BTG - instructions for use, doses, side effects, contraindications

Active substanceAklidinium bromideAklidinium bromide

Similar drugsTo uncover

Braternis® Genuine®

powder d / inhal.

AstraZeneca UK Ltd United Kingdom

Dosage form: & nbsppowder for inhalation dosed

Composition:

Composition of a single dose:

Active substance: Actinium bromide micronized - 0.400 mg *. Excipient: α-lactose monohydrate - 12.60 mg.

* One dose contains 400 μg of aclidinium bromide, which is equivalent to 343 μg of aclidinium. This corresponds to the delivered dose of 375 μg of aclidinium bromide, which is equivalent to 322 μg of aclidinium.

Description:

Inhaler

A plastic inhaler of white color with a green protective cover, with a green metering button and a fixed sliding cover, with a cartridge containing 30 or 60 doses of the drug and a dose counter.

Contents of the cartridge

A white or almost white, finely dispersed, free flowing powder that does not contain visible conglomerates or foreign particles.

Pharmacotherapeutic group:M-holinoblokator

ATX: & nbsp

R.03.B.B.05 Aklidinium bromide

Pharmacodynamics:

Aklidinia bromide is a competitive, selective antagonist of muscarinic receptors (also called anticholinergic), with a longer time binding to M3 receptors than with M2 - receptors. M3 receptors mediate the contraction of the smooth muscles of the respiratory tract. Inhalation aklidinium bromide acts locally in the lungs, as an antagonist of the M3 receptors of the smooth muscles of the respiratory tract and causes an expansion of the bronchi. Preclinical studies in vitro and in vivo demonstrated a rapid, dose-dependent and prolonged inhibition of bronchospasm bronchospasm induced by acetylcholine by bronchodism. Aklidinium bromide rapidly degrades in plasma, so the amount of systemic anticholinergic side effects is low.

Pharmacodynamic action

Clinical efficacy studies have shown that Braternis® Genuine® provides a clinically significant improvement in lung function (measured by the volume of forced expiration in one second [FEV1]) for more than 12 hours after a morning and evening reception that manifested itself within 30 minutes after admission the first dose (the increase in FEV1 compared with the baseline is 124-133 ml). The maximum bronchodilation was achieved within 1-3 hours after taking the dose with an average peak of FEV1 improvements in relation to the baseline level of 227-268 ml in the equilibrium state.

Electrophysiology of the heart

When prescribing aclidinium bromide (200 μg or 800 μg) to healthy volunteers once a day for 3 days of influence on the interval QT (corrected by the method of Friederation or Bazetta or individually) was not observed.

Also, there was no clinically significant effect of Braternis Genuine® on cardiac rhythm with a 24-hour Holter monitoring in 336 patients (164 of whom received Braternis® Genuine® twice daily at a dose of 322 μg) after 3 months of use.

Clinical efficacy

The Phase III clinical trial of Brentace® Genuine® included 269 patients treated with Brataris® Genuine® at a dose of 322 μg twice daily in a single 6-month, randomized placebo-controlled study and 190 patients treated with Brataris® Genuine ® at a dose of 322 μg twice daily during another 3-month randomized placebo-controlled study. Efficacy was assessed by the dynamics of lung function and clinical symptoms, such as dyspnea, due to the diagnosis of the status Health, the use of emergency medicine and the presence of exacerbations. In long-term safety studies, the Braretis® Genuine® drug demonstrated bronchodilator efficacy with a duration of application of more than 1 year.

Bronchodilation

In a 6-month study, a clinically significant improvement in lung function (measured with FEV1) was observed in patients treated with Brataris® Genuine® at a dose of 322 μg twice daily. The maximum bronchodilator effect was manifested from the first day and was maintained during the 6-month period of therapy of application. After 6 months of therapy, the mean improvement before taking the morning dose (minimum) of FEV1 compared with placebo was 128 mL (95% CI = 85-170, p <0.0001).

Similar observations were made for the preparation of Brétaris® Genuine® during a 3-month study.

Health status, specific for the disease and symptomatic improvement

Preparation Bretatic® Genuine® provided a clinically significant improvement in dyspnea (assessed by a transient dyspnea index [TDI]) and health status due to the disease (assessed using the Respiratory questionnaire of St. George's Hospital [SGRQ]). The following table shows a decrease in symptoms after a 6-month period of use of the drug BretaRis® Genuine®.

