Onbrez Breezhaler, 300mcg powder inhalation capsules, 30pcs

Composition

Active ingredient:

indacaterol maleate;

Excipients:

lactose monohydrate — 24.806 / 24.611 mg

 Capsule shell:

gelatin-49/49 mg, black ink (for capsules 150 mg) and blue ink (for capsules 300 mg), which includes shellac (E 904), iron oxide black dye (E 172), purified water, propylene glycol (E 1520). The composition of blue ink also includes diamond blue dye (E 133) aluminum varnish, titanium dioxide (E 171)

Pharmacological action

Onbrez Breezhaler is a bronchodilator.

Pharmacodynamics

Indacaterol is a selective agonist of long-acting beta-2-adrenergic receptors (for 24 hours) with a single dose. The pharmacological action of beta-2-adrenergic agonists, including indacaterol, is associated with the stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3′,5′-AMP(cyclic AMP). An increase in the content of cyclic AMP leads to relaxation of the smooth muscles of the bronchi. Indacaterol is an almost complete beta-2-adrenergic agonist; the stimulating effect of the drug on beta-2-adrenergic receptors is 24 times stronger than on beta-1-adrenergic receptors, and 20 times stronger than on beta-3-adrenergic receptors.

After inhalation, the drug has a rapid and prolonged bronchodilating effect.

Indacaterol provides a sustained significant improvement in lung function (increased forced expiratory volume (FEV 1) in 1 second) 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-2-adrenergic agonist. The maximum effect of indacaterol is observed 2-4 hours after inhalation. Patients treated with indacaterol for 1 year did not develop tachyphylaxis to the bronchodilating effect of the drug. When using indacaterol, there was no dependence of the bronchodilating effect on the time of inhalation of the drug during the day (in the morning or in the evening).

Indacaterol reduces dynamic and static hyperinflation (increased lung volumes at the end of spontaneous exhalation) in patients with moderate to severe chronic obstructive pulmonary disease (COPD). When using the drug, there is a statistically significant increase in inspiratory capacity and FEV 1, a decrease in shortness of breath, and an improvement in exercise tolerance. There is also a significant reduction in the risk of COPD exacerbations (an increase in the time to the next exacerbation), a decrease in the need for short-acting inhaled beta-2-adrenergic agonists, and an improvement in the quality of life of patients (assessed using a certified questionnaire from St. George’s Hospital).

Pharmacokinetics

Absorption. After a single or repeated inhalation, the average time to reach the Cmax of Indacaterol in the blood serum is about 15 minutes. The systemic exposure of indacaterol increases with increasing dose (in the range from 150 to 600 mcg) 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 intestines. The concentration of indacaterol in the blood serum increases with repeated use of the drug. Css is achieved after 12-15 days of drug use. When the drug is inhaled once a day (in doses from 75 to 600 mcg) for 14 days, the accumulation coefficient of indacaterol, estimated by the drug exposure on the 1st and 14th (or 15th) days, (AUC0-24) is from 2.9 to 3.8.

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

Metabolism. When radiolabelled indacaterol is administered orally, unchanged indacaterol is the main component of serum and accounts for approximately 1/3 of the total AUC0-24 associated with the drug. Of the metabolites of the drug in the blood serum, the hydroxylated derivative of indacaterol is most determined. Further, hydroxylated indacaterol and phenolic O-glucuronide of indacaterol predominate. Later, diastereomers of the hydroxylated derivative, indacaterol N-glucuronide, and C – and N-dealkylated products are detected.

UDP-glucuronosyltransferase (UGT1A1) is the only isoenzyme that metabolizes indacaterol to phenolic O-glucuronide. Hydroxylation of indacaterol mainly occurs with the help of the CYP3A4 isoenzyme. It was also found that indacaterol is a substrate for the membrane transporter of P-glycoprotein (P-gp) molecules, but has a low affinity.

Elimination. The amount of unchanged indacaterol excreted in the urine is less than 2% of the dose. Renal clearance of indacaterol averaged 0.46–1.2 l/h. Given that the serum clearance of indacaterol is 18.8–23.3 l/h, it is obvious that the elimination of the drug through the kidneys is insignificant (approximately 2-5% of the systemic clearance).

