Ultibro Breezhaler: bronchodilator for chronic obstructive pulmonary disease

2021-06-11 08:13 AM

Ultibro Breezhaler is a bronchodilator indicated for once-daily maintenance therapy for the relief of symptoms and exacerbations in patients with chronic obstructive pulmonary disease (COPD).

Producer

Novartis Pharma.

Ingredient

Each tablet: Indacaterol (as Indacaterol maleate) 110 micrograms, glycopyrronium (as Glycopyrronium bromide) 50 micrograms.

Describe

Each capsule contains 143 micrograms of indacaterol maleate corresponding to 110 micrograms indacaterol and 63 micrograms glycopyrronium bromide corresponding to 50 micrograms glycopyrronium.

Each delivered dose (the dose that leaves the mouthpiece tip of the inhaler) corresponds to 85 micrograms of indacaterol and 43 micrograms of glycopyrronium.

Pharmacodynamic

Pharmacotherapeutic group: Adrenergic combined with anticholinergic

ATC code: R03AL04

Mechanism of action

Ultibro Breezhaler

When indacaterol and glycopyrronium are used in combination in Ultibro Breezhaler, the two drugs produce a synergistic effect due to the different mechanisms of action of the drugs acting on different receptors and different mechanisms of smooth muscle relaxation. Because of the difference in densities of the central beta2-adrenergic and M3 receptors relative to the smaller airways, beta2-agonists are more effective in dilating the small airways, whereas Anticholinergics may be more effective on large airways. Therefore, combining a beta2 agonist with an M receptor antagonist may be beneficial for optimal bronchodilator effects across all lung regions.

Indacaterol

Indacaterol is a long-acting “super” long-acting beta2-adrenergic agonist administered once daily. The pharmacological effects of beta2-adrenergic receptor agonists, including indacaterol, are at least in part due to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to 3', 5' -adenosine monophosphate (cyclic monophosphate). Increased levels of cyclic AMP lead to the relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has an agonist effect on beta2-receptors 24 times more potent than on beta1-receptors and 20 times stronger on beta3-receptors. This selective property is similar to formoterol.

After inhalation, indacaterol acts locally on the lungs as a bronchodilator. Indacaterol is an almost complete agonist of human beta2-adrenergic receptors at nanomolar concentrations. In isolated human bronchi, indacaterol has a rapid and prolonged action.

Although in humans, beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenergic receptors are the predominant receptors on the heart, beta2-adrenergic receptors on the heart are still present. percentage from 10% to 50% of total adrenergic receptors. The exact function of beta2-adrenergic receptors on the heart is unknown, but their presence leads to the possibility that selective beta2-adrenergic agonists can still cause adverse effects. action on the heart.

Glycopyrronium

Glycopyrronium is a long-acting inhaled muscarinic receptor antagonist (anticholinergic) administered once daily for the maintenance treatment of bronchiectasis in patients with chronic obstructive pulmonary disease. The parasympathetic nerve is the predominant nerve pathway for bronchoconstriction in the airways, and parasympathetic tone is the major reversible component of airway obstruction in chronic obstructive pulmonary disease. Glycopyrronium inhibits the effect of acetylcholine, which is a bronchoconstrictor, on the smooth muscle cells of the airways, thereby dilating the airways.

Of the 5 known muscarinic receptor subtypes, only the M1-3 subtypes have been identified with physiological function in the human lung. Glycopyrronium bromide is a high-affinity antagonist of these three muscarinic receptor subtypes. Competing studies have shown that the drug binds 4 to 5 times more selectively to the M3 and M1 receptors than to the human M2 receptors. The drug has a short onset of action as demonstrated by the kinetics of receptor binding/dissociation and the immediate effect of the drug after inhalation in clinical studies.
 
The prolonged effect of the drug may be partly due to the concentration of the drug maintained in the lungs as reflected by the prolonged elimination half-life of glycopyrronium following inhalation via the glycopyrronium inhalation system as opposed to the half-life discharged after intravenous administration. Pulmonary pharmacokinetic data in rats following inhalation of glycopyrronium bromide provide additional evidence for this effect.

