Sibri Brizhaler - instructions for use, dose, side effects, contraindications

Active substanceGlycopyrronium bromideGlycopyrronium bromide

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Sybri® Brizhaler®

capsulespowder d / inhal.

Novartis Pharma AG Switzerland

Dosage form: & nbspcapsules with powder for inhalation

Composition:

active substance: glycopyrronium base - 50 μg (equivalent to 0.063 mg glycopyrronium bromide);

Excipients: lactose monohydrate - 24.9 mg, magnesium stearate - 0.037 mg.

Capsule shell: hypromellose - 45.59 mg, water - 2.70 mg, carrageenan - 0.42 mg, sodium chloride - 0.18 mg, dye sunset yellow (El 10), 0.12 mg.

The composition of black ink includes: shellac, iron oxide, black oxide, propylene glycol, sodium hydroxide.

Description:

Capsules 50 μg: Solid capsules No. 3 with a transparent lid and an orange-colored body, marked "" under a black stripe on the lid and an inscription "GPL50" black ink above the black stripe on the body.

Pharmacotherapeutic group:m-holinoblokator

ATX: & nbsp

R.03.B.B.06 Glycopyrronium bromide

Pharmacodynamics:

The drug Sibri Breezhaler inhalation is a long-acting drug. Glycopyrronium bromide - (m-holinoblokator), mechanism whose action is based on blocking the bronchoconstrictive the action of acetylcholine on the smooth muscle cells of the respiratory tract, which leads to a bronchodilating effect.In the human body, five subtypes of muscarinic receptors (M1-5).

It is known that only subtypes M1-3 are involved in the physiological function of the respiratory system. Glycopyrronium bromide, being antagonist of muscarinic receptors, possesses

high affinity for the receptors of the M1-3 subtype. Wherein glycopyrronium bromide has a 4-5-fold greater selectivity for M1 and M3 receptor subtype, compared to the M2 receptor subtype. This leads to a rapid occurrence of a therapeutic effect after inhalation of the drug, which is confirmed by clinical studies. The duration 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 half-life of the drug after inhalation, compared with intravenous administration. In numerous clinical studies, it has been shown that the pulmonary function significantly improves with the use of glycopyrronium bromide in patients with chronic obstructive pulmonary disease (COPD) (the evaluation was carried out by changing the volume of forced expiration in 1 min (FEV1)): the therapeutic effect occurs during the first 5 minutes after inhalation,with a significant increase in FEV1 from baseline in the range of 0.091 L 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 a background of regular use up to 52 weeks.

There were no changes in the heart rate (heart rate) and the duration of the QTc interval with the use of the Sibri® Brizhaler® preparation at a dose of 200 μg in patients with COPD.

Pharmacokinetics:

Absorption

After inhalation glycopyrronium bromide quickly absorbed into the systemic bloodstream and reaches the maximum concentration in the blood plasma (Cmax) after 5 minutes. Absolute bioavailability of glycopyrronium bromide after inhalation is approximately 40%. About 90% of the systemic exposure of glycopyrronium bromide occurs in absorption in the lungs, and 10% in absorption in the gastrointestinal tract (GIT). Absolute bioavailability after oral administration of gliropyrronium 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.The maximum concentration of glycopyrronium bromide in the equilibrium state (inhalation 50 μg once a day) and the concentration of glycopyrronium bromide in blood plasma immediately before taking the next dose are 166 pg / ml and 8 pg / ml, respectively. Urinary excretion in the equilibrium state compared with the first administration suggests that systemic cumulation does not depend on the dose in the dose range of 25-200 μg.

Distribution

After intravenous administration, the volume of distribution in the equilibrium state (Vss) of glycopyrronium bromide was 83 liters and the volume of distribution in the terminal phase (Vz) was 376 liters. Apparent volume of distribution in the terminal phase after inhalation (Vz / F) was 7310 liters, 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 equilibrium, achieved in plasma against the background of the drug at a dose of 50 μg 1 time per day.

Metabolism

It was noted that the hydroxylation of glycopyrronium bromide results in the formation. 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 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 were found in human urine after repeated inhalation in an amount of about 3% of the dose. In vitro inhibition studies demonstrated , what glycopyrronium bromide did not take significant part in inhibiting the isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 / 5, MDR1, MRP2 or MXR transporter, and the transports OATP1B1, OATP1B3, OAT1, OAT3, OST1 or OST2.