When administered orally, indacaterol was mainly excreted through the intestines (90% of the dose): in unchanged form (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 T1 / 2 in the range from 45.5 to 126 h. T1 / 2, calculated on the basis of accumulation of indacaterol after repeated use, varied from 40 to 56 h, which was consistent with the established time to reach an equilibrium state (12-15 days).

Pharmacokinetics in special patient groups

Age, gender, and body weight do not affect the pharmacokinetics of indacaterol in patients with COPD. The effect of race on the pharmacokinetic parameters of indacaterol is unlikely. The experience of using the drug in people of the black race is limited.

Patients with impaired liver function. The pharmacokinetics of indacaterol (AUC, Cmax, protein binding) did not significantly change in patients with mild to moderate hepatic impairment. The use of the drug in patients with severe hepatic impairment has not been studied.

Patients with impaired renal function. Since indacaterol is only slightly excreted by the kidneys, the pharmacokinetics of the drug in patients with impaired renal function have not been studied.

Indications

Long-term maintenance therapy of bronchial patency disorders in patients with chronic obstructive pulmonary disease (COPD).

Contraindications

• hypersensitivity to indacaterol or any of the components of the drug;
• pregnancy and lactation;
• age up to 18 years (efficacy and safety have not been established).

With caution:  patients with concomitant cardiovascular disorders (ischemic heart disease, acute myocardial infarction, arrhythmias, arterial hypertension), convulsive disorders, thyrotoxicosis, diabetes mellitus, in patients with congenital QT prolongation syndrome, in patients simultaneously taking drugs that prolong the QT interval (class IA and III antiarrhythmic drugs, tricyclic and tetracyclic antidepressants, neuroleptics, macrolides, antifungal drugs, imidazole derivatives, some antihistamines, including astemizole, terfenadine, Ebastinee), general anesthesia drugs from the barbiturate group, as well as patients with a history of inadequate response to the action of beta-2-adrenergic agonists.

Side effects

Infections and infestations:  often-nasopharyngitis, upper respiratory tract infections, sinusitis.

Respiratory system disorders:  often — cough, sore throat, rhinorrhea.

Musculoskeletal disorders:  often — muscle spasms, myalgia, bone pain.

Nervous system disorders:  infrequently — dizziness, paresthesia.

From the CCC side:  often-coronary heart disease, infrequently-atrial fibrillation.

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, chest pain (non-cardiogenic), infrequently-chest discomfort.

Interaction

Drugs that prolong the QT interval

As with other beta-2-adrenergic agonists, prolongation of the QT interval is possible during drug therapy. Since this effect of indacaterol on the QT interval can be potentiated by other drugs, Onbrez ® Breezhaler® should be used with caution in patients receiving MAO inhibitors, tricyclic antidepressants, or other drugs that prolong the QT interval. Prolongation of the QT interval increases the risk of ventricular arrhythmia.

Sympathomimetic drugs

Concomitant use of indacaterol with sympathomimetics (either alone or in combination therapy) may increase the risk of adverse events.

The drug should not be used simultaneously with other long-acting beta-2-adrenergic agonists or with drugs that include long-acting agonists

Hypokalemic conditions BOS

Concomitant use with methylxanthine derivatives, corticosteroids, or potassium-withdrawing diuretics may increase possible hypokalemia caused by beta-2-adrenergic agonists.

Beta-2-adrenergic blockers

Since beta-2 blockers may weaken the effect or inhibit the action of beta-2 agonists, Onbrez® Breezhaler® should not be used concomitantly with beta-2 blockers (including eye drops).

If it is necessary to use both classes of drugs, it is preferable to use cardioselective beta-2-adrenergic blockers, but they should be used with caution.

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

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

Concomitant use of indacaterol with verapamil resulted in a 1.4-2-fold increase in AUC and a 1.5-fold increase in Cmax. When using indacaterol with erythromycin, an increase in AUC by 1.4–1.6 times and Cmax by 1.2 times was noted. Combination therapy with indacaterol and ketoconazole resulted in a 2-fold and 1.4-fold increase in AUC and Cmax, respectively. This increase in exposure due to drug interaction did not lead to a change in the safety profile. When using indacaterol with ritonavir (an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein), an increase in AUC by 1.6-1.8 times was noted, but Cmax remained unchanged.