Main pharmacodynamic effects

The combination of indacaterol and glycopyrronium in Ultibro Breezhaler shows an immediate effect of the drug within 5 minutes of administration. The effect of the drug was maintained for 24 hours between dose intervals.

The mean bronchodilator effect obtained from 24-hour FEV1 volume measurements was 0.32 L after 26 weeks of treatment when compared with placebo. Ultibro Breezhaler was significantly more potent when compared with indacaterol, glycopyrronium or tiotropium alone (difference 0.11 L in each comparison), (sequential spirometry).

There was no evidence of dependence on Ultibro Breezhaler over time when compared with placebo or the individual components of the drug.

Secondary pharmacodynamic effects

The systemic adverse effects of inhaled beta2-adrenergic agonists and inhaled muscarinic receptor antagonists result from activation of systemic beta2-adrenergic receptors and blockade of muscarinic receptors after the drug is administered. absorbed into the general circulation. Data on the adverse effects of Ultibro Breezhaler were collected in healthy subjects and in patients with chronic obstructive pulmonary disease.

Effects on heart rate

The effect of the drug on heart rate was studied in healthy volunteers after a single dose of Ultibro Breezhaler 440/200 micrograms administered in 4 divided doses 1 hour apart and compared with the effects of placebo, 600 micrograms indacaterol, 200 micrograms glycopyrronium and 200 micrograms salmeterol.

The time when Ultibro Breezhaler's heart rate increased the most compared to placebo was +5.69 beats/min, the biggest decrease was -2.51 beats/min. The overall effect on heart rate overtime does not reflect the stable pharmacodynamic profile of Ultibro Breezhaler.

While there was no significant difference when comparing Ultibro Breezhaler with indacaterol and glycopyrronium alone, there appeared to be a slight increase in heart rate (greatest difference at about 11 beats/min) after inhalation of 200 micrograms of salmeterol.

Heart rate in patients with chronic obstructive pulmonary disease at doses above the therapeutic dose range studied with Ultibro Breezhaler up to 150/100, 300/100, and 600/100 micrograms. No significant effect was observed with respect to the effect of Ultibro Breezhaler on mean heart rate over 24 hours or heart rate assessed after 30 minutes, 4 hours, and 24 hours of dosing.

QT interval

It is not known whether the components of Ultibro Breezhaler (indacaterol and glycopyrronium) have the potential to prolong the QT interval when administered at therapeutic doses. A comprehensive QT assessment (TQT) in healthy volunteers with inhaled doses of indacaterol up to 600 micrograms did not show a clinically significant effect on the QT interval. Similar to glycopyrronium, no QT prolongation was observed in the TQT study after inhalation of 400 micrograms.

The effect of Ultibro Breezhaler on the QT interval was studied in healthy volunteers following inhalation of Ultibro Breezhaler 440/200 micrograms in 4 divided doses 1 hour apart. The largest time difference achieved when compared with placebo was 4.62 ms (90% confidence interval 0.4; 8.85 ms), the largest time reduction was -2.71 ms (confidence interval). 90% -6.97; 1.54 ms), indicating that Ultibro Breezhaler had no effect on the QT interval as expected based on the properties of the constituent drugs.

In patients with chronic obstructive pulmonary disease, doses up to 600/100 micrograms of Ultibro Breezhaler have not been found to have a significant effect on the QTc interval on the electrocardiogram recorded continuously from 15 minutes to 24 minutes after dosing. . A small percentage of patients had a QT interval prolongation of more than 450 ms in the Ultibro Breezhaler 600/100 microgram group. The number of patients with a notable QTcF change from baseline (>30 ms) was similar across all drug treatment groups (Ultibro Breezhaler 600/100 micrograms, 300/100 micrograms, 150/100 micrograms, and indacaterol 300 micrograms), but lower than in the placebo group.

Serum potassium and blood glucose

In healthy volunteers, after administration of Ultibro Breezhaler 440/200 microgram, the effect of the drug on serum potassium was very small (maximum difference -0.14 mmol/L when compared with placebo). The maximum effect on blood glucose is 0.67 mmol/L. When comparing Ultibro Breezhaler 440/200 micrograms with 200 micrograms of salmeterol, the effect on serum potassium (maximum difference 0.21 mmol/L) and blood glucose were lower (maximum difference, respectively, 0. 21 and 1.19 mmol/L).

