Universal reference book for medicines
Product name: ONBREZ® BREEZHALER® (ONBREZ BREEZHALER)
International name: indacaterol (indacaterol)

ATC codes: R03AC18

Owner reg.
Certificates: NOVARTIS PHARMA AG (Switzerland)
Capsules with powder for hard gelatin inhalation , size 3, with transparent colorless lid and body, with the company logo under the black stripe on the lid and the inscription "IDL 150" in black ink over the black stripe on the body; the contents of the capsules are white or almost white powder.
1 caps.

indacaterol maleate 194 mcg,

which corresponds to the content of indacaterol 150 μg

Excipients: lactose monohydrate - 24.806 mg.

The composition of the capsule shell: gelatin - 49 mg, black ink (shellac (E904), ferric oxide black oxide (E172), purified water, propylene glycol (E1520)).

10 pieces.
- Blisters (1) complete with device for inhalation (breezing) - packs of cardboard.
10 pieces.
- blisters (3) complete with device for inhalation (breezing) - packs of cardboard.
Capsules with powder for hard gelatin inhalation , size 3, with transparent colorless lid and body, with the company logo under the blue stripe on the lid and the inscription "IDL 300" in blue ink above the blue stripe on the body;
the contents of the capsules are white or almost white powder.
1 caps.

indacaterol maleate 389 mcg,

which corresponds to the content of indacaterol 300 μg

Excipients: lactose monohydrate - 24.611 mg.

The composition of the capsule shell: gelatin - 49 mg, blue ink (shellac (E904), iron dye oxide black (E172), water purified, propylene glycol (E1520), dye diamond blue (E133) aluminum varnish, titanium dioxide (E171)).

10 pieces.
- Blisters (1) complete with device for inhalation (breezing) - packs of cardboard.
10 pieces.
- blisters (3) complete with device for inhalation (breezing) - packs of cardboard.


The description of the preparation is based on an approved instruction for use and approved by the manufacturer for the 2012 edition.


PHARMACHOLOGIC EFFECT



Is indacaterol a selective agonist?
2- adrenoreceptors of long-acting (within 24 hours) with a single admission. Pharmacological action of agonists? 2-adrenoreceptors, including indacaterol, is associated with stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3 ', 5'-adenosine monophosphate (cyclic AMP). An increase in the content of cyclic AMP leads to a relaxation of the smooth muscles of the bronchi. Is indacaterol an almost complete agonist? 2- adrenoreceptors; stimulating effect of the drug on? 2- adrenoreceptors are 24 times stronger than on? 1-adrenoreceptors, and 20 times stronger than? 3- adrenoreceptors.
After inhalation, the drug has a rapid and prolonged bronchodilator effect.

Indacaterol provides a persistent significant improvement in lung function (increased volume of forced expiration in the first second, FEV 1 ) 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 agonist?
2-adrenoreceptors. The maximum action of indacaterol is observed 2-4 hours after inhalation. In patients who received indacaterol for 1 year, there was no development of tachyphylaxis to bronchodilator effect of the drug. When using indacaterol, there was no dependence of bronchodilating action on the inhalation time 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 COPD.
When using the drug, a statistically significant increase in the inspiratory capacity and FEV 1 , a decrease in dyspnea, an improvement in the tolerance of physical exertion is noted. There is also a significant reduction in the risk of exacerbations of COPD (an increase in the time until the next exacerbation), a reduction in the need for inhalation agonists? 2- adrenoreceptor short-acting and improving the quality of life of patients (evaluation using the certified questionnaire of St. George's Hospital).
PHARMACOKINETICS



Suction

After a single or repeated inhalation, the mean time to reach C max of indacaterol in the 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. C ss is achieved after 12-14 days of application. With inhalation of the drug 1 time / day (in doses from 150 μg to 600 μg) for 14 days, the cumulation index of indacaterol, estimated from the exposure of the drug on the 1st and 14 days (AUC 0-24 ) is from 2.9 to 3.5.
Distribution

After IV introduction, the volume of distribution (Vz / F) of indacaterol was 2.557 l, indicating a significant distribution of the drug.
Binding to human serum and plasma proteins is 94.1-95.3% and 95.1-96.2%, respectively.
Metabolism

