The use of high doses of glycopyrronium may lead to the development of symptoms associated with m-holinoblokiruyuschim action, and require appropriate symptomatic therapy.
In patients with COPD, regular inhaled administration of Sibri® Breezehaler® at a total dose of 100 and 200 mcg once a day for 28 days, it was well tolerated.
Acute intoxication with accidental ingestion of the Sibri capsule® Breezehaler® it is unlikely due to the low bioavailability of glycopyrronium bromide with oral administration (about 5%).
Cmax blood plasma and total systemic exposure after intravenous administration of 150 mcg of glycopyrronium bromide (equivalent to 120 mcg of glycopyrronium) in healthy volunteers were approximately 50 and 6 times higher, respectively, than Cmax in the blood plasma and the total systemic exposure in the equilibrium state, achieved with the use of the drug Sibri® Breezehaler® inhaled at the recommended doses (50 mcg 1 time per day). There were no signs of overdose.
hypersensitivity to glycopyrronium bromide or any other components that are part of the drug,
simultaneous administration with inhaled drugs containing other m-holinoblockers,
galactose intolerance, lactase deficiency, or glucose-galactose malabsorption (the drug contains lactose),
age up to 18 years.
With caution: angle-closure glaucoma, diseases accompanied by urinary retention, severe renal failure (GFR below 30 ml / min/1.73 m2), including end-stage renal failure requiring hemodialysis (Sibri drug® Breezehaler® should only be used if the expected benefit exceeds the potential risk), unstable coronary heart disease, a history of myocardial infarction, cardiac arrhythmias, prolongation of the QTc interval (QT adjusted >0.44 s).
The concomitant use of the drug with other drugs for inhalation use containing m-holinoblokatory agents has not been studied, and therefore the simultaneous use of the above drugs is contraindicated.
Simultaneous inhaled use of glycopyrronium bromide and indacaterol, beta agonist2- adrenergic receptors, does not affect the pharmacokinetics of both drugs.
Despite the fact that no clinical studies have been conducted to study drug interaction, no clinical manifestations of drug interaction have been observed in clinical practice with the simultaneous use of Sibri® Breezehaler® with other drugs that are widely used for the treatment of COPD, including beta-adrenomimetics, methylxanthines, and corticosteroids for inhaled and oral use.
In clinical studies in healthy volunteers, cimetidine, an inhibitor of organic cation transporters that affect renal clearance of glycopyrronium bromide, increased the total exposure (AUC) of glycopyrronium bromide by 22% and reduced renal clearance by 23%. Based on these indicators, no clinically significant interaction is expected with the simultaneous use of Sibri® Breezehaler® with cimetidine or other cation transporter inhibitors.
Researches in vitro showed that the drug Sibri® Breezehaler® probably does not affect the metabolism of other drugs.
Inhibition or induction of glycopyrronium bromide metabolism does not lead to significant changes in the systemic exposure of the drug.
Inhalation powder, solid capsule
Safety profile of Sibri® Breezehaler® it is characterized by symptoms associated with m-holinoblokiruyuschim action, including dryness of the oral mucosa (2.2%), while other effects from the gastrointestinal tract and signs of urinary retention were infrequent.
Adverse drug reactions (NLR) associated with local drug tolerance included pharyngeal irritation, nasopharyngitis, rhinitis, and sinusitis. In the recommended doses, the drug Sibri® Breezehaler® it does not affect blood pressure and heart rate.
Safety and tolerability of Sibri® Breezehaler® It was studied when used in 1353 patients with COPD at the recommended dose of 50 mcg once a day, of which 842 patients were treated with the drug for at least 26 weeks and 351-for at least 52 weeks.
NLR is grouped according to the classification of organs and organ systems MedDRA, listed in order of decreasing frequency of occurrence.
The following criteria were used to assess the incidence of NLR: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000), very rarely (<1/10000).
Infectious and parasitic diseases: often-nasopharyngitis, infrequently-rhinitis, cystitis.
From the side of metabolism and nutrition: infrequently-hyperglycemia.
Mental disorders: often-insomnia.
From the nervous system: often-headache, infrequently-hypesthesia.
From the heart: infrequently — atrial fibrillation, palpitations.
From the respiratory system, chest and mediastinal organs: infrequently-congestion in the paranasal sinuses, productive cough, sore throat, nosebleeds.
From the digestive system: often-dryness of the oral mucosa, gastroenteritis, infrequently-dyspepsia, dental caries.
From the skin and subcutaneous tissues: infrequently-skin rash.
From the musculoskeletal system and connective tissue: infrequently - pain in the extremities, musculoskeletal pain in the chest.
From the kidneys and urinary tract: often-urinary tract infection, infrequently-dysuria, urinary retention.