Pharmacokinetics

Absorb

Following inhalation of Ultibro Breezhaler, the meantime to peak plasma concentrations of indacaterol and glycopyrronium were approximately 15 minutes and 5 minutes, respectively.

Based on in vitro data, the dose distribution of indacaterol to the lungs is expected to be similar to Ultibro Breezhaler 110/50 microgram and indacaterol 150 microgram administered alone. Steady-state exposure to indacaterol following inhalation of Ultibro Breezhaler at 110/50 micrograms was similar or slightly lower than total circulating exposure following inhalation of indacaterol 150 micrograms alone.

The absolute bioavailability of indacaterol after inhalation of Ultibro Breezhaler 110/50 micrograms ranges from 47% to 66% while with glycopyrronium it is about 40%.

Steady-state exposure to glycopyrronium following inhalation of Ultibro Breezhaler 110/50 micrograms was similar to systemic exposure following inhalation of glycopyrronium 50 micrograms alone.

Indacaterol

The mean time to peak plasma concentrations of indacaterol is approximately 15 minutes after inhalation of a single or repeated dose.

Serum indacaterol concentrations increased following repeated once-daily dosing. Steady state is reached within 12 to 15 days. The mean cumulative incidence of indacaterol, i.e. AUC over the 24-hour dose range on day 14 or 15 compared with day 1 ranged from 2.9 to 3.8 with once-daily inhaled dosing at dose levels. from 75 micrograms to 600 micrograms.

Glycopyrronium

Following oral inhalation using a glycopyrronium inhaler, glycopyrronium is rapidly absorbed and reaches peak plasma concentrations 5 minutes after dosing.

Approximately 90% of the total drug in the circulation achieved after inhalation is due to absorption from the lungs and 10% from the absorption from the gastrointestinal tract. The absolute oral bioavailability of glycopyrronium is estimated at 5%.

Following repeated once-daily inhalations in patients with chronic obstructive pulmonary disease, steady-state pharmacokinetics of glycopyrronium were achieved within 1 week of treatment. Mean steady-state peak and trough concentrations of glycopyrronium at 50 micrograms once daily were 166 pg/mL and 8 pg/mL, respectively. At doses of 100 and 200 micrograms once daily, steady-state concentrations of glycopyrronium (AUC during dosing) were approximately 1.4 to 1.7 times higher than after the first dose. Urine excretion data at steady-state relative to the first dose showed dose-independent systemic accumulation at doses ranging from 25 to 200 micrograms.

Distribution

Indacaterol

Following intravenous infusion, the volume of distribution (Vz) of indacaterol ranged from 2.361 to 2,557 L indicating that the drug is widely distributed. In in vitro tests, the degree of binding to human serum and plasma proteins was 94.1 to 95.3% and 95.1 to 96.2%, respectively.

Glycopyrronium

Following intravenous administration, the steady-state volume of distribution (Vss) of glycopyrronium is 83 L and the terminal volume of distribution (Vz) is 376 L. The apparent volume of distribution in the posterior terminal phase. on inhalation (Vz/F) is 7310 L, reflecting a much slower elimination rate after inhalation. In in vitro models, glycopyrronium is 38% to 41% bound to human plasma proteins over a concentration range of 1 to 10 ng/mL. These concentrations are at least 6 times higher than the mean steady-state peak plasma concentrations achieved at a dose of 50 micrograms once daily.

Biotransformation/Metabolism

Indacaterol

In an ADME (absorption, distribution, metabolism, excretion) study in humans following oral administration of radiolabeled indacaterol, unchanged indacaterol was the major serum component, accounting for approximately one-third of total drug exposure. AUC for 24 hours. The hydroxylated derivative is the major serum metabolite. The phenolic O-glucuronic conjugates of indacaterol and hydroxy indacaterol are the next major metabolites. A diastereomer of the hydroxyl derivative, the N-glucuronic conjugate of indacaterol, and the C- and N-dealkylated derivatives were the next identified metabolites.