When orally administered to a radiolabeled indacaterol, unchanged indacaterol is the main component of serum and is approximately 1/3 of the total AUC0-24 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, hydroxylated indacaterol and phenolic O-glucuronide indacaterol predominate. Later, diastereomers of hydroxylated derivative, indacaterol N-glucuronide and C- and N-dealkylated products are detected. 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 substrate for the membrane carrier of P-glycoprotein molecules (P-gp), but it has a low affinity.
Excretion

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 23.3 l / h, it is obvious that excretion through the kidneys is negligible (approximately 2-5% of the system clearance).
When administered 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 T 1/2 in the range from 45.5 to 126 hours. The effective T 1/2 , calculated on the basis of accumulation of indacaterol after repeated application, varied from 40 to 52 hours, which was consistent with the established time of reaching equilibrium state (12-14 days).

Pharmacokinetics in special clinical cases

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.
The 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.
Since 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 COPD.

DOSING MODE



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 removed from it immediately before use. Inhalation of the drug is carried out daily 1 time / day at the same time. In the case of missed inhalation, the next day, Onbres ®Breezhaler ® is used at normal times.
The recommended dose of the drug is 150 μg (the contents of 1 capsule 150 μg) 1 time / 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 content 300 μg) 1 time / 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) 1 time / day (1 inhalation per day).
The maximum permissible dose of the drug can not be exceeded.
No dose adjustment is required in patients aged 65 years and over, patients with mild or moderate impairment of liver and kidney function.

The use of the drug in patients with severe impairment of liver or kidney function has not been studied.

Application rules


Each package of Onbrez ® Breezhaler ® contains:

1. One inhalation device - Brizhaler.


2. Blisters 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

Remove the cover.


Open the Brizhaler.
Holding Brizhaler by the base and, having deflected the mouthpiece in the direction of the arrow, open it.

With dry hands, remove the capsule from the blister immediately before use.


Insert the capsule into the Breezyhaler.
Place the capsule in a specially designed place for Breezyhaler. Never put the capsule in the mouthpiece.

Close Бризхалер.
When closing, there should be a click.

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

Completely release the Breezhaler's buttons on both sides.


1. Next, the patient should make a full exhalation (before he takes the Brizhaler's mouthpiece into his mouth).
Do not blow into the mouthpiece.
2. Next insert the mouthpiece of Brizhaler in the mouth and tightly compress the lips around it.
Holding Brizhaler by hand, make a quick, uniform, deepest inhalation. Do not press the buttons of the piercing device.
3. During inhalation, the patient should hear a characteristic rattling sound created by rotating the capsule and spraying the powder.
He can feel the sweetish taste of the drug in his mouth. If the patient has not heard the sound, then you need to open Brizhaler and see what happened to the capsule.Perhaps she was stuck in the cell. In this case, carefully remove the capsule by tapping it lightly on the base of the device. Do not try to release the capsule by repeatedly pressing the buttons on the sides.
4. If the patient has heard a characteristic sound when inhaled, he should hold his breath as long as possible (so as not to experience unpleasant sensations), and at the same time remove the mouthpiece from his mouth.
After that, breathe out.
Then the patient should open Brizhaler and see if the powder remains in the capsule.
If the powder remains in the capsule, close the Brizhaler and repeat the steps described in points 1 to 4. 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, the patient should not worry, because during inhalation he received a full dose of the drug.
After the patient has made inhalation, he must open the Brizhaler, rejecting 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.

If the patient is comfortable, he can make a mark 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.
The patient should know:

1. Do not swallow capsules with powder for inhalation.

2. Use only Brizhaler in the package.

3. Capsules should be stored in a blister and removed immediately before use.

4. Never put the capsule in the Brizhaler's mouthpiece.

5. Do not press the piercing device more than once.

6. Never blow into the Brizhaler's mouthpiece.

7. Always pierce the capsule prior to inhalation.

8. Do not wash Brizhaler.
Keep it dry.
9. Do not disassemble Brizhaler.

10. Starting a new package of the drug, for the inhalation of capsules always use a new Breezhaler, located in the package.