Variable	Treatment			Improvement compared with placebo	Value R
	Braternis® Genuine®	Placebo
Transient dyspnea index
Percentage of patients with minimal clinically important difference^a	56,9		45,5	1.68-fold^from rise probabilities	0,004
Average change from baseline	1,9		0,9	1.0 unit	<0,001
Respiratory questionnaire of St. George Hospital
Percentage of patients with a minimal clinically important difference^b	57,3		41,0	1.87-fold^from rise probabilities	<0,001
Average change from baseline	-7,4		-2,8	- 4.6 units	<0,0001

^a Minimally clinically important difference (MCID) at least 1 unit of change in the Transient Dyspnea Index.

^b Minimally clinically important difference (MCID) at least 4 units of change according to the Respiratory Questionnaire of the St. George Hospital.

^from The odds ratio, the increased likelihood of achieving a minimal clinically important difference compared to placebo.

Patients who received the Brétaris® Genuine® drug required fewer emergency therapies than patients receiving placebo (a decrease of 0.95 injections per day for 6 months p = 0.005). The preparation Bretatis® Genuine® also improved daytime symptoms of COPD (dyspnea, cough and sputum), and night and early morning clinical symptoms.

A pooled analysis of the efficacy of 6-month and 3-month placebo-controlled studies demonstrated a significant reduction in the incidence of moderate to severe exacerbations (requiring antibiotic or glucocorticosteroid therapy or leading to hospitalization) with 322 μg of active dose twice daily compared with placebo (frequency per patient per year: 0.31 against 0.44, respectively, p = 0.0149).

Tolerance to physical activity

During a 3-week, randomized, cross-sectional clinical trial with placebo control in the foyer of Brataris® Genuine®, there was a statistically significant increase in exercise duration by 58 seconds compared with placebo (95% CI = 9-108; p = 0.021; therapy: 486 seconds).

The statistically significant reduction in excessive overgrowth of the lung at rest was noted with the use of the Bretatis® Genuine® drug (functional residual capacity [FDE] = 0.197 l [95% CI = 0.322, 0.072, p = 0.002], residual volume [PJ] = 0.238 L [95 % DIF = 0.396, 0.079, p = 0.004]), and an improvement in the minimum inspiratory capacity (by 0.078 liters, 95% CI = 0.01, 0.145, p = 0.025) and a decrease in dyspnea during exercise (Borg scale) by 0.63 Borg units, 95% CI = 1.11, 0.14, p = 0.012).

Pharmacokinetics:

Suction

Aklidinia bromide is rapidly absorbed from the lungs, reaching a maximum concentration in the blood plasma within 5 minutes after inhalation in healthy volunteers, and usually within the first 15 minutes in patients with COPD. The fraction of the inhaled dose that has reached the systemic circulation as unchanged aclidinium is very low, less than 5%.

The maximum plasma concentration achieved after inhalation of dry powder in patients with COPD with a single dose of 400 μg of aclidinium bromide was approximately 80 pg / ml. Equilibrium concentration in blood plasma was achieved within 7 days when taken twice a day and, given the short half-life, the equilibrium concentration can be reached soon after the first dose. Accumulations at repeated reception at an equilibrium level of concentrations were not observed.

Distribution

The total amount of Bremoris® Genuine® Accutinium Bromide entering the lungs was approximately 30% of the metered dose.

Binding of albuminium bromide to plasma proteins in vitro, corresponds, most likely, to the binding of metabolites to proteins,in connection with the rapid hydrolysis of aclidinium bromide in plasma, binding to plasma proteins was 87% for the metabolite of the carboxylic acid and 15% for the alcohol metabolite. The main plasma protein that binds aklidinium bromide, is albumin.

Biotransformation

Aklidinium bromide is rapidly and actively hydrolyzed to its pharmacologically inactive alcohol derivatives and carboxylic acid derivatives. It occurs as a chemical hydrolysis (non-enzymatic), and enzymatic, with the participation of esterases. The main esterase involved in hydrolysis in humans is butyrylcholinesterase. The level of acid metabolite in blood plasma after inhalation is approximately 100 times higher than the level of alcohol metabolite and unchanged active substance.

Low absolute bioavailability of aclidinium bromide with inhalation (<5%) is due to the fact that aklidinium bromide is subjected to active systemic and presystemic hydrolysis both in the presence of the lungs and in ingestion.

Biotransformation with the participation of cytochrome P450 isoenzymes (CYP450) plays an insignificant role in the overall metabolic clearance of aclidinium bromide.

Testing in vitro showed that aklidinium bromide in a therapeutic dose or its metabolites do not inhibit or induce ns any cytochrome P450 isozymes (CYP450) and does not inhibit the activity of esterases (karboksilesterazg. acetylcholinesterase and butyrylcholinesterase). Testing in vitro showed that aklidinium bromide or its metabolites are not substrates or inhibitors of P-glycoprotein.

