ONBREZ caps. 150 mcg
ONBREZ caps. 150 mcg
Onbrez Breezhaler 150 microgram inhalation powder, hard capsules
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains indacaterol maleate equivalent to 150 microgram indacaterol.
Released the mouthpiece of the inhaler Onbrez Breezhaler dose indacaterol maleate equivalent to 120 microgram indacaterol.
Each capsule contains 24,8 mg lactose.
For a full list of excipients,
Inhalation powder, hard capsule
Clear colorless capsules containing a white powder, with "IDL 150" printed in black above
company logo () printed in black below a black bar.
Onbrez Breezhaler is indicated for maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease
Posology and method of administration
The recommended dose is the inhalation of the content of one 150 microgram capsule once a day, using inhaler Onbrez Breezhaler. The dose should only be increased on medical advice.
It was found that inhalation of the content of one 300 microgram capsule once a day using the inhaler Onbrez Breezhaler provide additional clinical benefit with regard to breathlessness, particularly in patients with severe COPD. The maximum dose is 300 micrograms daily.
Onbrez Breezhaler should be administered at the same time each day.
If a dose is missed, the next dose should be taken at the usual time the next day.
The maximum plasma concentration and overall systemic exposure increase with age, but does not require dose adjustment in elderly patients.
There is no relevant use of Onbrez Breezhaler in the pediatric population (under 18 years).
Not require dosage adjustment in patients with mild to moderate hepatic impairment.
No data available for use of Onbrez Breezhaler in patients with severe hepatic harmless.
Not require dosage adjustment in patients with renal impairment.
Route of administration
For inhalation use only.
Onbrez Breezhaler capsules should be used only with the inhaler Onbrez Breezhaler.
Onbrez Breezhaler capsules should not be swallowed.
Hypersensitivity to the active substance, to lactose or to any of the excipients.
Special warnings and precautions for use
Onbrez Breezhaler should not be used in asthma due to the lack of data on long-term outcome of Onbrez Breezhaler in patients with asthma.
As with other inhalation therapy, administration of Onbrez Breezhaler may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, use Onbrez Breezhaler should be discontinued immediately and alternative therapy substituted.
Deterioration of disease
Onbrez Breezhaler is not indicated for the treatment of acute episodes of bronchospasm, ie as "rescue" therapy. In case of deterioration of COPD during treatment with Onbrez Breezhaler should reassess the patient and the therapeutic regimen of COPD. It is not appropriate increase in daily dose of Onbrez Breezhaler the maximum dose of 300 micrograms.
Although usually not clinically relevant effects on the cardiovascular system in applying Onbrez Breezhaler at recommended doses, like other beta2-adrenergic agonists, indacaterol should be used with caution in patients with cardiovascular disorders (coronary heart disease , acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists.
Like other beta2-adrenergic agonists, indacaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure and / or symptoms. If such effects occur, it may be necessary discontinued. In addition, beta-adrenergic agonists in the electrocardiogram (ECG) as flattening of the T wave and ST segment depression, although the clinical significance of these changes is unknown.
There was no clinically significant prolongation of the QTc-interval in clinical trials Onbrez Breezhaler, administered at the recommended therapeutic dose.
Beta2-adrenergic agonists may produce significant hypokalemia in some patients, which could potentially cause adverse effects on the cardiovascular system. The decrease in serum potassium is usually transient, not requiring supplementation of potassium supplements. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant medications that may increase susceptibility to cardiac arrhythmias.
Inhalation of high doses of beta2-adrenergic agonists may produce increases
plasma glucose. When initiating treatment with Onbrez Breezhaler plasma glucose levels should be monitored in patients with diabetes.
During clinical trials, clinically relevant changes in blood sugar levels are generally 1-2% more frequent in patients treated with Onbrez Breezhaler recommended doses versus placebo. Onbrez Breezhaler has not been studied in patients with poorly controlled diabetes.
Interaction with other medicinal products and other forms of interaction
Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the adverse effects of Onbrez Breezhaler.
Onbrez Breezhaler should not be used in conjunction with other long-acting beta2-adrenergic agonists or medicinal products containing long-acting beta2-adrenergic agonists.
Concomitant therapy with methylxanthine derivatives, steroids, or potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists, therefore use should be undertaken with caution vnimanie.
Beta-adrenergic blockers may weaken or antagonize the effect of beta2-adrenergic agonists. Therefore indacaterol should not be used concomitantly with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. If necessary to prefer cardioselective beta-adrenergic blockers, although they should be used with caution.
Metabolic interactions and interactions transporter molecules
Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-glycoprotein (P-gp) increased the systemic exposure of indacaterol twice. The rate of increase in systemic exposure is not associated with any concerns about the safety of the drug, taking into account the data from the application of Onbrez Breezhaler during the one-year study at doses up to twice the maximum recommended therapeutic dose.
It was found that indacaterol comedication does not interact with other medicines. In vitro studies have shown that levels of systemic exposure achieved in clinical practice, indacaterol has negligible potential to cause metabolic interactions with other drugs.
Pregnancy and lactation
No data on the use of indacaterol in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures (see section 5.3). Like other beta2-adrenergic agonists, indacaterol may inhibit labor due to a relaxant effect on the smooth muscle of the uterus. Onbrez Breezhaler should be used during pregnancy only if the expected benefits outweigh the potential risks.
It is not known whether indacaterol / metabolites are excreted in human milk. Available pharmacokinetic / toxicological data in animals have shown that indacaterol / metabolites
excreted in milk (see section 5.3). It can not be excluded infant. Should be made whether to discontinue nursing or to discontinue / abstain from treatment with Onbrez Breezhaler, taking into account the benefit of breast-feeding to the child and the benefit of therapy for the mother.
A decreased pregnancy rate in rats. However, it is considered unlikely that indacaterol will affect reproductive or fertility performance in humans following inhalation of the maximum recommended dose.
Effects on ability to drive and use machines
Onbrez Breezhaler no or negligible influence on the ability to drive and use machines.
Summary of the safety profile
The most common side effects at the recommended doses were nasopharyngitis (9.1%), cough (6.8%), upper respiratory tract infection (6.2%) and headache (4.8%). The majority of adverse reactions were mild or moderate and resolved spontaneously during treatment.
At the recommended doses, the adverse reaction profile of Onbrez Breezhaler in patients with COPD showed no clinically significant systemic effects of beta2-adrenergic stimulation. The average change in heart rate is less than one beat per minute, and tachycardia was infrequent and reported at a frequency similar to that of placebo.
At twice the maximum recommended dose safety profile of Onbrez Breezhaler is generally similar to that at recommended doses. Additional adverse reactions were tremor (common) and anemia (uncommon).
Description of selected adverse reactions
In Phase III clinical studies, healthcare providers observed during clinical visits that on average 17-20% of patients experienced a sporadic cough that occurred usually within 15 seconds after inhalation, and typically lasting about 5 seconds (about 10 seconds in current smokers) . There is a higher incidence in women than in men and in current smokers than in former smokers. This cough experienced post inhalation was well tolerated and did not result in discontinuation of therapy with one of the participants in the studies in treatment at the recommended doses (cough is a symptom of COPD and only 6.8% of patients in January reported as an adverse reaction). There is no evidence that cough experienced post inhalation is associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.
In patients with COPD, single doses of 10 times the maximum recommended therapeutic dose is associated with modest increases in pulse rate, systolic blood pressure and QTc prolongation.
An overdose of indacaterol is likely to lead to exaggerated effects typical of
beta2-adrenergic agonists, ie tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalemia and hyperglycemia.
Shown is supportive and symptomatic. In serious cases, the patient should be hospitalized. You might consider the use of cardioselective beta-blockers, but only under medical supervision and with extreme caution, since the use of beta-adrenergic blockers may provoke bronchospasm.
Pharmacotherapeutic group: Long-acting beta2-adrenergic agonist, ATC code: R03AC18
Mechanism of Action
The pharmacological effects of beta2-adrenoceptor agonists are at least partly be explained by the activation of intracellular adenilattsiklaza - an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3 ', 5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol is a long-acting beta2-adrenergic agonist, has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors.
When inhaled, indacaterol acts locally in the lung as a bronchodilator.
Indacaterol is a partial agonist at the human beta2-adrenergic receptor with nanomolar potential. In indacaterol has a rapid onset and long duration of action.
Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle of the human heart prevail beta1-receptors in the heart is and beta2-adrenergic receptors, comprising 10-50% of the total adrenergic receptors.
The exact function of the beta 2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
Onbrez Breezhaler, administered once a day at doses of 150 and 300 micrograms over 24 provides clinically significant improvement in lung function (measured by forced expiratory volume in one second, FEV1) from a number of pharmacodynamic and clinical efficacy studies. There was a rapid onset of action within 5 minutes after inhalation, with an increase in FEV1 with 110-160 ml from baseline comparable to that of fast-acting beta2-agonist salbutamol
200 microgram and statistically significantly faster than that of salmeterol / fluticasone 50/500 micrograms. The maximum response in FEV1 from steady state average is 250-330 ml from baseline.
Bronchodilator effect did not depend on the time of dosing, morning or evening.
It was found that Onbrez Breezhaler svrahrazduvaneto reduces the lungs, increasing the inspiratory flow rate during exercise and at rest, compared to placebo.
Effects on cardiac electrophysiology
A double-blind, placebo and active (moxifloxacin)-controlled study for 2 weeks in 404 healthy volunteers showed maximum mean (90% confidence interval) prolongation of QTcF interval (in milliseconds) of 2.66 (0.55, 4.77 ), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) after multiple doses of 150 micrograms, 300 micrograms and 600 micrograms, respectively. Therefore, there was no potential for proaritmogenna activity associated with prolongation of the QT-interval prolongation when administered at the recommended dose or twice the maximum recommended dose. No evidence of more frequent monitoring of dependence between concentration and QTc interval with delta waves in the range of doses.
In a 26-week, double-blind, placebo-controlled Phase III study in 605 patients
COPD found no clinically significant difference in the incidence of arrhythmias in 24-hour monitoring, at baseline and up to 3 times during the 26-week treatment period in patients treated with Onbrez Breezhaler recommended doses of those treated with placebo and tiotropium.
Clinical efficacy and safety
The clinical development program includes a 12-week, six-two (one of which is extended to one year to assess the safety and tolerability) and one one-year randomized controlled clinical trials in patients with a clinical diagnosis of COPD. Studies include measurements of several indicators to assess lung function and health status as dyspnoea, exacerbations and health-related quality of life.
Onbrez Breezhaler administered once daily at doses of 150 micrograms and 300 micrograms demonstrated clinically meaningful improvements in lung function. Regarding the 12 - week primary endpoint (24-hour FEV1) administration of a dose of 150 microgram dose resulted in a 130-180 ml increase compared to placebo (p <0,001) and a 60 ml compared to salmeterol at a dose of 50 microgram twice daily (p <0,001). A dose of 300 micrograms resulted in an increase in FEV1 with 170-180 ml versus placebo (p <0,001) and rising to 100 ml dose of formoterol 12 microgram twice daily (p <0,001). Both doses increased FEV1 compared with 40-50 ml dose of tiotropium 18 micrograms once daily (150 micrograms, p = 0,004; 300 micrograms, p = 0,01) during the open-label study. 24-hour bronchodilator effect of Onbrez Breezhaler is retained by the first dose for a period of one year, with no evidence of loss of efficacy (tachyphylaxis).
Indacaterol is a chiral molecule with R-configuration.
Pharmacokinetic data were obtained in a number of clinical studies in healthy volunteers and patients with COPD.
The median time to peak serum concentrations of indacaterol was approximately 15 min after single and repeated inhalation.