11. Do not store capsules in Brizhaler.

12. 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.
The patient should not worry about this. It should be noted that if the capsule is punctured more than once, the risk of its breakage increases.
How to clean Brizhaler

Brizhaler should be cleaned once a week.
Wipe the mouthpiece from the outside and inside with a clean dry cloth. Never use water to clean Brizhaler. Keep it dry.
SIDE EFFECT



When applying the drug in therapeutic doses, the most frequently observed adverse events were nasopharyngitis, cough, upper respiratory tract infections and muscle spasms.
The majority of the above undesirable events were of mild or moderate severity, the incidence of these adverse events decreased as they continued to be used.
Below are the undesirable effects observed with the drug at doses of 150 and 300 μg 1 time / day in patients with COPD.
Undesired reactions are distributed according to the frequency of occurrence. The following criteria were used to estimate the frequency: very often (? 1/10); often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000), including individual messages.
Infections and infestations: often - nasopharyngitis, upper respiratory tract infections, sinusitis.

From the respiratory system: often - cough, sore throat, rhinorrhea.

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

From the nervous system: infrequently - dizziness, paresthesia.

From the cardiovascular system: often - IHD;
infrequently - atrial fibrillation.
From the digestive system: often - dry mouth.

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

Common disorders: often - peripheral edema, pain in the chest (non-cardiogenic);
infrequent - discomfort in the chest area.
When using the drug at a dose of 600 μg 1 time / day, the safety profile did not differ significantly from that in inhalation of therapeutic doses (150 and 300 μg 1 time / day).
Additional adverse events were anemia and tremor. Muscular spasms and nasopharyngitis were also more often detected. In patients with COPD with inhalation in the recommended doses the drug does not have a clinically significant systemic? 2- adrenomimeticheskogo action. The heart rate on average changed by no more than 1 bpm. The frequency of development of tachycardia (noted in rare cases), significant prolongation of the QT interval (> 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, development of 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 6.6% 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.
CONTRAINDICATIONS



- age under 18 years (effectiveness and safety not established);

- Pregnancy;

- the period of breastfeeding;

- Hypersensitivity to any of the components of the drug.

With caution should appoint the drug to patients with concomitant cardiovascular disorders (CHD, acute myocardial infarction, arrhythmias, arterial hypertension), with convulsive disorders, thyrotoxicosis, diabetes, as well as in patients who have a history of inadequate response to the action of agonists?2- adrenoreceptors.

PREGNANCY AND LACTATION



The safety of indacaterol in pregnancy is not established.
When using indacaterol in animals (in doses equivalent to therapeutic doses in humans), no reproductive toxicity was detected. In this regard, indacaterol may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Like other agonists? 2 -adrenoceptor, indacaterol may slow process due to the genera tocolytic action (the action of relaxing the smooth muscles of the uterus). It is not known whether indacaterol passes into breast milk in humans. Since the use of indacaterol in animals is excreted in breast milk, it is impossible to eliminate the adverse effects of the drug on the child through breastfeeding in humans. If necessary, the use of feeding a child breast milk drug should be discontinued.
SPECIAL INSTRUCTIONS



