrium state increased in proportion to the delivered dose in the range of 120 Ојg to 480 Ојg.
Linearity / nonlinearity
Glycopyrronium bromide
In patients with COPD, AUC, as well as total excretion by the kidneys of glycopyrronium bromide in the equilibrium state, increased in proportion to the dose in the range of 50 Ојg to 200 Ојg.
Indacaterol
The systemic exposure of indacaterol increases in proportion to the increase in dose (from 150 to 600 Ојg). Systemic exposure of the drug is due to its absorption in both the lungs and the gastrointestinal tract.
Pharmacokinetics in specific patient groups
UltibroВ® BrizhalerВ®
Age, sex and body weight do not significantly affect the pharmacokinetics of the drug ULTRIBRIC BREZHALER В® 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 FEV 1 do not have a visible effect on the AUC of the drug UltibroВ® BreezhalerВ®.
Based on the pharmacokinetic properties of each of the components used individually, the drug UltibroВ® BrizhalerВ® can be used in the recommended dose to patients with impaired hepatic and mild liver function. Data on the use of the drug in patients with severe impairment of liver function are absent.
Based on the pharmacokinetic properties of each of the components used individually, the drug UltibroВ® BreezhalerВ® can be used at the recommended dose to patients with impaired renal function of mild to moderate severity. In patients with severe renal dysfunction or with the terminal stage of chronic renal failure (CRF) requiring hemodialysis, the drug UltibroВ® Brizhaler В® should be used only if the expected benefit exceeds the possible risk.
There was no statistically significant effect of ethnicity on the AUC of both components.
Glycopyrronium bromide
Age and body weight are factors that influence interindividual differences in the AUC of the drug. The recommended dose of glycopyrronium bromide can be safely used in any age group and at any body weight. Sex, smoking, and baseline FEV 1 do not have a visible effect on AUC glycopyrronium bromide.
Clinical studies in patients with hepatic insufficiency have not been conducted. Elimination of glycopyrronium bromide is mainly due to 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.
Renal failure 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 in patients with COPD with concomitant renal failure of mild and moderate severity (estimated by GFR> 30 ml / min / 1.73 m 2 ), glycopyrronium bromide can be used in recommended doses.
There were no differences between ethnic subgroups.
Indacaterol
Age (adult patients under 88 years), sex 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 impaired liver function of mild and moderate severity. The use of the drug in patients with severe impairment of 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.
There were no differences between ethnic subgroups. The experience of using the drug in people of Negroid race is limited.
INDICATIONS
- long-term maintenance therapy of bronchial obstruction in patients with chronic obstructive pulmonary disease, alleviates the symptoms and reduces the number of exacerbations.
DOSING MODE
The preparation is a capsule with powder for inhalation, which should be used only for inhalation through the mouth with a special device for inhalation (brizhaler) provided. The drug should not be taken orally.
Capsules for inhalation with powder in the blister should be stored and retrieved therefrom immediately prior to use.
The recommended dose Ultibro В® Brizhaler В® is 110 mg + 50 mg (contents of 1 capsule) 1 time / day. Inhalation of the drug is administered daily at the same time. In case of skipping the dose it should be taken as quickly as possible. You should not take more than 1 dose per day.
When administering the drug Ultibro В® Brizhaler В® patient should be instructed on the proper use of the device for inhalation.
If there is no improvement of respiratory function, should be ascertained whether the patient uses the drug correctly. The drug should be inhaled rather than swallowed.
It does not require dose adjustment of the drug in patients aged ≥ 75 years .
In patients with impaired renal function or moderate does not require dose adjustment. In patients with severe renal impairment or end-stage , requiring dialysis , drug Ultibro В® Brizhaler В® should be used at the recommended dose only if the expected benefit outweighs the potential risk.
In patients with impaired liver mild to moderate severity function is required dose correction. Use of the drug in patients with severe liverIt has not been studied.
Instructions for use of the device for inhalation
Each pack preparation Ultibro В® Brizhaler В® comprises one device for inhalation (brizhaler) blisters and capsules with powder for inhalation.
Capsules with powder for inhalation can not be taken orally.
Inhalation device, which is in the package is approved for use only in conjunction with the capsules of the drug.
For inhalation capsules in the package, is used only brizhaler.
Do not use the drug capsules with any other device for inhalation and, in turn, should not be used brizhaler for inhalation of other drugs.
After 30 days of use brizhaler should be discarded.
Instructions for use of the device for inhalation
1. Remove the cover.
2. Open the inhaler device, which should be strong to take his base and tilt the mouthpiece.
3. Separate one blister from the blister package by tearing it along the perforations. Take one blister and remove the protection film to release the capsule.
