Instruction for use: Aclidinium bromide (Aclidinii bromidum)

chemical name

[(8R) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane-8-yl] -2-hydroxy-2,2-dithiophene-2-yl acetate bromide

The nosological classification (ICD-10)

J44 Other chronic obstructive pulmonary disease

Allergic bronchitis, Bronchitis asthma, Asthmatic bronchitis, wheeze bronchitis, Bronchitis is an obstructive, bronchi disease, Shortness of sputum in acute and chronic respiratory diseases, Cough in inflammatory diseases of the lung and bronchus, Reversible airflow obstruction, Reversible obstructive airway disease, Obstructive bronchitis disease, Obstructive lung disease, Obstructive bronchitis, Spastic bronchitis, Chronic lung disease, Chronic nonspecific lung diseases, Chronic obstructive pulmonary disease, Chronic obstructive bronchitis, Chronic obstructive airway disease, Chronic obstructive pulmonary disease, Restrictive lung pathology

J44.9 Chronic obstructive pulmonary disease, unspecified

Obstructive pulmonary diseases, Bronchial obstruction, bronchial obstruction, Exacerbation of chronic obstructive pulmonary disease, reversible airflow obstruction, Reversible airway obstruction, panbronchiolitis, Panbronhit, COPD, Chronic pulmonary infection, Chronic infection of the lower respiratory tract, Chronic obstructive pulmonary disease, Chronic obstructive pneumonia, Chronic lung disease, Chronic obstructive pulmonary disease, Chronic bronchopulmonary disease, Chronic broncho-pulmonary diseases, Airway obstruction

CAS code 320345-99-1

Characteristics

Selective competitive antagonist of muscarinic receptors.

A white powder with a molecular weight of 564.56. Very slightly soluble in water and ethanol, and sparingly soluble in methanol.

Pharmacology

bronchodilatory.

pharmacodynamics

Aclidinium bromide is a selective competitive antagonist of muscarinic receptors (anticholinergic) with a longer time-binding to m3 receptor, than to m2 receptor. M3 receptors mediate the reduction in airway smooth muscle. Inhaled Aclidinium bromide acts locally in the lung as a receptor antagonist m3 airway smooth muscle and causes bronchodilation. Preclinical studies in vitro and in vivo have demonstrated rapid and prolonged dose-dependent inhibition Aclidinium bromide bronchoconstriction induced by acetylcholine. Aclidinium bromide is rapidly degraded in the plasma, so the number of systemic anticholinergic side effects is low.

Pharmacodynamic effects

Studies of clinical efficacy showed that Aclidinium bromide provides a clinically significant improvement in lung function (measured by forced expiratory volume in 1 second (FEV1) for more than 12 hours after the morning and evening reception, which appeared within 30 minutes after the first dose (increase FEV1 compared with a baseline of 124-133 ml). Maximum bronchodilation is achieved within 1-3 hours after administration dose with a mean peak FEV1 improved relative to baseline 227-268 ml at steady state.

Electrophysiology of the heart. When assigning Aclidinium bromide (200 or 800 mg) in healthy volunteers 1 time per day for 3 days effect on QT interval was observed.

There were no clinically significant impact on aklidiniya bromide heart rate during the 24-hour Holter monitoring at 336 patients (164 from which the obtained aklidiny 2 times a day in a dose of 322 mg) after 3 months of use.

The clinical efficacy. Program clinical trials phase III Aclidinium bromide included 269 patients treated at a dose of 322 ug aklidiniya 2 times a day during a 6-month, randomized study with placebo control and the 190 patients treated at a dose of 322 ug Aclidinium 2 times per day during another 3-month, randomized, placebo-controlled study. Efficacy was assessed by the dynamics of lung function and clinical symptoms, such as shortness of breath, a diagnosis on the conditionality of health status, use of medicines and the availability of emergency treatment of exacerbations. During the long-term safety studies aklidiniya bromide demonstrated the effectiveness of bronchodilation with prolonged use over 1 year.