General disorders and disorders at the injection site: infrequently-fatigue, asthenia.
In a 12-month clinical trial, the following additional NLRs were identified, which were more common when using Sibri® Breezehaler® compared to placebo: nasopharyngitis (9 vs. 5.6%), vomiting (1.3 vs. 0.7%), muscle pain (1.1 vs. 0.7%), neck pain (1.3 vs. 0.7%), diabetes mellitus (0.8 vs. 0%).
The following are the NLRs identified in the course of post-registration studies and according to the literature. Since information about the NLR data was obtained by spontaneous reporting and the exact number of patients who took the drug is not determined, it is not possible to estimate the frequency of these reactions, and therefore for the NLR data it is indicated that the frequency is unknown. NLR is grouped according to the classification of organs and organ systems MedDRA, listed in descending order of importance.
On the part of the immune system: angioedema, hypersensitivity.
From the chest and mediastinal organs: paradoxical bronchospasm, dysphonia.
From the skin and subcutaneous tissues: itchy skin.
Special patient groups
In elderly patients over 75 years of age, the frequency of urinary tract infections and headaches when using Sibri® Breezehaler® It was higher than in the placebo group (3 vs. 1.5% and 2.3 vs. 0%, respectively).
If any of the described side effects worsen or the patient notices any other side effects not specified in the description, you should inform your doctor.
Maintenance therapy of bronchial conduction disorders in patients with chronic obstructive pulmonary disease.
Sibri drug® Breezehaler® - inhaled long-acting drug. Glycopyrronium bromide-m is a cholinoblocker, the mechanism of action of which is based on blocking the bronchoconstrictor action of acetylcholine on the smooth muscle cells of the respiratory tract, which leads to a bronchodilating effect. In the human body, 5 subtypes of muscarinic receptors (M1–5). It is known that only subtypes of M1–3 they are involved in the physiological function of the respiratory system. Glycopyrronium bromide, being an antagonist of muscarinic receptors, has a high affinity for the receptors of the M subtypes1–3. At the same time, glycopyrronium bromide has 4-5 times greater selectivity for M1- and M3- subtypes of receptors, compared to M2- a subtype of receptors. This leads to a rapid occurrence of the therapeutic effect after inhalation of the drug, which is confirmed by clinical studies. The duration of the drug after inhalation is due to the long-term maintenance of the therapeutic concentration of the drug in the lungs, which is confirmed by a longer T1/2 of the drug after inhaled administration compared to intravenous administration. In numerous clinical studies, it has been shown that against the background of the use of glycopyrronium bromide in patients with COPD, pulmonary function significantly improves (the assessment was carried out by measuring FEV for 1 min (FEV1): the therapeutic effect occurs within the first 5 minutes after inhalation, with a significant increase in FEV1 from the baseline values in the range of 0.091 to 0.094 l, the bronchodilating effect of glycopyrronium bromide after inhalation persists for more than 24 hours. According to clinical studies, there is no evidence of the development of tachyphylaxis to the bronchodilating effect of the drug against the background of regular use up to 52 weeks
No changes in heart rate and the duration of the QTc interval were observed during the use of Sibri® Breezehaler® at a dose of 200 mcg in patients with COPD.
Absorption. After inhalation, glycopyrronium bromide is rapidly absorbed into the systemic circulation and reaches Cmax in the blood plasma after 5 minutes. The absolute bioavailability of glycopyrronium bromide after inhalation is approximately 40%. About 90% of the systemic exposure of glycopyrronium bromide is due to absorption in the lungs and 10% - to absorption in the gastrointestinal tract. The absolute bioavailability after oral administration of glyropyrronium bromide is estimated at 5%. Against the background of regular inhalations (1 time per day), the equilibrium state of glycopyrronium bromide is reached within 1 week. Cmax glycopyrronium bromide in the equilibrium state (inhalation of 50 mcg 1 time per day) and the concentration of glycopyrronium bromide in the blood plasma immediately before taking the next dose are equal to 166 and 8 pg / ml, respectively. The steady-state urinary excretion compared to the first administration suggests that systemic accumulation is independent of the dose in the dose range of 25-200 mcg.
Distribution. After I / V introduction Vss glycopyrronium bromide was 83 L and Vd in the terminal phase (Vz) — 376 l. Apparent Vz after inhalation (Vz/F) was 7310 l, which reflects a slower elimination of the drug after inhalation. In vitro The association of glycopyrronium bromide with human plasma proteins was 38-41% at a concentration of 1-10 ng / ml. These concentrations are at least 6 times higher than those in the equilibrium state, achieved in plasma against the background of the drug at a dose of 50 mcg 1 time per day.