In vitro studies have shown that UGT1A1 is the only form of UGT that converts indacaterol to phenolic O-glucuronic. Oxidative metabolites have been found upon incubation with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 was identified as the major isoenzyme responsible for the hydroxylation of indacaterol. Subsequent in vitro studies showed that indacaterol is a substrate with a low affinity for the P-gp pump.

Glycopyrronium

In vitro metabolism, studies suggest that the metabolic pathways of glycopyrronium bromide are consistent between animals and humans. No human-specific metabolites have been found. The hydroxylation yielding mono- and bis-hydroxyl metabolites and the direct hydrolysis to the carboxylic derivatives (M9) have been reported.

In vitro studies have shown that many CYP isoenzymes are involved in the oxidation in the biotransformation of glycopyrronium. The hydrolysis of M9 can be catalyzed by enzymes in the cholinesterase group.

After inhalation, the systemic exposure of M9 was above average, about the same as that of the parent drug. From in vitro studies showing no pulmonary metabolism and minimal circulating M9 (approximately 4% Cmax and AUC of parent drug) following intravenous administration, it is assumed that M9 is Formed from the fraction of the drug swallowed when glycopyrronium is inhaled by mouth through pre-circulation hydrolysis and/or first-pass metabolism. After inhalation as well as after intravenous administration, only small amounts of M9 were recovered in the urine (≤ 0.5% of the dose). The glucuronic and sulfate conjugates of glycopyrronium are found in approximately 3% of human urine following repeated inhalation administration.

In vitro inhibition studies have shown that glycopyrronium bromide is capable of inhibiting CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the ejection pump MDR1, MRP2 or MXR, and drug transport proteins. into OCT1 or OCT2. In vitro enzyme induction studies did not indicate clinically significant induction of glycopyrronium bromide with any cytochrome P450 isoenzyme, or with UGT1A1 and the drug transport proteins MDR1 and MRP2.

Elimination

Indacaterol

In clinical studies with urine collection, urinary excretion of indacaterol unchanged was generally less than 2% of the dose. The mean renal clearance of indacaterol ranged from 0.46 to 1.20 L/hour. When compared with the serum clearance of indacaterol from 18.8 to 23.3 L/hr, renal excretion plays a minor role (approximately 2-6% of systemic clearance) in the total elimination of indacaterol. Dear.

In the human ADME study, in which indacaterol was administered orally, faecal elimination was predominant over the urinary route of elimination. In humans, indacaterol is excreted in the feces mainly as the unchanged parent drug (54% of the dose) and to a lesser extent as the hydroxyl metabolite indacaterol (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the feces.

Serum concentrations of indacaterol decreased in several phases with the mean terminal half-life varying from 45.5 to 126 hours. The calculated half-life from the accumulation of indacaterol following repeated dosing ranged from 40 to 56 hours consistent with a time to steady-state of approximately 12 to 15 days.

Glycopyrronium

In humans, following intravenous administration of [3H]-bound glycopyrronium bromide, the average urinary excretion of radioactive material over 48 hours is up to 85% of the dose. 5% of the next dose is found in bile. Therefore, the balance in terms of mass is almost complete.

The parent drug is renally eliminated about 60 to 70% of the total clearance while the extrarenal clearance accounts for about 30 to 40%. Biliary clearance belongs to extrarenal clearance, but the majority of extrarenal clearance is thought to be metabolic.

Following single and once daily inhalation of single and repeated doses of glycopyrronium in healthy volunteers and patients with chronic obstructive pulmonary disease of 50 to 200 micrograms, mean renal clearance of glycopyrronium ranged from 17.4 up to 24.4 L/hour. Active tubular secretion is involved in the renal elimination of glycopyrronium. Approximately 20% of the administered dose is recovered in the urine as intact parent drug.

Plasma glycopyrronium concentrations decrease in several phases. The mean terminal half-life was longer after inhalation (33 to 57 hours) than after intravenous administration (6.2 hours) and after oral administration (2.8 hours). Elimination kinetics indicate sustained pulmonary absorption and/or transport of glycopyrronium into the general circulation 24 h and 24 h after inhalation.