Asthma
Due to lack of data on prolonged use of indacaterol in patients with asthma, the drug should not be used in these patients.
Paradoxical bronchospasm
As with any other inhalation therapy, the use of the drug may lead to the development of paradoxical bronchospasm, which represents a threat to the life of the patient. In the case of paradoxical bronchospasm drug treatment should be discontinued immediately and alternative therapy is appointed.
The deterioration of the underlying disease
The drug should not be used for the relief of acute bronchospasm, ie not be used as a rescue therapy. In the event of deterioration of COPD on a background of drug treatment, it is necessary to re-evaluate the patient and review the regimen of the disease.
Influence on the cardiovascular system
in some patients the drug Onbrez ® Brizhaler ® , as well as other agonists? 2 adrenoceptor may affect the cardiovascular system (increased heart rate, blood pressure). In the case of adverse events may require cessation of drug therapy. In addition, if agonists? 2adrenoceptor may occur following electrocardiographic changes: T wave flattening, lengthening the interval QT segment depression and ST (however, the clinical significance of these changes is not installed).
In applying the drug in clinical trials (in recommended therapeutic doses) significant lengthening QT interval versus placebo were observed.
Hypokalemia
in some patients when agonists? 2adrenoceptor may experience significant hypokalemia, leading to the development of adverse events in 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, hypokalaemia may be aggravated by hypoxia and concomitant treatment, which, in turn, may increase the likelihood of arrhythmias.
Hyperglycaemia
Inhalation of high doses of agonists? 2adrenoceptor may increase the level of glucose in the blood plasma. In applying the drug in patients with diabetes must regularly monitor the concentration of glucose in blood plasma. In clinical studies of patients receiving the drug (at recommended doses) there was an increase in the incidence of clinically significant hyperglycaemia an average of 1-2% compared to placebo. Efficacy and safety of the drug in patients with uncompensated diabetes mellitus have not been studied.
Effects on ability to drive vehicles and management mechanisms
Data on the effect of the drug on the ability to drive vehicles and operate with no mechanisms.
OVERDOSE



Symptoms: after a single drug application in patients with COPD in a dose 10 times higher than the maximum therapeutic, indicated a moderate increase in heart rate, increased blood pressure and lengthening the interval QT c .
The most likely symptoms of overdose are tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalemia and hyperglycemia (due to increased systemic beta 2 -adrenomimeticheskogo action).
Treatment:It shows supportive and symptomatic therapy. In severe cases, patients need to be hospitalized. If necessary, the possible application of cardioselective beta-blockers. Use cardioselective beta-blockers should be cautious, only under strict medical supervision, since their use can induce bronchospasm.
DRUG INTERACTION



Drugs prolonging the QT interval
As with other agonists? 2 adrenoceptor on background therapy with possible prolongation of the interval QT. Since this effect indacaterol on QT interval length may potentiate other drugs, a drug Onbrez ® Brizhaler ® should be used with caution in patients receiving MAO inhibitors, tricyclic antidepressants or other drugs, lengthening the interval QT. Prolongation of QT interval increases the risk of ventricular arrhythmias.
Sympathomimetic drugs
Concomitant use of indacaterol with sympathomimetics (both individually and as part of combination therapy) may increase the risk of adverse events.
The drug should not be used simultaneously with other agonists? 2 -adrenoceptor long acting or medicaments which include agonists? 2 -adrenoceptor prolonged action.
Hypokalemia
simultaneous use of methylxanthine derivatives, corticosteroids or diuretics, potassium leading out, can enhance possible hypokalemia caused agonists? 2adrenoceptor.
Blockers? 2 adrenoceptor
Since blockers? 2 adrenoceptor may weaken the effect of agonists or interfere with the action? 2 adrenoceptor preparation Onbrez ® Brizhaler ®should not be used simultaneously with the blockers? 2 -adrenoceptor (including eye drops).
If necessary, use both classes of drugs are preferably used cardioselective blockers? 2 -adrenoceptor, however, you must use them with caution.
Interaction at the CYP3A4 isoenzyme level and membrane transporter P-glycoprotein
has been studied indacaterol interaction with specific inhibitors isoenzyme CYP3A4 and P-glycoprotein, such as ketoconazole, erythromycin and verapamil.
Concomitant use of indacaterol with verapamil resulted in a 1.4-2-fold increase in AUC and a 1.5-fold increase in the C max. In the application of indacaterol with erythromycin was an increase in AUC by 1.4 - 1.6 times, and the C max by 1.2 times. Combination therapy indacaterol and ketoconazole caused a 2-fold and 1.4-fold increase in AUC and C max , respectively. This increase in drug exposure due to interaction did not lead to a change in the safety profile.
In applying indacaterol drug interactions with other drugs was observed. Studies in vitro have shown that indacaterol has little potential for drug interaction on the level of metabolism, or enzymes at the level of membrane transporters in systemic exposure achieved when assigning therapeutic doses.
STORAGE CONDITIONS AND SHELF LIFETIME



The preparation should be stored in a dry place inaccessible to children at a temperature not higher than 30 ° C. Shelf life - 2 years. The drug should not be used beyond the expiration date.



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