4. Wipe hands dry and remove the capsule from the blister. You should not swallow a capsule.
5. Place the capsule in the capsule chamber. Do not place a capsule directly into the mouthpiece.
6. Tightly close brizhaler. When it is closed until the end, should hear a click.
7. It should retain brizhaler upright so that the die is facing upward. At the same time press until the end of the two buttons. When piercing the capsule has clicked. Do not press the buttons to pierce the capsule more than once.
8. Fully release brizhalera buttons on both sides.
9. Before you insert the mouthpiece into your mouth, you should make a full exhalation. You should not blow into the mouthpiece.
10. Attach the mouthpiece brizhalera in the mouth and tightly compressed lips around it. Keeping brizhaler hand, make a quick uniform as possible a deep breath. Do not press the buttons on the lancing device.
11. When the patient inhales through the device for inhalation must go off characteristic rattling noise generated by the rotation of the capsule in the chamber and the powder spray. The patient may feel the sweet taste of the drug. If you do not hear a rattling sound, it could mean that the capsule is stuck in brizhalera chamber. In this case, open brizhaler 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. steps 9 and 10 should be repeated if necessary.
12. If the patient has inhaled heard a distinctive sound, you need to hold your breath as long as possible (so as not to feel discomfort), and at the same time pull the mouthpiece out of his mouth. After that exhale. Then open brizhaler and see whether remains of the capsule powder. If the powder left in the capsule must be closed brizhaler and repeat steps 9-12. Most people can empty the capsule for 1 or 2 inhalations. In some people for a short time after inhalation of the drug observed coughing. If there is a cough, do not worry. If the powder in the capsule is left, it means that the patient has received the full dose of the drug.
13. After the accepted daily dose Ultibro В® Brizhaler В®It implies rejecting the mouthpiece, remove the empty capsule by tapping on the device for inhalation, and throw it away. Lower mouthpiece brizhalera and close the lid. Do not store the capsules in brizhalere.
Instructions for the patient
should not swallow capsules with powder for inhalation.
Use only brizhaler in the package.
The capsules should be stored in the blister and removing immediately before use.
You should never put a capsule in the mouthpiece brizhalera.
Do not press on the lancing device more than once.
You should never blow into the mouthpiece brizhalera.
Always pierce the capsule before inhalation.
You should not wash brizhaler, you must keep it dry.
Do not disassemble brizhaler.
Starting a new product package, for inhalation capsules should always use new brizhaler in the package.
Do not store the capsules in brizhalere.
Always keep the blisters with capsules and brizhaler in a dry place.
Additional Information
In very rare cases, a small amount of the contents of the capsules can get into the mouth. The patient should not have to worry if it is inhaled or swallowed the contents of the capsules.
If the patient is punctured the capsule more than once, increasing the risk of breakage.
How to clean brizhaler
should be cleaned brizhaler 1 time per week. Mouthpiece wipe the outside and inside a clean, dry cloth. Never use water for cleaning brizhalera necessary to keep it dry.
SIDE EFFECT
Adverse effects when using the drug Ultibro В® Brizhaler В® characterized by symptoms typical m-anticholinergics and beta 2 -adrenomimetikov used in monotherapy. Other most frequent adverse events associated with the drug (which occurred at least 3% of patients taking the drug Ultibro В® Brizhaler В® , and whose frequency is higher than on placebo application) relates cough and pain in the oropharynx ( including sore throat).
COPD patients inhalation formulation at the recommended doses has no clinically significant systemic beta 2-adrenomimeticheskogo action. Average heart rate changes by no more than 1 u. / Min, and rarely developed tachycardia and with less frequency than in the placebo group application. The incidence of significant lengthening QT interval c (> 450 ms) and hypokalemia was similar to that in the placebo treatment group.
Below are undesirable phenomena noted when using the drug during clinical trials registration (of 6 and 12 months), the preparation was applied 1 time / day in patients with COPD. Adverse events are distributed in accordance with the frequency of occurrence. The following criteria are used to assess the frequency: very common (1/10?); often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000), including individual messages.
Infectious and parasitic diseases: very often - upper respiratory tract infection; often - nasopharyngitis, urinary tract infection, sinusitis, rhinitis.
From the immune system: infrequently - hypersensitivity.
On the part of metabolism: rarely - diabetes and hyperglycemia.
Psychiatric disorders: rarely - insomnia.
From the nervous system: often - dizziness, headache; rarely - paresthesia.
From a sight organ: seldom - Glaucoma 1 .
Cardio-vascular system: rarely - ischemic heart disease, atrial fibrillation, tachycardia, palpitations.
The respiratory system: often - cough, pain in the oropharynx, sore throat; rarely - nosebleeds.
From the digestive system: often - indigestion, tooth decay; infrequently - dryness of the oral mucosa.
Skin and subcutaneous tissue disorders:seldom - rash, itchy skin.
On the part of the musculoskeletal system: often - pain in the muscles and bones; rarely - muscle spasm, myalgia.