Excretion

The final half-life of aclidinium bromide is about 2-3 hours.

Following intravenous administration to healthy volunteers 400 micrograms of radiolabelled bromide aklidiniya about 1% of the dose is excreted unchanged in the urine.

Up to 65% of the dose excreted in urine as metabolites, and 33% in the form of metabolites with the faeces.

After inhalation administration to healthy volunteers and patients with COPD and 200 ug 400 ug bromide aklidiniya very small amount, about 0.1% of applied dose excreted unchanged in urine, indicating that renal clearance plays a minor role in the overall clearance aklidiniya from the blood plasma.

Linearity / nonlinearity

Aklidiniya bromide in the therapeutic range has a linear and time-independent pharmacokinetics.

Pharmacokinetic / pharmacodynamic ratio

Given the fact that aklidinium bromide has a local effect in the lungs and is rapidly destroyed in plasma, there is no direct relationship between pharmacokinetics and pharmacodynamics.

Special patient groups

Elderly patients

The pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD are similar in patients aged 40 to 59 years and in patients aged 70 years and older. Therefore, in elderly patients with COPD, dose adjustment is not required.

Patients with impaired hepatic function

In patients with impaired liver function tests were not conducted. As aklidinium bromide Metabolized mainly by chemical and enzymatic digestion in plasma, it is very unlikely that a dysfunction of the liver will alter it systemic impact. In patients with COPD and impaired liver function, dose adjustment is not required.

Patients with impaired renal function

In patients with normal renal function and with its violation, no significant differences in pharmacokinetics were found. Therefore, in patients with COPD and renal dysfunction, dose adjustment and additional monitoring is not required.

Indications:

The preparation Brétaris® Genuine® is intended for supporting bronchodilator therapy to alleviate the symptoms of chronic obstructive pulmonary disease (COPD) in adults.

Contraindications:

- Hypersensitivity to aclidinium bromide, atropine and its derivatives (ipratropium, oxytropium, or tiotropium) or to lactose.

- Age to 18 years (effectiveness and safety not established).

- Galactose intolerance, lactase deficiency or glucose-galactose malabsorption (formulation contains lactose).

Pregnancy and lactation:

Pregnancy

There are no clinical data on the use of aclidinium bromide in pregnant women. Preclinical studies demonstrated toxic effects on the fetus only at doses many times higher than the maximum therapeutic dose in humans. Aklidinium bromide can be used during pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding period

It is not known whether the aklidinium bromide and / or its metabolites in breast milk in women. Since preclinical studies have shown,that small amounts of bromide ascidinium and / or its metabolites penetrate into the milk, it is necessary to decide whether to stop breastfeeding or to stop the treatment with aclidinium bromide, comparing the benefits of breastfeeding to the baby and the benefit of prolonged therapy with aclidinium bromide for the woman.

Fertility

Preclinical studies demonstrated a slight decrease in fertility only at doses many times greater than the maximum therapeutic dose of aclidinium bromide in humans. It is considered unlikely that aklidinium bromide, prescribed in the recommended dose, affects fertility in humans.

Dosing and Administration:

For inhalation use.

The recommended dose is 322 μg of validity (one inhalation) twice a day.

If you miss the dose, the next dose should be taken as soon as possible. However, if the time for taking the next dose (after the miss) is almost right, the missed dose should not be taken.

Use in elderly patients

Older patients do not need to adjust the dose.

Use in patients with impaired renal function

Patients with impaired renal function to adjust the dose is not required.

Use in patients with impaired hepatic function

Patients with impaired liver function adjust the dose is not required.

Mode of application

Patients should be trained in the proper use of the Januar® Inhaler.

Instructions for the use of the Januar® Inhaler

Acquaintance with inhaler Bretaris® Genuine®

Remove the Genuain® inhaler from the package and familiarize yourself with its components.

To use the Brataris® Genuar® inhaler after removing the cap, you need to take 2 steps:

Step 1 - Press and RELEASE green button and completely exhale, but not in the inhaler.

Step 2 - Tightly grasp the mouthpiece and STRONG and DEEP inhale through an inhaler.

After inhalation, do not forget to put on the protective cap.

Start

-Before the first use, open the closed bag along the label and remove the Januar® Inhaler.

-When you are about to take a dose of a medicine, remove the protective cap, for what slightly Squeeze the arrows on each side and pull outward (see Figure 1).

-Make sure that the mouthpiece does not block anything.

- Hold the Januar® Inhaler horizontally with the mouthpiece towards you, with the green button facing straight up (see Figure 2).