Bronchodilation. During the 6-month study in patients receiving Aclidinium bromide in a dose equivalent to 322 mg Aclidinium , 2 times a day, there was a clinically significant improvement (as measured by FEV1) lung function. The maximum effect is bronchodilation from the first day and was maintained during the 6-month treatment period. After 6 months of therapy mean improvement before taking the morning dose (minimum) FEV1 compared to placebo was 128 mL (95% CI = 85-170; P <0.0001).

Similar observations were made for Aclidinium bromide during the 3-month study.

Health, disease-specific and symptomatic improvement. Aclidinium bromide provides a clinically significant improvement in breathlessness (assessed using transient index of dyspnea (TDI) and the state of health due to disease (assessed pomoschyo Respiratory Questionnaire Hospital St. George (SGRQ). Symptoms Decrease after 6 months of application Aclidinium bromide is characterized by the following indicators.

Transient dyspnea index:

- The percentage of patients with minimal clinically important difference (at least one unit change TDI) - 56,9 for Aclidinium bromide and 45.5 for the placebo; improvement compared with placebo - 1.68-fold increase in the likelihood (odds ratio, increasing the likelihood of achieving the minimum clinically important difference compared with placebo); p = 0,004;

- Mean change from baseline - 1.9 for Aclidinium bromide and 0.9 for placebo; improvement compared to placebo - 1 unit; p <0,001.

Respiratory questionnaire SGRQ:

- The percentage of patients with minimal clinically important difference (at least one unit change TDI) - 57,3 for Aclidinium bromide and 41 to placebo; improvement compared with placebo - 1.87-fold increase in the likelihood (odds ratio, increasing the likelihood of achieving the minimum clinically important difference compared with placebo); p <0,001;

- Mean change from baseline - -7.4 for Aclidinium bromide and -2.8 for placebo; improvement compared to placebo - -4.6 units; p <0,0001.

Patients receiving Aclidinium bromide, required less rescue therapy drugs than patients who received placebo (a decrease of 0.95 injections per day for 6 months (p = 0,005). Aclidinium bromide also improved daily symptoms of COPD (dyspnea, cough, and sputum formation) and night and early morning clinical symptoms.

Pooling analysis of the effectiveness of 6- and 3-month placebo controlled studies demonstrated a significant reduction in the incidence of moderate to severe exacerbations (requiring antibiotic therapy or corticosteroids or resulting in hospitalizations) when receiving 322 mcg Aclidinium 2 times a day compared to placebo (rate per patient year: 0.31 vs. 0.44, respectively; p = 0.0149).

Exercise capacity. During the 3-week, randomized, crossover clinical study with placebo control against application Aclidinium bromide there was a statistically significant increase in the duration of exercise at 58 compared with placebo (95% CI - 9-108, p - 0.021, and the values before the treatment: 486 from).

When using Aclidinium bromide showed a statistically significant decrease in excessive distension of the lungs alone (functional residual capacity (FRC) - 0.197 L (95% CI = 0.321, 0.072; p = 0.002), residual volume (RV) - 0.238 L (95% CI = 0.396, 0.079; p = 0.004) as well as an improvement in the minimum inspiratory capacity (0,078 to l, 95% CI = 0.01, 0.145; p = 0.025) and reduced dyspnea during exercise (Borg's scale) (0.63 Borg units; 95% CI = 1.11, 0.14; p = 0.012).

Pharmacokinetics

Suction. Aclidinium bromide rapidly absorbed from the lung, reaching Cmax plasma within 5 minutes after the inhalation in healthy volunteers, and usually within the first 15 min in patients with COPD. The fraction of an inhaled dose reached the systemic circulation as unchanged Aclidinium is very low, less than 5%.

Cmax in plasma attained after dry powder inhalation in patients with COPD in a single dose of 400 ug Aclidinium bromide was approximately 80 pg / ml. Css plasma was achieved within 7 days when 2 times a day and, given the short T1 / 2 can be achieved shortly after the first dose. Accumulation Repeated dose at an equilibrium level was observed concentrations.

Distribution. Total enters the lungs through the inhaler Aclidinium bromide was approximately 30% of the metered dose.