Linear/ Non-linear

Indacaterol

The total systemic exposure of indacaterol increased with increasing doses (from 150 micrograms to 600 micrograms) in a dose-dependent linear fashion. The total amount of drug in circulation is the result of both absorptions in the lungs and absorption in the small intestine.

Glycopyronnium

Total systemic exposure in patients with chronic obstructive pulmonary disease as well as total urinary excretion of glycopyrronium at steady state increased linearly with a dose over the dose range of 50 micrograms to 200 micrograms.

Special populations

Ultibro Breezhaler

Population pharmacokinetic analysis of patients with the chronic obstructive pulmonary disease after inhalation of Ultibro Breezhaler revealed no influence of age, sex, and (ideal) weight on systemic exposure to indacaterol and glycopyrronium. Ideal weight (calculated by weight and height) was determined as an independent variable. An inverse correlation between total body weight and ideal body weight (or bodyweight) has been observed; however, no dose adjustment is required due to the variability or predictive accuracy of ideal body weight.

Smoking status and baseline FEV1 values ​​had no appreciable effect on total circulating concentrations of indacaterol and glycopyrronium following inhalation of Ultibro Breezhaler.

Indacaterol

Population analysis of the effects of age, sex, and weight on systemic exposure in patients with chronic obstructive pulmonary disease showed that indacaterol could be used at the recommended dose levels across all groups. age and weight and not affected by gender.

The pharmacokinetics of indacaterol were studied in two different UGT1A1 genotypes, the fully functional [(TA)6, (TA)6] and the poorly expressed [(TA)7, (TA) genotypes. )7] (genotype of Gilbert syndrome). The results showed that the area under the curve (AUC) and the peak concentration (Cmax) of indacaterol were about 1.2 times higher in the group of people with genotype [(TA)7, (TA)7]. These results suggest that the total circulating drug intake of indacaterol is not significantly affected by the change in the UGT1A1 genotype.

Glycopyrronium

Analysis of population pharmacokinetic data in patients with chronic obstructive pulmonary disease identified weight and age as factors associated with inter-patient variability in systemic exposure. The dose level of glycopyrronium 50 micrograms administered once daily as recommended may be used in all age and weight groups of patients.

Gender, smoking status, and baseline FEV1 values ​​had no significant effect on systemic exposure.

Liver failure

On the basis of the clinical pharmacokinetic properties of the individual components of the drug, Ultibro Breezhaler can be used at the recommended dose levels in patients with mild and moderate hepatic impairment. There are no data in patients with severe hepatic impairment.

No change in Cmax or AUC of indacaterol was observed in patients with mild and moderate hepatic impairment, nor was there any difference in the protein binding of the drug in patients with mild hepatic impairment. and average compared with healthy volunteers. Studies in patients with severe hepatic impairment have not been performed.

Clinical studies in patients with impaired liver function have not been performed. Glycopyrronium is eliminated primarily from the general circulation via renal excretion. Impaired hepatic metabolism of glycopyrronium is not believed to be the cause of a clinically significant increase in total systemic exposure.

Kidney failure

Based on the clinical pharmacokinetic properties, the individual components of Ultibro Breezhaler can be used at the recommended dose levels in patients with mild to moderate renal impairment. In patients with severe or end-stage renal failure requiring dialysis, Ultibro Breezhaler should only be used if the potential benefits outweigh the risks.

Indacaterol

Because urinary excretion of the drug is less involved in the complete elimination of indacaterol from the body, studies in patients with renal impairment were not performed.

Glycopyrronium

Renal impairment has an impact on systemic exposure to glycopyrronium. The mean increase in total systemic exposure (end AUC) increased to 1.4-fold in patients with mild and moderate renal impairment and up to 2.2-fold in patients with severe renal impairment and in patients with impaired renal function end-stage kidney. Based on population pharmacokinetic analysis, it can be concluded that in patients with a chronic obstructive pulmonary disease with mild to moderate impairment of renal function (estimated glomerular filtration rate eGFR ≥ 30 mL/min/1). ,73m2) can use glycopyrronium at the recommended dose.