Studies in vitro enzyme induction showed no significant induction of glycopyrronium bromide of any of the cytochrome P450 isozymes tested, as well as for UGT1A1 and transporters MDR1 and MRP2.

Excretion

Excretion glycopyrronium bromide kidney reaches 60-70% of the total plasma clearance, 30-40% is excreted in other ways - with bile or by metabolism. Following single and repeated inhalation glycopyrronium bromide in a range from 50 to 200 mg 1 time per day to healthy volunteers and patients with COPD, mean renal clearance was in the range 17.4-24.4 l / h.Active tubular secretion contributes to the excretion of glycopyrronium bromide by the kidneys. Up to 20% of the accepted dose is found in the urine in unchanged form. The plasma concentration of glycopyrronium bromide decreases multiphase. The mean final half-life is longer after the inhalation route of administration (33-57 h) than after intravenous administration (6.2 h) and 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.

In patients with COPD, systemic exposure, as well as total urinary excretion of glycopyrronium bromide in the equilibrium state, increased in proportion to the dose in the range of 50 μg to 200 μg.

Use in special patient groups. Population pharmacokinetic analysis of data in patients with COPD revealed that body weight and age are factors that influence interindividual differences in the systemic exposure of the drug. The drug Sybri * Brizhaler ® in a dose of 50 mcg once a day can

It is safe to apply in any age group and with any body weight.

Sex, smoking and baseline FEV1, do not have a visible effect on the systemic exposure of glycopyrronium bromide.

Patients with impaired hepatic function

Clinical studies in patients with impaired liver function were not performed.

Elimination of glycopyrronium bromide is mainly due to

excreted by the kidneys. It is assumed that the deterioration of the hepatic metabolism of glycopyrronium bromide will not result in a clinically significant increase in systemic exposure.

Patients with impaired renal function

Systemic exposure of glycopyrronium bromide depends on the state of kidney function. A modest increase in total systemic exposure (AUC) up to 1.4 times was observed in patients with mild to moderate renal dysfunction and up to 2.2 times in patients with impaired renal function or a terminal stage of kidney disease. The use of population pharmacokinetic analysis led to the conclusion that in patients with COPD and mild to moderate renal dysfunction filtration GFR> 30 ml / min / 1.73 m2) preparation Sibri® Brizhaler® can be used in recommended doses.

Indications:

Supportive therapy of bronchial conduction disorders in patients with chronic obstructive pulmonary disease.

Contraindications:

Hypersensitivity to glycopyrronium bromide or any other components that make up the drug.
Age to 18 years.
Simultaneous reception with inhaled drugs containing other m-holinoblokatory.
Galactose intolerance, lactase deficiency or glucose-galactose malabsorption (formulation contains lactose).

Carefully:

Closed-angle glaucoma, diseases accompanied by urinary retention, severe renal failure (GFR below 30 mL / min / 1.73 m2), including the terminal stage of renal failure requiring hemodialysis (Sibri® Brizhaler® should only be used if the expected benefit exceeds potential risk); unstable ischemic heart disease (IHD), myocardial infarction in history, heart rhythm disturbances, lengthening of the interval QTc (Q-T corrected> 0.44 s).

Pregnancy and lactation:

In preclinical studies, the drug was shown to have no teratogenic effect after inhalation.Due to the lack of clinical data on the use of the Sibri® Brizhaler® preparation in pregnant women, the drug can be used during pregnancy only if the intended use of the drug for the patient exceeds the potential risk to the fetus. It is not known whether glycopyrronium bromide in human milk. The use of the Sibri® Brizhaler® in breastfeeding should be considered only if the benefit to the mother exceeds any potential risk to the infant. Neither reproductive toxicity studies nor other animal studies suggest that the drug may affect fertility in men or women.

Dosing and Administration:

Only for inhalation use!