Hold the inhaler with the green button facing straight up. DO NOT TURN IT.

STEP 1: CLICK and RELEASE green button (see figure 3 and 4).

DO NOT KEEP THE GREEN BUTTON PRESSED.

CLICK green button to the full depth

RELEASE green button

Stop and check: Make sure that the dose is ready for inhalation

-Check that the color control window has become green (see Figure 5).

-The green color of the control window confirms that the drug is ready for inhalation.

IF THE WINDOW OF COLOR CONTROL REMAINS RED, CLICK AND RELAX GREEN BUTTON MORE TIMES (SEE STEP 1).

-Before putting the inhaler to your mouth, exhale completely. Do not exhale into the inhaler.

STEP 2: Tightly grasp the mouthpiece of the Januar® inhaler and STRONG and DEEP inhale through the mouthpiece (see Figure 6).

Such a strong, deep breath brings the medication through the inhaler into the lungs.

WARNING: DO NOT KEEP THE APPLIANCE WITH THE GREEN DOWN KEY DURING YOUR INHALATION.

-In time of inspiration you will hear "CLICK", meaning the proper use of the Januar® Inhaler.

-To make sure that you took the whole dose, keep breathing, even after you heard "CLICK" inhaler.

- Remove the Genuarter® inhaler from your mouth and hold your breath for so long that it is comfortable, then exhale slowly through your nose.

Note: Some patients, depending on individual characteristics, can feel a slight sweetish or bitter taste when inhaled this drug. Do not take an extra dose if you do not feel any taste after inhalation.

Stop and check: Make sure you have properly inhaled

-Make sure that the control window has become red (see Figure 7). This is confirmed by the fact that you performed the full dose inhalation correctly.

IF THE WINDOW OF THE COLOR CONTROL IS REMAINING GREEN, YOU NEED TO EVERYTHING UP AND DEEP INTO THE MUNDSTOCK (SEE STEP 2).

-If the window still does not change its color to red, then it's possible that you could Forget to release the green button before inhaling or could not breathe in properly. If so, try again.

Make sure that you HAVE RELEASED green button and do STRONG a deep breath through the mouthpiece.

Note: If after several attempts you have not been able to properly carry out the inhalation, contact your doctor.

-Once the window turns red, put the protective cap on the mouthpiece (see Figure 8).

When do you need a new Genuar® inhaler?

-Engineer® is equipped with indicator doses, showing how many doses remained in the inhaler. The dose indicator slowly descends, showing intervals of up to 10 (60, 50, 40, 30, 20, 10, 0) (see Figure A). Each Januar® inhaler contains at least 30 or 60 doses, depending on the type of package.

-When the ribbon with red strips appears on the dose indicator (see Figure A), this means that you are approaching the last dose and you need to purchase a new Genuar® inhaler.

The dose indicator decreases at intervals of 10: 60, 50, 40, 30, 20, 10, 0.

Note: If your Januar® Inhaler appears to be damaged or if you have lost the cap, it is necessary to replace the inhaler. The Januar® Inhaler should not be cleaned. However, if necessary, this should be done with a dry cloth or paper napkin on the outside of the mouthpiece.NEVER use water to clean the Januar® inhaler, as this may damage the drug.

How can I tell if your Januar® inhaler is empty?

- When 0 (zero) appears in the middle of the dose indicator, you must continue using all the remaining doses in the JEHEUER® inhaler.

-When the last dose is prepared for inhalation, the green button will not return fully to its upper position, but remain locked in the middle position (see Figure B). Even when the green button is locked, you can still take the last dose. After that, the Januar® Inhaler can not be used again, and you will need to start using the new Januar® Inhaler.

Side effects:

The most common side effects with Braretis® Genuine® are headache (6.6%) and nasopharyngitis (5.5%).

The incidence of side effects is based on an assessment of the overall incidence of side effects (ie, events associated with the use of the drug Brétaris® Genuine®) observed with the use of Brétaris® Genuine® at a dose of 322 μg (636 patients) with puff analysis of a single 6-month and two 3-month randomized clinical trials with placebo control.

The frequency of side effects is defined as follows: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10,000 to <1/1000), very rarely (<1/10000); and the frequency is unknown (side effects, the incidence of which is unknown, that is, the frequency can not be estimated from the available data).

Infectious and parasitic diseases

Often: sinusitis, nasopharyngitis.

Immune system disorders

Rarely: hypersensitivity reactions;

Frequency unknown: angioedema.

Disturbances from the nervous system

Often: headache;

Infrequently: dizziness.