Race/ethnicity

Ultibro Breezhaler

When adjusted for ideal body weight, the effect of the race (Japanese versus non-Japanese) on exposure to both components of the drug was not statistically significant.

Indacaterol

No differences were identified between the racial groups. Treatment experience in blacks is limited.

Glycopyrronium

There were no major differences in total systemic exposure (AUC) between Japanese and Caucasian patients. There are insufficient pharmacokinetic data in other ethnicities or races.

Indications and uses

Ultibro Breezhaler is a bronchodilator indicated for once-daily maintenance therapy for the relief of symptoms and exacerbations in patients with chronic obstructive pulmonary disease (COPD).

Dosage and Administration

Subjects of patients in the general population

The recommended dose of Ultibro Breezhaler is one inhalation per day with the amount contained in 1 110/50 microgram capsule via the Ultibro Breezhaler inhaler.

Special Objects

Decreased kidney function

Ultibro Breezhaler can be used at the recommended dose for patients with mild to moderate impairment of renal function. Ultibro Breezhaler should be used in patients with severe renal impairment or end-stage renal disease requiring dialysis only if the benefits outweigh the risks.

Decreased liver function

Ultibro Breezhaler can be used at the recommended dose levels in patients with mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment.

Children under 18)

Do not use Ultibro Breezhaler in patients under 18 years of age.

Elderly (over 75 years old)

Ultibro Breezhaler can be used at the recommended dose for patients over 75 years of age.

How to use

Use only Ultibro Breezhaler capsules by mouth inhalation and Ultibro Breezhaler inhaler only. Ultibro Breezhaler capsules must not be swallowed.

Ultibro Breezhaler should be taken at the same time each day. If you forget to take your medicine, take it back as soon as possible. Patients should be instructed not to take more than one dose per day.

Ultibro Breezhaler capsules should be stored in an aluminum blister to prevent moisture, and only remove the medicine from the blister IMMEDIATELY BEFORE USE.

When prescribing Ultibro Breezhaler, the patient should be instructed to use the inhaler correctly. It is important to ask carefully if the patient has swallowed the medication and not inhaled it if the patient does not have an improvement in breathing.

Warning

Ultibro Breezhaler should not be co-administered with drugs containing long-acting beta-adrenergic agonists or long-acting muscarinic receptor antagonists. The drugs included in the composition of Ultibro Breezhaler belong to these pharmacological groups.

Asthma

Ultibro Breezhaler should not be used for the treatment of asthma due to the lack of data for this indication.

Long-acting beta2-adrenergic agonists may increase the risk of asthma-related adverse events, including asthma-related death, when used to treat asthma.

Do not use the drug in acute cases

Ultibro Breezhaler is not indicated for the treatment of acute bronchospasm.

Indacaterol-related hypersensitivity

Immediate hypersensitivity reactions have been reported following the administration of indacaterol or glycopyrronium, an ingredient of Ultibro Breezhaler. If signs of an allergic reaction occur (especially difficulty breathing or swallowing, swelling of the tongue, lips and face, hives, skin rash), the drug should be discontinued immediately and appropriate treatment instituted. .

Paradoxical bronchospasm

As with other inhaled therapies, the use of Ultibro Breezhaler can lead to paradoxical, sometimes life-threatening, bronchospasm. If paradoxical bronchospasm occurs, Ultibro Breezhaler should be discontinued immediately and appropriate treatment instituted.

Anticholinergic effects associated with glycopyrronium

As with other anticholinergics, Ultibro Breezhaler should be used with caution in patients with angle-closure glaucoma or urinary retention.

Patients should be counseled about the signs and symptoms of acute angle-closure glaucoma and should be advised to discontinue Ultibro Breezhaler and to contact their physician immediately if any of the above signs or symptoms develop. .

Patients with severe renal impairment

Ultibro Breezhaler should only be used in patients with severe renal impairment (estimated glomerular filtration rate less than 30 mL/min/1.73 m2), including patients with an end-stage renal disease requiring dialysis, if the benefits of the drug outweigh the risks. outweigh the risk. These patients should be closely monitored for adverse drug reactions.