Metabolism. It was noted that the hydroxylation of glycopyrronium bromide leads to the formation of various mono - and bis-hydroxylated metabolites, and direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). Researches in vitro CYP isoenzymes have been shown to contribute to the oxidative biotransformation of glycopyrronium bromide. Hydrolysis to M9 appears to be catalyzed by enzymes of the cholinesterase family. Since the research in vitro No active substance metabolism was detected in the lungs, and M9 makes an insignificant contribution to the circulation (4% of Cmax and AUC of glycopyrronium bromide) after intravenous administration, it is assumed that M9 is formed from the fraction of the active substance absorbed from the gastrointestinal tract (after inhalation) by presystemic hydrolysis and/or during primary passage through the liver. After inhalation or intravenous administration, only a minimal amount of M9 was detected in the urine (<0.5% of the administered dose). Glucuronic conjugates and / or glycopyrronium bromide sulfates were detected in human urine after repeated inhalations in an amount of approximately 3% of the dose. Inhibition studies in vitro Glycopyrronium bromide was not significantly involved in the inhibition of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isoenzymes, MDR1, MRP2, or MXR transporters, and OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 transporters. Studies of enzyme induction in vitro No significant induction of glycopyrronium bromide by any of the tested cytochrome P450 isoenzymes, as well as for UGT1A1 and MDR1 and MRP2 transporters, was detected.
Output. The excretion of glycopyrronium bromide by the kidneys reaches 60-70% of the total plasma clearance, 30-40% is excreted in other ways — with bile or through metabolism. After single and repeated inhalations of glycopyrronium bromide in the range of 50 to 200 mcg once a day in healthy volunteers and patients with COPD, the average renal clearance was in the range of 17.4-24.4 l / h. Active tubular secretion contributes to the renal excretion of glycopyrronium bromide. Up to 20% of the dose taken is detected in the urine in unchanged form. The plasma concentration of glycopyrronium bromide decreases in multiphase. Average final T1/2 it is longer after the inhaled route of administration (33-57 hours) than after intravenous administration (6.2 hours) and oral administration (2.8 hours). 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. In patients with COPD, the systemic exposure, as well as the total urinary excretion of glycopyrronium bromide in the steady state, increased proportionally to the dose in the range from 50 to 200 mcg.
Special patient groups
Population pharmacokinetic analysis of data in patients with COPD revealed that body weight and age are factors influencing inter-individual differences in the systemic exposure of the drug. Sibri drug® Breezehaler® at a dose of 50 mcg once a day, it can be safely used in any age group and at any body weight.
Gender, smoking, and baseline FEV1 values have no apparent effect on systemic exposure to glycopyrronium bromide.
Impaired liver function. No clinical studies have been conducted in patients with impaired liver function. The elimination of glycopyrronium bromide occurs mainly due to renal excretion. It is assumed that the deterioration of hepatic metabolism of glycopyrronium bromide will not lead to a clinically significant increase in systemic exposure.
Impaired renal function. The systemic exposure of glycopyrronium bromide depends on the state of renal function. A moderate increase in total systemic exposure (AUC) of up to 1.4 times was observed in patients with mild to moderate renal impairment and up to 2.2 times in patients with severe or end-stage renal impairment. The use of population pharmacokinetic analysis allowed us to conclude that in patients with COPD and impaired renal function of mild to moderate severity (estimated by GFR ≥30 ml / min/1.73 m2) Sibri drug® Breezehaler® it can be used in the recommended doses.
Enurev Breezhaler
Glycopyrronium
Inhaled.
The drug is a capsule with powder for inhalation, which should only be used for inhalation through the mouth using a special device for inhalation Brezhaler®, which is included in the package. 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.
Recommended dose of Sibri® Breezehaler® it is 50 mcg (content of 1 capsule) 1 time per day. Inhalation of the drug is carried out daily 1 time a day at the same time. If you miss an inhalation, the next dose should be inhaled as soon as possible. Patients should be instructed not to use more than 1 dose of the drug (50 mcg) per day.
Before starting the use of the drug Sibri® Breezehaler® patients should be instructed about the proper use of the inhaler.
If there is no improvement in respiratory function, make sure that the patient is using the drug correctly. The drug should be inhaled, not swallowed.
Special patient groups
Kidney failure. In patients with mild to moderate renal impairment, the recommended dose of Sibri may be used® Breezehaler®. In patients with severe renal impairment or end-stage renal disease requiring hemodialysis, the drug Sibri® Breezehaler® it should be used at the recommended dose only if the intended benefit exceeds the potential risk.
Liver failure. No special clinical studies have been conducted in patients with impaired liver function. Sibri drug® Breezehaler® it is mainly excreted by renal excretion, so a significant increase in exposure in patients with impaired liver function is not expected. In patients with impaired liver function, the recommended dose of Sibri may be used® Breezehaler®.