When using indacaterol with other drugs, drug interactions were not observed. In vitro studies have shown that indacaterol has little potential for interaction with drugs at the level of metabolism by enzymes or at the level of membrane transporters at the systemic exposure achieved with the appointment of therapeutic doses.

How to take, course of use and dosage

For inhalation use only!

The preparation consists of capsules with powder for inhalation, which should be used only for inhalation by mouth using 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 removed from it immediately before use. Inhalation of the drug is carried out daily 1 time a day at the same time. If the inhalation is missed, Onbrez® Breezhaler® is used the next day at the usual time.

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

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

The maximum dose is 300 mcg (contents of 1 capsule 300 mcg) 1 time per day (1 inhalation per day). The maximum allowable dose of the drug should not be exceeded.

Dosage regimen for special patient groups

No dose adjustment is required in patients aged ≥65 years, patients with mild to moderate hepatic and renal impairment.

The use of the drug in patients with severe hepatic or renal impairment has not been studied.

Instructions for use of the Breezhaler®inhalation device

Each package of Onbrez® Breezhaler® contains:

– one Breezhaler® inhalation device;

– blisters with powder capsules for inhalation.

Capsules with powder for inhalation should not be taken orally!

The Breezhaler® inhalation device included in the package is intended for use only with capsules of the drug.

Only the Breezhaler®inhalation device is used to inhale the capsules in the package.

Do not use the capsules of the drug with any other inhalation device and, in turn, do not use Breezhaler® for inhalation of other drugs.

1. Remove the cover.

2. Open Breezhaler®. Hold the Breezhaler® by the base and tilt the mouthpiece in the direction of the arrow to open it.

3. Remove the capsule from the blister immediately before use with dry hands.

4. Insert the capsule into Breezhaler®. Place the capsule in the designated place of the Breezhaler®. Never place the capsule in the mouthpiece.

5. Close Breezhaler®. When you close it, you will hear a click.

6. Puncture the capsule. While holding the Breezhaler® strictly vertically, press the buttons of the piercing device simultaneously from both sides, and a click will be heard. This means that the capsule is punctured. Do not click on the buttons more than once.

7. Fully release the Breezhaler® buttons on both sides.

8. Exhale. Before taking the Breezhaler® mouthpiece in your mouth, make a full exhalation. Never blow into the mouthpiece.

9. Inhale the drug. Place the Breezhaler® mouthpiece in your mouth and press your lips tightly around it.

While holding the Breezhaler® with your hand, take a quick, even, as deep breath as possible. Do not press the buttons of the piercing device.

10. Pay attention. During inhalation, you will hear a characteristic rattling sound created by rotating the capsule and spraying the powder. The patient may feel a sweet taste of the drug in the mouth. If the characteristic sound is not present, then open the Breezhaler® and see what happened to the capsule. It may be stuck in a cell. In this case, it is necessary to carefully remove the capsule by lightly tapping on the base of the device. Never attempt to release the capsule by repeatedly pressing the buttons on the sides.

11. Hold your breath. If there is a distinctive sound when inhaling, hold your breath as long as possible (so as not to experience unpleasant sensations), and at the same time remove the mouthpiece from your mouth. Then exhale.

Open Breezhaler® and see if the powder is still in the capsule. If the powder remains in the capsule, close Breezhaler® and repeat the steps described in points 8 to 11. As a rule,1-2 inhalations are enough to completely release the capsule.

Some patients may start coughing immediately after inhalation. If this happens, do not worry, because the patient received the full dose of the drug during inhalation.

12. Get the capsule out. After inhalation, open the Breezhaler® by tilting the mouthpiece, remove the empty capsule and discard it. Close the Breezhaler mouthpiece and cover the inhaler. Do not leave capsules in Breezhaler®.