The preparation is a capsule with powder for inhalation, which should be used only for inhalations through the mouth with the help of a special device for inhalation Bryshaler®, which is included in the package. The drug should not be taken orally. Capsules with powder for inhalation should be stored in a blister and extracted from it immediately before use. The recommended dose of Sibri® Brizhaler® is 50 μg (1 capsule) once a day. Inhalation of the drug is carried out daily once a day at the same time. In case of missed inhalation, the next dose should be taken as soon as possible. Patients should be instructed not to take more than 1 dose of the drug (50 micrograms) per day.

Before using Sibri® Breezhaler® patients should be instructed about the proper use of the inhaler.

If there is no improvement in the function of breathing, whether the patient is using the drug correctly. The drug should be inhaled, but not swallowed.

Use in patients with renal insufficiency

In patients with impaired renal function of mild to moderate severity, the recommended dose of Sibri® Breezhaler® can be used. In patients with severe renal dysfunction or terminal stage of kidney disease requiring hemodialysis, the Sibri® Brizhaler® drug should be used at the recommended dose only if the intended benefit exceeds the potential risk.

Use in patients with hepatic impairment

Special clinical studies in patients with impaired liver function were not performed. The drug Sibri® Broshaler® is excreted primarily 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® Brizhaler® can be used.

Use in elderly patients

The drug Sybry® Breezhalerv can be used at the recommended dose in patients aged 75 years and older.

Side effects:

Safety profile of the preparation Sybri Brizhaler is characterized by symptoms, associated with m-cholin-blocking action, including dry mucosa of the oral cavity (2.2%), while Other effects on the part of the gastrointestinal tract and signs retention of urination was infrequent.

Unwanted drug reactions (NLR) associated with local tolerability drug, included pharyngeal irritation, nasopharyngitis, rhinitis and sinusitis. AT recommended doses of the drug Sybri Brizhaler does not affect blood pressure (BP) and heart rate.

Safety and tolerability of the drug Sybri Bieshaler was investigated at use in 1353 patients with COPD in recommended dose of 50 mcg once a day, of which 842 patients were treated for less than 26 weeks and 351 - not less than 52 weeks.

NLR are grouped according to the classification of organs and systems of organs MedDRA, are listed in order of decreasing frequency of occurrence.

The following criteria were used to estimate the frequency of occurrence 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.

Disorders from the metabolism and nutrition: infrequently - hyperglycemia.

Mental disorders: often - Insomnia.

Disturbances from the nervous system: often - headache; infrequently - hypoesthesia.

Disorders from the heart: infrequently - atrial fibrillation, palpitation.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - congestion in the paranasal sinuses, productive cough, irritation of the pharynx, nosebleeds.

Disorders from the digestive system: often - dryness of the oral mucosa, gastroenteritis; infrequently - Dyspepsia, dental caries.

Disturbances from the skin and subcutaneous tissues: infrequently - skin rash.

Disturbances from musculoskeletal and connective tissue: infrequent - Pain in the extremities, musculoskeletal pain in the chest area.

Infringements from kidneys and urinary tract: often - urinary tract infection; infrequently - dysuria, urinary retention.

General disorders and disorders at the site of administration: infrequently - fatigue, asthenia.

In a 12-month clinical trial, the following additional NLRs were detected, which were more common with the Sibri Bischaler drug compared with placebo: nasopharyngitis (9.0% versus 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%).

Below are listed NLRs, identified during post-registration studies and according to the literature. Since the data are reported voluntarily from a population of undetermined size, it is not possible to determine their frequency (frequency is unknown).

NLR are grouped according to the classification of organs and systems of organs MedDRA, are listed in decreasing order of importance.

Disorders from the immune system system: angioedema, hypersensitivity.

Disturbances from the organs of the thorax and mediastinum: paradoxical bronchoconstriction.

Disturbances from the skin and subcutaneous tissues: itching.

Special patient groups In elderly patients over the age of 75 years, the incidence of urinary tract infections and headache with Sibri Brizhaler was higher than in the placebo group (3.0% vs. 1.5% and 2.3% vs. 0%, respectively).

If any of the side effects indicated in the instruction are aggravated, or you noticed any other side effects refer to the instructions of the doctor.

Overdose:

The use of high doses of glycopyrronone can lead to the development of symptoms associated with m-holinoblocking action, and require appropriate symptomatic therapy.