From the urinary system: rarely - obstruction of the bladder, urinary retention.
Other: often - fever 1 , chest pain; rarely - peripheral edema, fatigue.
1 - new adverse events noted in the background of a combined preparation Ultibro В® Brizhaler В® and is not marked in the application of each component separately.
Against the background of glycopyrronium bromide or indacaterol as monotherapy as observed following undesirable phenomenon.
The respiratory system: rarely - paradoxical bronchospasm.
From the digestive system: often - gastroenteritis.
On the part of the musculoskeletal system: rarely - pain in the limbs.
The description of adverse drug reactions
Of undesirable phenomena typical m-holinoblokatorov most frequently observed xerostomia (0.6% in the group of the drug Ultibro В® Brizhaler В® vs. 0.3% in the placebo treatment group); However, against the background of the drug Ultibro В® Brizhaler В®this adverse event was noted less frequently than on the background of glycopyrronium bromide as a monotherapy. In most cases, xerostomia has been associated with the use of the drug and the severity was mild; dry mouth, severe manifestation was not observed.
Coughing was noted frequently, but usually had a mild degree. Some serious adverse effects, including hypersensitivity reactions, and coronary artery disease were noted as adverse events during treatment with indacaterol monotherapy. The patients in the drug group Ultibro В® Brizhaler В® hypersensitivity reactions and CHD 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 Ultibro ® Brizhaler ® , urinary tract infections are occurring at a frequency of 3.5% (2.8% in the placebo treatment group).
Adverse events were identified in 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 these instructions are compounded side effects or any other observed adverse effects, not defined in the instruction, the patient should inform the physician.
CONTRAINDICATIONS
- increased sensitivity to glycopyrronium bromide, indacaterol or any other components forming part of the formulation;
- age under 18 years (effectiveness and safety not established);
- galactose intolerance, lactase deficiency or glucose-galactose malabsorption (formulation contains lactose).
Not recommended simultaneous with medicinal preparations containing other beta 2 -adrenomimetiki m long acting or long-acting-holinoblokatory.
Carefully
Despite the fact that clinically significant effect on the cardiovascular system preparation Ultibro В® Brizhaler В® at a therapeutic dose is not revealed, caution should be exercised when administered to patients with underlying heart disease (CHD (including unstable angina), acute myocardial infarction (including history), hypertension, cardiac arrhythmias, lengthening the interval QT c (corrected QT> 0.44)), convulsive disorders, thyrotoxicosis, diabetes, syndrome of congenital udli neniya QT interval.
Should be used with caution preparation Ultibro В® Brizhaler В®patients receiving both drugs, lengthening the interval QT (antiarrhythmics IA and Class III, tricyclic and tetracyclic antidepressants, antipsychotic drugs, macrolide antibiotics, antifungals, 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 beta 2 -adrenomimetikov.
It should also be cautious when using the drug in patients with narrow-angle glaucoma, severe liver dysfunction, diseases accompanied by urinary retention, renal failure severe (GFR below 30 ml / min / 1.73 m 2), Including end-stage renal disease requiring hemodialysis (Preparation Ultibro В® Brizhaler В® should be used only if the expected benefit outweighs the potential risk).
PREGNANCY AND LACTATION
Information about the use of the drug Ultibro В® Brizhaler В® in pregnant women are not available. Data on the use in pregnant glycopyrronium bromide and indacaterol also absent.
In the study of early and late embryogenesis in rats no drug effects Ultibro В® Brizhaler В®Used in different doses, on the embryo or fetus is revealed. In rats and rabbits treated with inhalation of glycopyrronium bromide, teratogenic effects have been detected. There was a low concentration of glycopyrronium bromide in cord blood plasma after 86 minutes after a single i / m glycopyrronium bromide injection at a dose of 0.006 mg / kg women who underwent caesarean section. Indacaterol not teratogenic in rats or rabbits by n / k the introduction. However, indacaterol has a toxic effect on the reproductive system, which manifested itself in an increase in the frequency of skeletal changes in rabbits.
In absence of clinical data on the application of the drug Ultibro В® Brizhaler В®pregnant women, the drug can be used during pregnancy only if the intended use of the benefit to the mother outweighs the potential risk to the fetus.
Indacaterol may inhibit the birth process as a result of a relaxing effect on the smooth muscles of the uterus.
It is unknown whether glycopyrronium bromide allocated and / or indacaterol with breast milk in women. However, indacaterol and glycopyrronium bromide (including metabolites) were detected in the milk of lactating rats. With this in mind, the use of the drug Ultibro В® Brizhaler В® in lactating women is allowed only if the expected benefit to the mother outweighs the potential risk to the child.
No reproductive toxicity studies, no other studies on animals do not suggest that the drug may affect fertility in males or females.
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution must be exercised when using the drug in patients with diseases accompanied by urinary retention,