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

It is necessary to remember: do not swallow capsules containing powder for inhalation; use only the Breezhaler® contained in the package; capsules should be stored in a blister and removed immediately before use; never insert the capsule into the Breezhaler® mouthpiece, do not press the piercing device more than once; never blow into the Breezhaler® mouthpiece; always pierce the capsule before inhalation; do not wash the Breezhaler®, keep it dry (see the section “How to clean Breezhaler”); do not disassemble Breezhaler®; when starting a new package of the drug, always use the new Breezhaler® contained in the package for inhalation of capsules; do not store capsules in Breezhaler®; always store blisters with capsules and Breezhaler®in a dry place.

Additional information. In very rare cases, a small amount of the capsule contents may enter the mouth. The patient should not worry if he has inhaled or swallowed part of the contents of the capsule.

It should be remembered that if the capsule is punctured more than once, the risk of its breaking increases.

How to clean Breezhaler®. Clean the Breezhaler® once a week. Wipe the mouthpiece inside and out with a clean, dry cloth. Never use water to clean the Breezhaler®. Keep it dry.

Overdose

Symptoms: after a single use of the drug in patients with COPD at a dose 10 times higher than the maximum therapeutic dose, a moderate increase in heart rate was noted, an increase in blood pressure was observed. BP and prolongation of the QTc interval.

The most likely symptoms of overdose are tachycardia, tremor, palpitation, headache, nausea, vomiting, drowsiness, ventricular arrhythmia, metabolic acidosis, hypokalemia and hyperglycemia (caused by increased systemic beta-2-adrenomimetic action).

Treatment: supportive and symptomatic therapy is indicated. In severe cases, patients should be hospitalized. If necessary, cardioselective beta-blockers may be used. Cardioselective beta-blockers should be used with caution, only under strict medical supervision, since their use can provoke the development of bronchospasm.

Special instructions

Hypersensitivity reactions

Immediate hypersensitivity reactions have been reported with the use of Onbrez® Breezhaler®. If there are signs that indicate the development of an allergic reaction (in particular, difficulty breathing or swallowing, swelling of the tongue, lips and face, urticaria, skin rash), the drug should be discontinued and alternative therapy should be selected.

Bronchial asthma

Due to the lack of data on the long-term use of indacaterol in patients with bronchial asthma, the drug should not be used in this category of patients.

Paradoxical bronchospasm

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

Worsening of the underlying disease

The drug should not be used for relief of acute bronchospasm, i. e. it should not be used as an emergency therapy. If the course of COPD worsens during treatment with the drug, it is necessary to re-evaluate the patient’s condition and review the treatment regimen for the disease.

Impact on CVS

In some patients, Onbrez ® Breezhaler®, like other beta-2-adrenergic agonists, may affect the cardiovascular system (increase heart rate, blood pressure, etc. ). In case of adverse events, discontinuation of therapy with the drug may be necessary. In addition, the following electrocardiographic changes may occur with beta-2-adrenergic agonists: flattening of the T wave, prolongation of the QT interval, and ST-segment depression (however, the clinical significance of these changes has not been established).

When using the drug in clinical trials (at the recommended therapeutic doses), there was no significant prolongation of the QT interval compared to placebo.

Hypokalemia

In some patients, when using beta-2-adrenergic agonists, significant hypokalemia may occur, leading to the development of adverse events from the cardiovascular system. A decrease in serum potassium 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.

Hyperglycemia

When inhaling high doses of beta-2-adrenergic agonists, it is possible to increase the level of glucose in the blood plasma. When using the drug in patients with diabetes mellitus, the concentration of glucose in the blood plasma should be regularly monitored. In clinical trials, patients treated with the drug (at the recommended doses) showed an increase in the incidence of clinically significant hyperglycemia by an average of 1-2% compared to placebo. The efficacy and safety of the drug in patients with uncompensated diabetes mellitus have not been studied.

Form of production

Capsules with powder for inhalation

Storage conditions

In a dry place, at a temperature not exceeding 30 °C

Shelf life

2 years

Active ingredient

Indacaterol

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Purpose

For adults as directed by your doctor

Indications

Bronchial Asthma, Chronic Obstructive Pulmonary Disease, Bronchospasm