Old age. Sibri drug® Breezehaler® it can be used at the recommended dose in patients 75 years and older.
Instructions for using the inhaler
Each package of Sibri preparation® Breezehaler® contains:
- 1 inhalation device-Breezehaler®,
- blisters with capsules with powder for inhalation.
Capsules with powder for inhalation should not be taken orally.
Brezhaler Inhalation Device® The contents of the package are intended for use only with capsules of the drug.
For the inhalation of capsules in the package, only the Brezhaler inhalation device is used®.
Do not use the capsules of the drug with any other inhalation device and, in turn, do not use the Brezhaler® for the inhalation of other drugs.
After 30 days of using Breezehaler® it should be discarded.
How to use an inhaler
1. Remove the cover.
2. Open the Breezehaler®: to open the inhaler, hold it firmly by the base and tilt the mouthpiece.
3. Prepare the capsule: separate 1 bl. from the blister pack, tear off the esl by perforation, take 1 bl. and remove the protective film from it to release the capsule, do not squeeze the capsule through the protective film.
4. Remove the capsule: The capsules should be stored in the blister and removed only immediately before use, wipe your hands dry and remove the capsule from the blister, do not swallow the capsule.
5. Insert the capsule into the Breezehaler®: put the capsule in the capsule chamber, never put the capsule directly into the mouthpiece.
6. Close the Breezehaler®: close the inhaler tightly, when it closes completely, there should be a click.
7. Pierce the capsule: hold the Breezehaler® in a vertical position, so that the mouthpiece is directed upwards, simultaneously press both buttons to the end, when piercing the capsule, a click should be heard, do not press the buttons to pierce the capsule more than 1 time.
8. Fully release the buttons of the Brezhaler inhaler® on both sides.
9. Exhale, before you insert the mouthpiece into your mouth, make a full exhalation, never blow into the mouthpiece.
10. Inhale the drug: hold the Breezehaler® in your hand, so that the buttons are on the left and right (and not on the top and bottom), insert the mouthpiece of the Brezhaler inhaler® in the mouth and press the lips tightly around it, take a quick, even, as deep as possible breath, do not press the buttons of the piercing device.
11. Pay attention. When inhaled through the inhaler, the characteristic rattling sound created by the rotation of the capsule in the chamber and the spray of the powder should be heard. The patient may feel the sweet taste of the drug in the mouth. If the rattling sound is not heard, it may mean that the capsule is stuck in the inhaler chamber. In this case, open the inhaler and gently release the capsule by tapping on the base of the device. To release the capsule, do not press the buttons to pierce the capsule. Repeat steps 9 and 10 if necessary.
12. Hold your breath: if you hear a characteristic sound when inhaling, hold your breath as long as possible (so as not to experience unpleasant sensations) and at the same time remove the mouthpiece from your mouth, then exhale. Open a Breezehaler® and see if there's any powder left in the capsule. If there is any powder left in the capsule, close the Breezehaler® and repeat steps 9-12. Most people can empty a capsule in 1 or 2 inhalations. Some people have a cough for a short time after inhaling the drug, you should not worry about it. If there is no powder left in the capsule, it means that the patient has received the full dose of the drug.
13. Remove the capsule: after taking the daily dose of Sibri® Breezehaler® after removing the mouthpiece, remove the empty capsule by tapping on the inhaler and discard it. Close the mouthpiece of the Brezhaler inhaler® and close the Breezehaler® with a lid. Do not store capsules in the Brezhaler inhaler®.
Important information
Do not swallow capsules with powder for inhalation.
Use only Breezehaler®, which is in the package.
Capsules should be stored in a blister and removed immediately before use.
Never put the capsule in the mouthpiece of the Brezhaler inhaler®.
Do not press the piercing device more than 1 time.
Never blow into the mouthpiece of a Breezehaler inhaler®.
Always pierce the capsule before inhaling.
Do not wash the Breezehaler®. Keep it dry (see fig. How to clean a Breezehaler®).
Do not disassemble the Breezehaler®.
When starting a new package of the drug, always use a new Breezehaler to inhale the capsules®, which is in the package.
Do not store capsules in the Brezhaler inhaler®.
Always store blisters with capsules and Breezehaler® in a dry place.
Additional information
In very rare cases, a small amount of the contents of the capsules may enter the mouth.
Do not worry when inhaling or swallowing the drug.
If the capsule is punctured more than 1 time, the risk of its breaking increases.
How to clean a Breezehaler®
Cleaning The Breezehaler® 1 time per week. Wipe the mouthpiece inside and out with a clean, dry cloth. Never use water to clean the Brezhaler inhaler®. Keep it dry.