Systemic effects of beta-agonists

Although clinically significant cardiovascular effects are not infrequently observed after administration of Ultibro Breezhaler at recommended doses, as with other beta2-adrenergic agonists, Ultibro should be used with caution. Breezhaler for patients with cardiovascular disease (coronary artery disease, acute myocardial infarction, arrhythmia, hypertension), patients with epilepsy or thyrotoxicosis, and patients with an abnormal response to beta2-adrenergic agonists.

As with other drugs containing inhaled beta2-adrenergic agonists, Ultibro Breezhaler should not be used more frequently or at higher than recommended doses.

Cardiovascular effects of beta-agonists

As with other beta2-adrenergic agonist-containing medicinal products, Ultibro Breezhaler may have clinically significant cardiovascular effects in some patients manifested by increased heart rate, blood pressure, with or without symptoms. . In these cases, discontinuation of the drug should be considered. Furthermore, beta-adrenergic agonists have been reported to induce electrocardiographic changes such as T wave flattening, QT interval prolongation, and ST-segment depression, despite the clinical significance of these effects. These phenomena are not well known.

Clinically significant effects related to QTc interval prolongation have not been observed in clinical trials of Ultibro Breezhaler using the recommended therapeutic doses.

Hypokalemia of beta agonists

Beta2-adrenergic agonists may markedly decrease serum potassium levels in some patients, leading to adverse cardiovascular effects. The decrease in serum potassium is usually reversible and does not require additional potassium supplementation. In patients with severe chronic obstructive pulmonary disease, hypokalemia, aggravated by hypoxia and other concomitant medications, increases the risk of arrhythmias.

Clinically significant effects related to hypokalemia have not been observed in clinical studies with Ultibro Breezhaler using the recommended therapeutic doses.

Hyperglycemia with beta-agonists

High doses of inhaled beta2-adrenergic agonists may increase blood glucose. Patients with diabetes mellitus should be monitored more closely when initiating therapy with Ultibro Breezhaler. In the long-term clinical trials ([ENLIGHTEN] and [RADIATE]), a higher proportion of patients receiving Ultibro Breezhaler experienced clinically significant glycemic changes (4.9%) compared with placebo (2, 7%). Ultibro Breezhaler has not been studied in patients with poorly controlled diabetes.

Effects on ability to drive and use machinery

This product has negligible influence on the ability to drive and use machines. However, dizziness may occur and affect the ability to drive and use machines.

Overdose

Information regarding Ultibro Breezhaler

In a study in healthy volunteers, a single dose 4 times the therapeutic dose of Ultibro Breezhaler (4 doses, 110/50 micrograms given every hour) was well tolerated, with no adverse effects. heart rate, QT interval, serum potassium, or blood glucose levels.

In patients with COPD, up to 600/100 micrograms of Ultibro Breezhaler inhaled for 2 weeks, no effects were observed on heart rate, QTc interval, blood glucose, or serum potassium. There was an increase in ventricular extrasystoles after 14 days of administration of 300/100 and 600/100 microgram Ultibro Breezhaler but at a low rate. The small number of patients (N=49 and N=51 with 600/100 microgram and 300/100 microgram Ultibro Breezhaler, respectively) did not allow for an accurate analysis of this ratio. In a total of 4 patients with intermittent ventricular tachycardia, the longest recorded ventricular tachycardia episode was 9 beats (4 seconds).

Overdosage may lead to typical beta2-adrenergic overstimulation effects such as tachycardia, tremor, palpitations, headache, nausea, vomiting, somnolence, ventricular arrhythmias, metabolic acidosis, hypokalemia. blood and hyperglycemia or may cause anticholinergic effects, such as glaucoma (causing pain, visual disturbances, or red eyes), constipation, or difficulty urinating. Supportive and symptomatic treatment is indicated in this case. In severe cases, the patient should be hospitalized. Use of cardioselective beta-blockers may be considered for the treatment of symptoms of hyper-beta2-adrenergic hyperactivity but should be under the supervision of a physician and with extreme caution as the use of beta-adrenergic blockers may cause adverse effects. can cause bronchospasm.