Binding Aclidinium bromide with plasma proteins in vitro corresponds likely metabolite binding proteins due to the rapid hydrolysis aklidiniya bromide in plasma, plasma protein binding of 87% of the carboxylic acid metabolite, and 15% for the alcohol metabolite. The major plasma protein that binds Aclidinium bromide is albumin.

Biotransformation. Aclidinium bromide is rapidly and extensively hydrolysed to its famakologicheski inactive alcohol derivatives and carboxylic acid derivatives. Chemical hydrolysis occurs as the (non-enzymatic) or enzyme with esterase. Main esterase involved in the hydrolysis of a person is butyrylcholinesterase. Acid metabolite level in the blood plasma after inhalation is about 100 times higher than the alcohol metabolite and unchanged active substance.

The low absolute bioavailability Aclidinium bromide inhalation administration (<5%) due to the fact that Aclidinium bromide is subjected to an active system and a first-pass hydrolysis when in the lungs, and by ingestion.

The biotransformation involving cytochrome P450 isoenzymes (CYP450) plays a minor role in the overall metabolic clearance Aclidinium bromide.

The tests in vitro showed that Aclidinium bromide in a therapeutic dose or its metabolites do not suppress and do not induce any P450 isoenzymes (CYP450) and does not inhibit the activity of esterase (carboxyl esterase, acetylcholinesterase, butyrylcholinesterase). The tests in vitro showed that aklidiniya bromide or its metabolites are not substrates or inhibitors of P-gp.

Withdrawal. The final T1 / 2 aklidiniya bromide is about 2-3 hours.

After the on / in the healthy volunteers 400 mg radiolabeled Aclidinium bromide is about 1% of the dose is excreted unchanged in the urine. Up to 65% of the dose excreted as metabolites in the urine and up to 33% as metabolites in the feces.

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

Linearity / non-linearity. Aclidinium bromide in the therapeutic range has a linear and time-independent pharmacokinetics.

Pharmacokinetic / pharmacodynamic relationship. Given that aklidiniya bromide has a local effect in the lungs and is rapidly degraded in plasma, direct correlation between pharmacokinetics and pharmacodynamics not.

Special patient groups

Elderly patients. The pharmacokinetic properties of aklidiniya bromide in COPD patients with moderate to severe are similar in patients aged 40-59 years and in patients aged 70 years and older. Therefore, in elderly patients with COPD dose adjustment is required.

Patients with impaired liver function. In patients with liver function impairment tests have not been conducted. So Aclidinium bromide is metabolised mainly by chemical and enzymatic degradation in the plasma, it is highly unlikely that the liver changes its systemic impact. Patients with COPD and hepatic impairment dose adjustment is required.

Patients with impaired renal function. In patients with normal renal function and its violation found significant differences in the pharmacokinetics. Therefore, in patients with COPD and renal impairment dose adjustment and additional monitoring is required.

Pharmacokinetics

Absorption. The absolute bioavailability of Aclidinium bromide is about 6% in healthy volunteers. When perooralnom inhalation use 2 times a day in a dose of 400 ug Aclidinium CSS bromide in healthy subjects was observed within 10 minutes after inhalation.

Distribution. After the on / in the introduction of bromide 400 mcg Aclidinium people Vd is approximately 300 l.

Metabolism. Clinical pharmacokinetic studies, including mass balance showed that the main route of metabolism is hydrolysis of the bromide Aclidinium both chemical and enzymatic means esterase. Aclidinium bromide rapidly and extensively hydrolyzed to the alcohol and acid metabolites ditienilglikolnogo, neither of which binds to muscarinic receptors and are devoid of pharmacological activity.

Therefore, due to the low plasma concentrations achieved at clinically relevant doses, it is not expected to Aclidinium bromide and its metabolites will influence drug exposure, metabolized by CYP 450.

Elimination. Total clearance Aclidinium bromide after the on / in the healthy young volunteers was approximately 170 l / h at interindividual variability of 36%. Assigned to healthy volunteers in / Aclidinium bromide radiolabeled undergo extensive metabolism, excretion of unchanged Aclidinium amounted to 1%. Approximately 54 to 65% of the radiolabeled dose excreted in the urine and 20 to 33% - the faeces. The combined data indicate that almost all of the dose received Aclidinium bromide eliminated by hydrolysis. After dry powder inhalation renal excretion Aclidinium approximately 0.09% of the dose, and assess the effectiveness of T1 / 2 is from 5 to 8 hours.

Drug interactions. Formal drug interaction studies have not been conducted. Studies in vitro using human liver microsomes have shown that Aclidinium bromide and its main metabolites does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 / 5 or CYP4A9/11 at concentrations greater than 1000-fold Cmax , when used in the anticipated therapeutic dose. Therefore, it is unlikely cho Aclidinium bromide causes drug interactions associated with CYP450 (see. "Interaction").

Application of the substance Aclidinium bromide

Aclidinium bromide for supporting bronchodilatory therapy to relieve the symptoms of COPD in adults.

Contraindications

Hypersensitivity to Aclidinium bromide, atropine and its derivatives (ipratropium bromide, tiotropium bromide) or lactose, age 18 years (effectiveness and safety have not been established), galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Pregnancy and breast-feeding

No clinical data on the use of Aclidinium bromide in pregnant women. Preclinical studies have demonstrated a toxic effect on the fetus only at doses many times higher than the maximum therapeutic dose in humans. Aclidinium bromide can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

It is unknown whether Aclidinium bromide and / or its metabolites in breast milk of women penetrates. Since the pre-clinical studies have shown that small amounts of aklidiniya bromide and / or its metabolites into breast milk, it is necessary to take a decision to stop breastfeeding or termination of therapy Aclidinium bromide, comparing the benefits of breastfeeding for the child and the benefit of long-term therapy Aclidinium bromide for women.

Fertility. Preclinical studies have demonstrated only a slight decrease in fertility at doses many times higher than the maximum therapeutic dose aklidiniya bromide in humans. It is considered unlikely that aklidiniya bromide, designated at the recommended dose, the effect on fertility in humans.

Side effects

The most common side effects when using Aclidinium bromide were headache (6.6%) and nasopharyngitis (5.5%).

The frequency of side effects is based on an assessment of the overall coefficient of side effects (ie, the events associated with the use Aclidinium bromide), seen with Aclidinium bromide at a dose equivalent to 322 mg Aclidinium (636 patients) in the analysis of pools of 6-month and two 3-month randomized clinical trials with placebo control.

The frequency of side effects is defined as follows: very common (greater than or equal to 1/10); frequently (by greater than or equal to 1/100 <1/10); infrequently (by greater than or equal to 1/1000 <1/100); rare (by greater than or equal to 1/10000 <1/1000); very rare (<1/10000), and unknown frequency (side effects, the incidence of which is unknown, ie it is impossible to estimate the frequency, based on the available data).

Infectious and parasitic diseases: often - sinusitis, nasopharyngitis.

Immune system: rarely - hypersensitivity reactions; the frequency is unknown - angioedema.

From the nervous system: often - headache; Infrequent - dizziness.

On the part of the organ of vision: rarely - blurred vision.

From the CCC: rarely - tachycardia, palpitations.

The respiratory system, organs, thoracic and mediastinal disorders: often - cough; infrequently - dysphonia.

On the part of the digestive tract: often - diarrhea; infrequently - mucosal dryness oral stomatitis.

For the skin and subcutaneous tissue disorders: rare - rash, itchy skin.

On the part of the kidney and urinary tract: rarely - urinary retention.

The following adverse reactions are described in more detail in other sections of this specification:

- Paradoxical bronchospasm (see "Precautions.");

- Deterioration of angle-closure glaucoma (see "Precautions.");

- Worsening of urinary retention (see "Precautions.");

- Immediate hypersensitivity reactions (see "Safety precautions.").

Experience in clinical trials

Since clinical tests performed with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not coincide with that obtained in other studies, and observed in clinical practice.

Three-month and six-month trial. Aclidinium bromide was studied in two 3-month (Test B and C) and a 6-month test (D) placebo-controlled trials in patients with COPD. In these trials, patients received 636 Aclidinium bromide at the recommended dose of 400 mg 2 times a day.

The average age of the population was 64 years (range 40 to 89 years), 58% of patients were men, 94% - Caucasians and 48% of them had COPD as measured by the average value of FEV1 (bronchodilation up). Patients with unstable cardiac disease or symptomatic closure glaucoma prostatic hyperplasia outlet obstruction or urinary bladder were excluded from the test data. Below are listed all of the side reactions (in terms of preferred) that arose during the 3- and 6-month, placebo-controlled trials with a frequency equal to or more than 1% in the treated groups Aclidinium bromide (N = 636), when the frequency of adverse events in the groups receiving Aclidinium bromide was higher than in the placebo group (N = 640). The first figure - the number of patients receiving Aclidinium bromide, the second - a placebo; in parentheses - Percentage of the number of participants.

Headache 42 (6.6%) and 32 (5%), nasopharyngitis 35 (5.5%) and 25 (3.9%), cough 19 (3%) 1 (2.2%), diarrhea 17 (2.7%), and 9 (1.4%), sinusitis, 11 (1.7%) and 5 (0.8%) rhinitis 10 (1.6%), and 8 (1.2%), tooth pain 7 (1.1%) and 5 (0.8%) falling 7 (1.1%) and 3 (0.5%), vomiting 7 (1.1%) and 3 (0.5%) .

In addition, in clinical trials, the following adverse reactions were observed, observed at a frequency <1%: diabetes, dryness of the oral mucosa, AV block I degree, osteoarthritis, heart failure and cardiorespiratory arrest.

Safety during prolonged use. Aklidiniya bromide was studied in three tests with the observation for a long time, two bilateral blind trials and one open clinical trial duration of 40 to 52 weeks in patients with COPD, moderate to severe. Two of these trials were the extended 3-month trial, and one - a specialized test with supervision for a long time. In these tests, the patient received 891 Aclidinium bromide at the recommended dose of 400 mg 2 times a day. Demographic and baseline characteristics of the tests with supervision for a long time were similar to those in the placebo-controlled studies. Adverse events noted during the tests with supervision for a long time, were similar to those that occurred during the placebo-controlled 3- and 6-month trials; new side effects were found.

Experience postmarketing observations. Since the resolution Aclidinium bromide for medical use have been identified following side reactions. Since the reports of these adverse reactions received from an unknown size volunteer populations it is not always possible to realistically assess their frequency or establish a causal relationship with the exposure of the drug.

In postmarketing observations using Aclidinium bromide marked immediate hypersensitivity reactions, including anaphylaxis, angioedema (including swelling of the lips, tongue or throat), urticaria, rash, bronchospasm, or itching.

Interaction

Concomitant use Aclidinium bromide with other m-holinoblokatorami not been studied and is not recommended.

Despite the lack of studies in vivo, the use of inhaled Aclidinium bromide optionally in combination with other drugs for the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines and inhaled or oral corticosteroids.

Studies in vitro have demonstrated that Aclidinium bromide in a therapeutic dose or its metabolites do not interact with drugs that are substrates of P-gp or cytochrome P450 metabolized (CYP450) and esterases.

Results of in vitro studies demonstrate the limited potential interaction with drugs metabolized by the CYP450, so the study of drug interactions aklidiniya bromide was carried out.

Sympathomimetics, methylxanthines, steroids. In clinical trials, the combined use aklidiniya bromide and other drugs commonly used in the treatment of COPD, including sympathomimetics (beta2-agonists, short-acting), and methylxanthines oral or inhaled corticosteroids, does not lead to increased side reactions.

Anticholinergic drugs. There is the possibility of an additive interaction with the co-anticholinergic drugs. Therefore, concomitant administration should be avoided Aclidinium bromide with other anticholinergic drugs, because it can lead to increased anticholinergic action.

Overdose

Symptoms. High doses Aclidinium bromide can result in symptoms associated with anticholinergic action. However, single inhaled dose Aclidinium bromide to 6000 mg in healthy volunteers did not result in systemic side effects of anticholinergic. There were no clinically significant side effects after a 7-day treatment Aclidinium bromide at doses up to 800 mg 2 times daily in healthy volunteers.

The development of acute intoxication Accidental overdose aklidiniya bromide is unlikely due to low oral bioavailability and inhalation dosing method.

Treatment. Symptomatic.

Routes of administration

Inhalation.

Precautions substance Aklidiniya bromide

Asthma. Aclidinium bromide should not be used in asthma; clinical studies on the use of Aclidinium bromide were not carried out for the treatment of asthma.

Paradoxical bronchospasm. As with other inhalation therapy, the use of Aclidinium bromide can cause paradoxical bronchospasm. If this occurs, treatment should be discontinued Aclidinium bromide and to consider other therapy.

Increased symptoms. Aclidinium bromide for the maintenance treatment of patients with COPD and should not be used as an emergency treatment. If during treatment the patient Aclidinium bromide there was a change of severity of COPD symptoms, which required additional emergency treatment, re-evaluation of the patient's condition and treatment policy revision should be carried out.

Impact on SCS. The safety profile concerning CCC is characterized by an anticholinergic action.

Like other m-holinoblokatory, Aclidinium bromide should be used with caution in patients with myocardial infarction in the preceding 6 months, unstable angina, first diagnosed with arrhythmia in the previous 3 months, or patients in the previous 12 months, hospitalized for heart failure, III and IV NYHA functional class classification, because these patients were excluded from clinical studies, and anticholinergic effects may have an impact on the course of these diseases.

Anticholinergic Effects. The dryness of the oral mucosa observed in the application of anticholinergic drugs over time may be associated with the development of dental caries.

Because of the anticholinergic effects Aclidinium bromide should be used with caution in patients with narrow-angle glaucoma (despite the fact that the direct contact of the drug with the eyes is unlikely), hyperplasia of the prostate and bladder neck obstruction. Patients should be proifnormirovany about the signs and symptoms of an acute attack of angle-closure glaucoma and the need to stop using the product and consult a doctor if they occur.

Aclidinium bromide for the maintenance treatment of patients with COPD. Due to the fact that in the general population of COPD patients predominate over the age of 40 years, when assigning Aclidinium bromide and 40 patients required COPD spirometric confirmation of the diagnosis.

Effects on ability to drive vehicles and other mechanisms. Aclidinium bromide may affect the ability to drive vehicles and other mechanisms. Given the possibility of side effects such as headache, dizziness, blurred vision, be careful when managing trnansportnymi means other mechanisms, as well as classes of potentially hazardous activities that require high concentration and speed of psychomotor reactions.

Not for use in acute situations. Aclidinium bromide for COPD maintenance therapy two times a day and is not indicated for the initial treatment of acute episodes of bronchospasm (ie life-threatening conditions).

Paradoxical bronchospasm. Inhaled medicines, including Aclidinium bromide, may cause paradoxical bronchospasm. In this case, the use of aklidiniya bromide should stop and consider other treatment.

Deterioration of angle-closure glaucoma. Aclidinium bromide should be used with caution in patients with narrow-angle glaucoma. Physicians and patients should be warned about the signs and symptoms of angle-closure glaucoma (such as pain or discomfort in the eyes, blurred vision, visual halo or colored images in combination with red eyes due to conjunctival hyperemia and edema) of the patient should be instructed him to immediately contact consult a doctor if you develop any of the above signs or symptoms.

Delay Deterioration of urine. Aclidinium bromide should be used with caution in patients with urinary retention. Physicians and patients should be warned about the signs and symptoms of benign prostatic hyperplasia or bladder outlet obstruction (such as difficulty urinating, painful urination). It should instruct the patient that he immediately seek the advice of your doctor if you develop any of the above signs or symptoms.

Immediate type hypersensitivity reactions. After applying aklidiniya bromide there were reactions of immediate type hypersensitivity, including anaphylaxis, angioedema (including swelling of the lips, tongue or throat), urticaria, rash, bronchospasm, or itching. In the event of such reactions aklidiniya bromide therapy should be stopped and nemdlenno should consider alternative therapies. In appointing aklidiniya bromide patients receiving drugs with the structural formula similar to atropine, in patients with a known history of hypersensitivity to atropine should be carefully monitored for similar hypersensitivity reactions to aklidiniya bromide. In addition, aklidiniya bromide should be used with caution in patients with severe hypersensitivity to milk proteins.