Disturbances on the part of the organ of sight

Infrequently: blurred vision.

Disorders from the cardiovascular system

Infrequently: tachycardia, palpitation.

Disturbances from the respiratory system, chest and mediastinal organs

Often: cough;

Infrequently: dysphonia.

Disorders from the gastrointestinal tract

Often: diarrhea;

Infrequently: dryness of the oral mucosa, stomatitis.

Disturbances from the skin and subcutaneous tissues

Infrequently: rash, itchy skin.

Disorders from the kidneys and urinary tract

Infrequently: retention of urine.

Overdose:

High doses of aclidinium bromide can lead to symptoms associated with anticholinergic action.

However, a single inhalation dose of aclidinium bromide up to 6000 μg in healthy volunteers nc resulted in systemic side effects of anticholinergic effects. There were no clinically significant side effects after 7-day treatment with aclidinium bromide in doses up to 800 μg twice daily in healthy volunteers.

The development of acute intoxication with accidental overdose of aclidinium bromide is unlikely due to low bioavailability when ingestion and inhalation dosing method of the drug Bretatis® Genuine®.

Treatment: symptomatic.

Interaction:

Simultaneous use of aclidinium bromide with other M-holinoblokatorami not studied and not recommended.

Despite the lack of research in vivo, the use of aclidinium bromide for inhalation is possible in combination with other drugs for COPD therapy, including sympathomimetics, bronchodilators, methylxanthines and inhaled or oral glucocorticosteroids.

Research in vitro demonstrated that aklidinium bromide in a therapeutic dose or its metabolites do not interact with drugs that are substrates of P-glycoprotein or drugs that are metabolized by cytochrome P450 isoenzymes (CYP450) and esterases.

Special instructions:

Asthma

The drug Brittis® Genuine® should not be used in asthma; clinical studies on the use of aclidinium bromide for the treatment of asthma have not been conducted.

Paradoxical bronchospasm

As with other inhalation therapies, the use of Braternis® Genuine® can cause a paradoxical bronchospasm. If this is the case, then treatment with Braternis® Genuine® should be discontinued and another therapy should be considered.

Increased symptoms of the disease

Aklidinia bromide is intended for maintenance treatment of patients with COPD and should not be used as an emergency medicine. If during the treatment of aclodynia with bromide the patient experienced a change in the severity of COPD symptoms, which required additional emergency therapy, a reassessment of the patient's condition and a review of the treatment tactics should be carried out.

Influence on the cardiovascular system

The safety profile for the cardiovascular system is characterized by the presence of anticholinergic action.

Like other m-holinoblokatory drugs, the drug Brataris® Genuine should be administered with caution to patients who have had myocardial infarction in the previous 6 months, with unstable angina, first diagnosed arrhythmia in the previous 3 months, or patients in the previous 12 months hospitalized for cardiac deficiency III and IV functional classes according to the classification of the "New York Heart Association", because such patients were excluded from clinical studies, and anticholinergic effects Assortments can influence the course of these diseases.

Anticholinergic effects

The dryness of the oral mucosa, observed with the use of anticholinergic drugs, over time can be associated with the development of dental caries.

Due to the presence of anticholinergic effects, aklidinium bromide should be administered with caution to patients with closed-angle glaucoma (despite the fact that direct contact of the drug with the eyes is very unlikely)hyperplasia of the prostate and obstruction of the neck of the bladder. Patients should be informed of the signs and symptoms of an acute attack of an angle-closure glaucoma and the need to stop using the drug and consult a doctor if they occur.

The drug Brétaris® Genuine® is designed to support the treatment of patients with COPD. Due to the fact that patients in the general population of COPD are significantly older than 40, the prescription of a drug for patients under 40 years of age requires spirometric confirmation of the diagnosis of COPD.

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

Aklidinium bromide may affect the ability to drive vehicles and other mechanisms. Given the potential for the development of side effects such as headache, dizziness, blurred vision, caution should be exercised when driving vehicles, other mechanisms, or when engaging in potentially dangerous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

The powder for inhalation is dosed, 322 μg / dose.

Packaging:

30 doses of powder for inhalation in the inhaler.

1 inhaler in a package of laminated aluminum foil. For 1 package with instructions for use in a cardboard box with the control of the first opening.

For 60 doses of powder for inhalation in the inhaler.

1 inhaler in a package of laminated aluminum foil. For 1 or 3 bags with instructions for use in a cardboard box with the control of the first opening.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

After the first opening of the package - 90 days.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003216

Date of registration:23.09.2015 / 07.07.2016

Expiration Date:23.09.2020

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom