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

Active substanceIndacaterolIndacaterol

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Onbrez® Brizhaler®

capsules d / inhal.

Novartis Pharma AG Switzerland

Dosage form: & nbspcapsules with powder for inhalation

Composition:

1 capsule with powder for inhalation contains:

active substance: 194 μg or 389 μg indacaterol maleate (corresponding to 150 μg or 300 μg indacaterol);

Excipients: lactose monohydrate 24,806 mg / 24,611 mg;

capsule shell: gelatin 49.0 mg / 49.0 mg, black ink (for capsules 150 mg) and ink blue (for 300 mg capsules), which include shellac (E904), iron oxide, black oxide (E172), purified water, propylene glycol (E1520).

The composition of blue ink also includes the dye diamond blue (E133) aluminum varnish, titanium dioxide (El71).

Description:

Capsules 150 mcg: hard gelatin capsules №3 with transparent colorless lid and casing, marked under the black stripe on the lid and the inscription "IDL 150" in black ink over the black stripe on the body.

Capsules 300 mcg: hard gelatin capsules №3 with transparent colorless lid and casing, marked under the blue stripe on the lid and the inscription "IDL 300" with blue ink above the blue stripe on the body.

The contents of the capsules are white or almost white powder.

Pharmacotherapeutic group:Bronchodilator - beta2-adrenomimetic selective

ATX: & nbsp

R.03.A.C.18 Indacaterol

Pharmacodynamics:

Indacaterol is selective agonist beta₂-adrenoceptor long-acting (within 24 hours) with a single admission.

Pharmacological action of agonists beta₂-adrenoceptors, including indacaterol, is associated with stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3 ', 5'-adenosine monophosphate (cyclic AMP). Increase the content of cyclic AMP leads to relaxation of smooth muscles bronchi. Indacaterol is an almost complete beta agonist₂-adrenoceptors; stimulating effect of the drug on beta₂-adrenoceptors are 24 times stronger than on beta₁-adrenoceptors, and 20 times stronger than beta₃-adrenoceptors.

After inhalation the drug has a fast and long bronchodilator effect.

Indacaterol provides a persistent significant improvement in lung function (increased volume of forced expiration in 1 sec, FEV₁) for 24 hours. The drug is characterized by a rapid onset of action (within 5 minutes after inhalation), comparable to the effect of salbutamol, a short acting beta agonist₂adrenoreceptors.The maximum action of indacaterol is observed 2-4 hours after inhalation. In patients who received indacaterol within 1 year, there was no development of tachyphylaxis to bronchodilating effect of the drug. When using indacaterol, no dependence was found bronchodilating action from the time of inhalation of the drug during the day (morning or evening).

Indacaterol reduces dynamic and static hyperinflation (increased lung volume at the end of spontaneous exhalation) in patients with moderate to severe chronic obstructive pulmonary disease (COPD). When the drug is used, there is a statistically significant increase in inspiratory capacity and FEV₁ reduction of dyspnea, improvement of exercise tolerance. There is also a significant reduction in the risk of exacerbations of COPD (an increase in the time until the next exacerbation), a decrease in the need for inhalation agonists beta₂-adrenoceptor short-acting and improving the quality of life of patients (assessment with the help of a certified questionnaire of St. George's Hospital).

Pharmacokinetics:

Absorption

After a single or repeated inhalation, the mean time to reach the maximum concentration (C_max) indacaterol in the blood serum is about 15 minutes. Systemic exposure of indacaterol increases with increasing dose (in the range of 150 μg to 600 μg) and is dose-dependent. After a single inhalation, the absolute bioavailability of indacaterol is about 43%. Systemic exposure is the result of absorption of the drug in the lungs and in the intestine. The concentration of indacaterol in the blood serum increases with repeated use of the drug. Equilibrium concentration is achieved after 12-15 days of application. With inhalation of the drug once a day (in doses from 75 μg to 600 μg) for 14 days, the indacaterol cumulation coefficient, estimated from the exposure of the drug on the 1 st and 14 (or 15) days (area under the concentration-time curve in for 24 hours, AUC₀_-₂₄ ) is from 2.9 to 3.8.

Distribution

After intravenous administration, the volume of distribution (Vd) of indacaterol was 2.361-2.557 L, indicating a significant distribution of the drug. The connection with serum proteins and human blood plasma is 94.1-95.3% and 95.1-96.2%, respectively.

Metabolism

When administered orally to a radiolabeled indacaterol, the unchanged indacaterol is the main component of serum and is approximately 1/3 of the total AUCo-24 associated with the drug. From the metabolites of the drug in the blood serum, the hydroxylated indacaterol derivative is determined to the greatest extent. Further, phenolic O-glucuronide of indacaterol and hydroxylated indacaterol predominate. Later, diastereomers of hydroxylated derivative, indacaterol N-glucuronide and C- and N-dealkylated products are detected. UDF-glucuronosyl transferase (UGT1A1) is the only isoenzyme that metabolizes indacaterol to phenolic O-glucuronide. The hydroxylation of indacaterol mainly occurs with the help of the CYP3A4 isoenzyme. It was also found that indacaterol is a substratum for
membrane transporter of P-glycoprotein molecules (P-gp), but has low affinity.

Elimination

The amount of unchanged indacaterol excreted in the urine is less than 2% of the dose. The renal clearance of indacaterol averaged 0.46-1.20 l / h. Given that the serum clearance of indacaterol is 18.8-23.3 l / h, it is obvious that the excretion of the drug through the kidneys is insignificant (approximately 2-5% of the system clearance).

When taken orally indacaterol was excreted mainly through the intestine (90% of the dose): unchanged (54% of the dose) and in the form of hydroxylated metabolites (23% of the dose).

The concentration of indacaterol in the blood serum decreases stepwise with an average final half-life in the range from 45.5 to 126 hours. The half-life, calculated on the basis of accumulation of indacaterol after repeated application, ranged from 40 to 56 hours, which was consistent with the established time of reaching the equilibrium state (12- 15 days).

Pharmacokinetics in specific patient groups

Age, sex and body weight do not affect the pharmacokinetics of indacaterol in patients with COPD. The influence of race on the pharmacokinetic parameters of indacaterol is unlikely.

The experience of using the drug in people of Negroid race is limited.

Patients with hepatic impairment

Pharmacokinetics of indacaterol (AUC, C_max, the degree of binding to proteins) did not change significantly in patients with mild and moderate impairment of liver function. The use of the drug in patients with severe impairment of liver function has not been studied.

Patients with impaired renal function

Because the indacaterol is excreted by the kidneys to an insignificant degree, the pharmacokinetics of the drug in patients with impaired renal function has not been studied.

Indications:

Long-term maintenance therapy for bronchial obstruction in patients with chronic obstructive pulmonary disease (COPD).

Contraindications:

- Hypersensitivity to indacaterol or any of the components of the preparation;

- age to 18 years (effectiveness and security not established);

- pregnancy and the period of the breast feeding;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose).

Carefully:

In patients with concomitant cardiovascular disorders (with ischemic heart disease, acute myocardial infarction, arrhythmias, arterial hypertension), with convulsive disorders, thyrotoxicosis, diabetes mellitus, in patients with the QT prolongation syndrome, in patients concurrently taking medication, prolonging interval QT (antiarrhythmic drugs IA and III classes, tricyclic and tetracyclic antidepressants, neuroleptics, macrolides, antifungal agents, imidazo derivatives la, some antihistamines, including. astemizole, terfenadine, ebastine), drugs for general anesthesia from the barbiturate group, and also in patients who have a history of inadequate response to the action of beta agonists₂adrenoreceptors.

Pregnancy and lactation:

The safety of indacaterol in pregnancy is not established. The drug is contraindicated in pregnancy. When using indacaterol in animals (in doses equivalent to therapeutic doses in humans), there was no identified any reproductive toxicity.

Concerning indacaterol can be used during pregnancy only if the intended benefit to the mother exceeds the potential risk to the fetus. Like other beta agonists₂β-adrenoreceptors, indacaterol can slow the process of childbirth due to tocolytic action (a relaxing effect on the smooth muscles of the uterus).

It is not known whether the indacaterol in human milk from humans. Since when used in animals indacaterol was excreted in breast milk, it is impossible to exclude the adverse effect of the drug on the baby during breastfeeding in humans. If you need to use the drug, breastfeeding the baby with breast milk should be discontinued.

Dosing and Administration:

Only for inhalation use!

The drug is a capsule with powder for inhalation, which should be used only for inhalations through the mouth with the help of a special device - Breezhaler, which is included in the kit. 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.

Before using the drug, patients should be instructed about the proper use of the inhalation device.

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

Inhalation of the drug is carried out daily once a day at the same time. In the case of missed inhalation, Onbres® Breezhaler® is applied the next day at the usual time.

The recommended dose of the drug is 150 μg (the contents of 1 capsule 150 μg) 1 time per day (1 inhalation per day). The dose of the drug can be increased only on the advice of a doctor.

Inhalation of the drug at a dose of 300 μg (1 capsule 300 μg) once a day can provide an additional clinical effect in some patients, for example, in patients with severe COPD.

The maximum dose is 300 μg (the contents of 1 capsule 300 μg) once a day (1 inhalation per day). The maximum permissible dose of the drug can not be exceeded.

Dosage regimen for specific patient groups

No dose adjustment is required in patients aged ≥65 years, patients with impaired liver function and kidneys of mild to moderate severity. The use of the drug in patients with impaired hepatic or renal function not studied.

INDICATIONS FOR USE

Each package of Onbrez® Breezhaler® contains:

- aboutbottom inhalation device - Brizhaler;

- blister with capsules with powder for inhalation

Capsules with powder for inhalation can not be taken inside!

Inhalation device - Breezyhaler, contained in the package, is intended for use only with the capsules of the drug.

For the inhalation of capsules in the package, only the device for inhalation is used - Brizhaler.

Do not use the capsule of the drug with any other inhalation device and, in turn, do not use Brizhaler for inhalation with other medications.

How to use Brizhaler

1. Remove the cover.

2. Open Brizhaler. Hold the Brizhaler at the base and, by tilting the mouthpiece in the direction of the arrow, open it.

3. With dry hands take out the capsule from the blister immediately before use.

4. Insert the capsule into Beyhaler. Put the capsule in a specially designed place Breezyhaler. Never put the capsule on the mouthpiece.

5. Close the Brizhaler. When closing, you should hear a click.

6. Pierce the capsule. Holding Brizhaler strictly vertically, press simultaneously from both sides to the buttons of the piercing device (as shown in the picture). In doing so, you should hear a click. This means that the capsule is punctured. Do not press the buttons more than once.

7. Completely release the Breezyhaler's buttons on both sides.

8. Exhale. Before you take the mouthpiece Brizhaler in your mouth, you need to do a full exhalation. Never blow into the mouthpiece.

9. Inhale the drug. Put the mouthpiece of Brizhaler in your mouth and tightly compress your lips around it. Hold Brizhaler by hand, take a quick, even, maximum deep breath. Do not press the buttons of the lancing device.

10. Pay attention. During inhalation, you should hear a characteristic rattling sound produced by rotating the capsule and spraying the powder. You can feel the sweet taste of the drug in your mouth.

If you have not heard a characteristic sound, then you need to open Brizhaler and see what happened to the capsule. Perhaps she was stuck in the cell. In this case, you need to carefully remove the capsule by tapping lightly on the base of the device. Do not try to release the capsule by repeatedly pressing the buttons on the sides.

11. Hold your breath. If by inhalation you have heard a characteristic sound, hold your breath as long as possible (so as not to experience unpleasant sensations), and at the same time remove the mouthpiece from the mouth. After that, exhale.

Open Brizhaler and see if the powder remains in the capsule. If the powder remains in the capsule, close the Brizhaler and repeat the procedure described in points 8 to 11. As a rule, 1-2 inhalations are sufficient to completely empty the capsule. Some patients immediately after the inhalation may begin to cough. If this happens, do not worry, because you received a full dose of the drug during inhalation.

12. Remove the capsule. After you have inhaled, open the Breezyhaler by unscrewing the mouthpiece, take out the empty capsule and discard it. Close the Brizhaler mouthpiece and close the inhaler with a lid. Do not leave capsules in Brizhaler.

13. If it is convenient for you, make a note in the calendar to account for inhalations. On the inner surface of the package of the preparation is a calendar for the recording of inhalations. Filling this calendar will not forget about the need for the next inhalation of the drug.

Remember:

- Do not swallow capsules with powder for inhalation;

- Use only Breezhaler in the package;

- Capsules should be stored in a blister and extracted immediately before use;

- Never put the capsule in the Brizhaler's mouthpiece;

- Do not press the piercing device more than once;

- Never blow into Brizhaler's mouthpiece;

- Always pierce the capsule prior to inhalation;

- Do not wash Brizhaler. Keep it dry. See section "How to clean Brizhaler";

- Do not disassemble Brizhaler;

- When starting a new package of the drug, always use a new Breezhaler in the package to inhale the capsules;

- Do not store capsules in Brizhaler;

- Always store blisters with capsules and Brizhaler in a dry place.

Additional Information

In very rare cases, a small amount of the contents of the capsules can enter the mouth. Do not worry if you inhaled it or swallowed it.

Note, if you punctured the capsule more than once, the risk of breaking it up increases.

How to clean Brizhaler

Clean Brizhaler once a week.Wipe the mouthpiece from the outside and inside with a clean dry cloth. Never use water to clean Brizhaler. Savingits dry.

Side effects:

When applying the drug in therapeutic doses, the most frequently observed adverse events (AEs): nasopharyngitis, cough, upper respiratory tract infections, cough, headache and muscle spasms. Most of the above AEs were of mild or moderate severity, the incidence of AE data decreased as it continued to be used.

Below are the AEs observed when the drug was administered at doses of 150 and 300 μg once a day in patients with COPD. Undesired reactions are distributed according to the frequency of occurrence. To estimate the frequency, the following criteria were used: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), including individual messages.

Infections and invasions: very often - nasopharyngitis, infections of the upper respiratory tract, often - sinusitis.

From the respiratory system: often - cough, sore throat, sensation of irritation in the throat, rhinorrhea, infrequently - paradoxical bronchospasm.

From the skin and subcutaneous tissue: often - rash, itching.

From the musculoskeletal system: often - muscle spasm, myalgia, bone pain, infrequently - myalgia.

From the nervous system: often - dizziness, infrequently - paresthesia.

From the side of cardiovascular systems: often - ischemic heart disease, palpitations, infrequently - atrial fibrillation, tachycardia.

From the digestive system: often - dry mouth.

Metabolic disorders: often - hyperglycemia / newly diagnosed diabetes mellitus.

General disorders and reactions at the injection site: often - peripheral edema, pain in the chest (non-cardiogenic), infrequent - discomfort in the chest.

When using the drug in a maximum (non-recommended) dose of 600 μg once a day, the safety profile did not differ significantly from that in inhalation of therapeutic doses (150 and 300 μg once a day). Additional AEs were anemia and tremor. Nasopharyngitis, muscular spasms, headache and peripheral edema were also more common.

In patients with COPD with inhalation in the recommended doses, the drug does not have a clinically significant systemic beta₂-adrenomimeticheskogo action. Heart rate (heart rate) on average changed by no more than 1 beat per minute.The frequency of development of tachycardia (noted in rare cases), a significant lengthening interval QTc (> 450 ms for men and> 470 ms for women) and hypokalemia was similar to that of placebo.

Changes in plasma glucose concentration were similar to those in the placebo group.

In clinical trials, a sporadic cough lasting about 5 seconds was noted in patients (17-20% of cases) within 15 seconds after inhalation of the drug. The appearance of cough after inhalation of the drug slightly worried patients and did not require discontinuation of treatment with the drug (since cough is a symptom of COPD, and only in 8.2% of cases patients associated cough with the drug). There was no connection between the cough observed immediately after the inhalation of the drug, and the development of bronchospasm, exacerbation of COPD, worsening of the course of COPD, and a decrease in the effectiveness of the drug.

Overdose:

Symptoms

After a single application of the drug in patients with COPD in a dose 10 times higher than the maximum therapeutic, there was a moderate increase in heart rate, increased blood pressure (BP), and lengthening of the interval QTc.

The most likely symptoms of drug overdose are tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmia, metabolic acidosis, hypokalemia and hyperglycemia (caused by an increased systemic beta₂-adrenomimeticheskogo action).

Treatment

Supportive and symptomatic therapy is indicated. In severe cases, patients should be hospitalized. If necessary, the use of cardioselective beta-adrenoreceptor blockers is possible. Use cardioselective beta-adrenoreceptor blockers with caution, only under strict medical supervision, because their use can provoke the development of bronchospasm.

Interaction:

Drugs that extend the interval QT

As with the use of other beta agonists₂-adrenoceptors, on the background of drug therapy, the lengthening of the interval QT. Since this effect of indacaterol on the length of the interval QT may be potentiated by other drugs, Onbres® Breezhaler® should be administered with caution to patients receiving monoamine oxidase inhibitors,tricyclic antidepressants or other drugs, extension intervals QT. Interval lengthening QT increases the risk of ventricular arrhythmia.

Sympathomimetic drugs

The simultaneous use of indacaterol with sympathomimetics (both separately and as part of combination therapy) can increase the risk of developing unwanted phenomena.

The drug should not be used simultaneously with other beta agonists₂- long-acting adrenoreceptors or with drugs that include beta agonists₂long-acting adrenoreceptors.

Hypokalemia

Simultaneous use with methylxanthine derivatives, glucocorticosteroids or potassium-depleted diuretics can increase the possible hypokalemia caused by beta-agonists₂- adrenergic receptors.

Beta Blockers₂-adrenoceptor

Because beta blockers₂-adrenoceptors can weaken the effect or inhibit the action of beta agonists₂adrenoreceptors, Onbres® Brizhaler® should not be used concomitantly with beta blockers₂-adrenoceptors (including eye drops).

If it is necessary to use both classes of drugs, it is preferable to use cardioselective beta blockers₂adrenoreceptors, however, they must be used with caution.

Interaction at the level of isoenzyme CYP3A4 and membrane transporter of P-glycoprotein

The interaction of indacaterol with specific inhibitors of the isoenzyme CYP3A4 and P-glycoprotein, such as ketoconazole, erythromycin, verapamil and ritonavir.

The simultaneous use of indacaterol with verapamil resulted in 1,4-2-multiply AUC and a 1.5-fold increase in C_mOh. When using indacaterol with erythromycin, there was an increase AUC in 1,4-1,6 times and C_mOh in 1,2 times. Combination therapy with indacaterol and ketoconazole caused a 2-fold and 1.4-fold increase AUC and C_mOh respectively. This increase in exposure due to drug interactions did not lead to a change in the safety profile. With simultaneous use of indacaterol with ritonavir (inhibitor of the isoenzyme CYP3A4 and P-glycoprotein), there was an increase AUC in 1,6-1,8 times, however FROM_mOh remained unchanged.

When using indacaterol with other drugs, drug interactions were not observed. Research in vitro showed that indacaterol has little potential for interaction with drugs at the level of metabolism by enzymes or at the level of membrane carriers at systemic exposure, achieved with the appointment of therapeutic doses.

Special instructions:

Hypersensitivity reactions

On the background of the use of the drug Onbrez® Brizhaler®, hypersensitivity reactions immediate type. If there are signs indicating the development of an allergic reaction (in particular, shortness of breath or swallowing, swelling of the tongue, lips and face, urticaria, skin rash), the drug must be withdrawn and alternative therapy should be selected.

Bronchial asthma

Due to the lack of data on continued use indacaterol in patients with bronchial asthma, the drug should not be used in this category of patients. The use of beta agonists₂-adrenoceptor long-acting for the therapy of bronchial asthma can associated with an increased risk of serious side effects (data obtained as a result of a multicenter clinical studies of the use of salmeterol in patients with bronchial asthma).

Paradoxical bronchospasm

Like any other inhalation therapy, the use of the drug can lead to the development of paradoxical bronchospasm, which is a threat to the life of the patient. In the case of paradoxical bronchospasm, treatment with the drug should be stopped immediately and alternative therapy is prescribed.

Deterioration of the course of the underlying disease

The drug can not be used to stop acute bronchospasm, i.e. Do not use as an emergency therapy. In the case of worsening of the course of COPD on the background of drug treatment, it is necessary to reassess the patient's condition and reconsider the treatment regimen of the disease.

Influence on the cardiovascular system

In some patients, Onbres® Breezhaler®, like other beta-agonists₂-adrenoreceptors, can affect the cardiovascular system (increase heart rate, blood pressure, etc.). In the event of adverse events, it is necessary to stop the therapy with the drug. In addition, with the use of beta agonists₂-adrenoceptors may be noted the following electrocardiographic changes: flattening of the tooth T, lengthening of the interval QT and segment depression ST (however, the clinical significance of these changes is not established).

When the drug is used in clinical trials (at recommended therapeutic doses), a significant lengthening interval QT compared with placebo was not noted.

Hypokalemia

In some patients with the use of beta agonists₂β-adrenoreceptors, there may be significant hypokalemia, leading to the development of adverse events from the cardiovascular system. Reducing the concentration of potassium in the blood serum is usually transient and does not require correction. In patients with severe COPD, hypokalemia may be exacerbated by hypoxia and concomitant therapy, which in turn may increase the likelihood of arrhythmias.

Hyperglycaemia

When inhaled high doses of beta agonists₂-adrenoceptors may increase the concentration glucose in the blood plasma. When using the drug in patients with diabetes should regularly monitor the concentration of glucose in the blood plasma. In clinical trials, patients receiving the drug (at recommended doses) experienced an increase in the incidence of clinically significant hyperglycemia an average of 1-2% compared with placebo.The efficacy and safety of the drug in patients with uncompensated diabetes mellitus have not been studied.

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

Data on the effect of the drug on the ability to drive vehicles and work with mechanisms there.

Form release / dosage:

Capsules with powder for inhalation, 150 mcg and 300 mcg.

Packaging:

10 capsules and a blister.

For 1, 3 or 9 blisters together with instructions for medical use and device for inhalation - Brizhaler in a cardboard box.

Storage conditions:

In a dry place, at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.