In patients with COPD, a regular inhalation of the Sibri preparation "Brizhaler * in a total dose of 100 and 200 μg once a day for 28 days was well tolerated.

Acute intoxication with accidental ingestion of the capsule of the drug Sybri Brizhaler is unlikely due to low bioavailability of glycopyrroic bromide after oral administration (about 5%).The maximum plasma concentration and total systemic exposure after intravenous administration of 150 μg of glycopyrroic bromide (equivalent to 120 μg of glycopyrroic) in healthy volunteers was approximately 50 and 6 times higher than the maximum plasma concentration and total systemic exposure in the equilibrium state, Sibri Brizhaler inhalation in recommended doses (50 mcg once a day). Signs of an overdose were not detected.

Interaction:

Simultaneous use of the drug with other drugs for inhalation, containing m-holinoblokatory, not studied, and therefore the simultaneous use of the above funds is contraindicated.

Simultaneous inhalation use of glycopyrronium bromide and indacaterol, a beta2-adrenoceptor agonist, does not affect the pharmacokinetics of both drugs. In spite of the fact that clinical studies on the drug interaction have not been conducted, clinical manifestations of drug interaction have not been observed in clinical practice with the simultaneous use of the drug Sybri Brizhaler with other drugs widely used for the treatment of COPD in s.ch.beta-adrenomnsticami, revenged with xanthines, glucocorticosteroids for inhalation and oral administration.

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

In vitro studies have shown that the preparation of Sibri Brizhaler probably does not affect the metabolism of other drugs. Inhibition or induction of glncopyrronium bromide metabolism does not lead to significant changes in the systemic exposure of the drug.

Special instructions:

The drug Sibri® Breezhaler® is not recommended for relief of acute episodes of bronchospasm.

Hypersensitivity reactions Cases of development of reactions have been reported Immediate hypersensitivity after the use of the drug Sibri® Breezhaler®.If there are signs indicating the development of an allergic reaction, including angioedema (including shortness of breath or swallowing, swelling of the tongue, lips and face), hives or skin rashes, the drug should be discontinued and alternative therapy should be selected.

Paradoxical bronchospasm

As with other inhalation therapies, the use of the Sibri® Brizhaler® preparation can lead to paradoxical bronchospasm, which can pose a threat to life. In the event of a paradoxical bronchospasm, the use of the Sibri® Brizhaler® drug should be immediately discontinued and alternative therapy applied.

M-anticholinergic effect

Like other m-holinoblocking medicines Sibri® Brizhaler® should be used with caution in patients with closed-angle glaucoma or urinary retention.

Patients should be informed about the signs and symptoms of an acute attack Closed-angle glaucoma and the need to stop using preparation Sybri® Brizhaler®, and immediately notify your doctor if any of these signs or symptoms develop.

Severe renal insufficiency

Patients with impaired renal function (GFR less than 30 ml / min / 1.73 m), including patients with terminal stage diseases requiring hemodialysis should be carefully observed for the development of possible unwanted drug reactions.

The preparation Sibri® Breezehaler® is intended for supporting treatment of patients with COPD. Due to the fact that patients over 40 years of age predominate in the general population of COPD, the use of the drug in patients under 40 years of age requires spirometric confirmation of the diagnosis of COPD.

Effect on the ability to drive transp. cf. and fur:

The preparation Sibri® Brizhaler® does not adversely affect the ability to drive vehicles, mechanisms.

Form release / dosage:

Capsules with powder for inhalation, 50 mcg.

Packaging:

For 6 capsules in the blister PA / Al / PVC and aluminum foil.

For 1, 2, 4 or 5 blisters together with instructions for medical use and device for inhalation (breezhaler) in a cardboard box.

Multi-pack. 3 packs of 5 blisters together with the device for inhalation (breezhaler), 4 packs of 4 blisters together with the device for inhalation (breezhaler) or 25 packs of 1 blister in together with the device forinhalation (breezhaler).

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002244

Date of registration:23.09.2013

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, AG Switzerland

NOVARTIS PHARMA STEIN, AG Switzerland

Information update date: & nbsp20.01.2016

Illustrated instructions

Instructions

Sybri® Brizhaler® (Sibry Breathhaler)