Information related to indacaterol

In patients with chronic obstructive pulmonary disease, a single dose of 3000 micrograms resulted in a moderate increase in heart rate, systolic blood pressure, and QTc interval.

Information regarding glycopyrronium

In patients with chronic obstructive pulmonary disease, repeated oral inhalation of glycopyrronium at total doses of 100 and 200 micrograms once daily for 28 days has been well tolerated.

Acute poisoning by inadvertent ingestion of glycopyrronium capsules is unlikely due to the low oral bioavailability of the drug (about 5%).

In healthy volunteers, peak plasma concentrations and total systemic exposure following intravenous administration of 150 micrograms of glycopyrronium bromide (equivalent to 120 micrograms of glycopyrronium) were approximately 50 times the peak and six times the total dose. circulating at a steady state following the recommended dose (50 micrograms once daily) of glycopyrronium and was well tolerated.

Contraindications

Ultibro Breezhaler is contraindicated in patients with known hypersensitivity to indacaterol or glycopyrronium, a component of Ultibro Breezhaler, or any of the excipients.

Use in pregnant and lactating women

Women of reproductive age

There are no special recommendations for women of childbearing age.

Pregnant

There are no data on the use of Ultibro Breezhaler in pregnant women. Similarly, there are no data on the use of indacaterol or glycopyrronium in pregnant women.

Ultibro Breezhaler had no effect on the embryo or fetus at any dose level in a rat embryonic development study. Indacaterol was not teratogenic in rats or rabbits after subcutaneous administration. Reproductive toxicity has been observed for indacaterol such as an increased frequency of a frame mutation the following administration to rabbits. Glycopyrrinium was not teratogenic in rats or rabbits after inhalation. In women having a cesarean section, 86 minutes after a single intramuscular injection of 0.006 mg/kg glycopyrronium bromide, cord plasma concentrations were very low.

The potential hazard of the drug in humans is unknown. Because there is insufficient experience with the drug in pregnant women, Ultibro Breezhaler should be used during pregnancy only if the effect of the drug outweighs the risk to the fetus.

Breastfeeding Women

It is not known whether indacaterol and/or glycopyrronium is excreted in human milk. Indacaterol and glycopyrronium (including its metabolites) were detected in the milk of lactating rats. Therefore, Ultibro Breezhaler should be used in lactating women only when the potential benefits outweigh the risks to the pediatric population.

Fertility

Information regarding indacaterol and glycopyrronium

Fertility studies or other animal data have not revealed an effect on male or female fertility.

Birth process

Information related to indacaterol

Like other beta2-adrenergic agonists, Ultibro Breezhaler may inhibit labor by relaxing uterine smooth muscle.

Interactive

Interactions related to Ultibro Breezhaler

Concomitant oral inhalation of indacaterol and glycopyrronium at a steady state of both agents did not affect the pharmacokinetics of the either drug.

No specific drug-drug interaction studies have been performed on Ultibro Breezhaler. Information on the potential for interactions of Ultibro Breezhaler is based on the potential for interactions of each of its monotherapy components.

Indacaterol-related interactions

In vitro studies have shown that indacaterol has a significant potential to interact at the metabolic level with drugs at concentrations comparable to those achieved after clinical use.

Beta-adrenergic blocking agents

Beta-adrenergic blocking agents may reduce or antagonize the effects of beta2-adrenergic agonists.

Therefore, Ultibro Breezhaler should not be used with beta-adrenergic blocking agents (including eye drops) unless there are compelling reasons for the combination. Where necessary, preference should be given to cardioselective beta-adrenergic blockers but should be used with caution.

Drugs capable of prolonging the QTc interval

As with drugs containing beta2-adrenergic agonists, Ultibro Breezhaler should be used with caution in patients receiving monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the interval. QT interval, as they may potentiate the effects of these drugs on the QT interval. Drugs that prolong the QT interval may increase the risk of ventricular arrhythmias.

Sympathomimetic drugs

Concomitant use with other sympathomimetic agents (alone or in combination) may potentiate the adverse effects of indacaterol.

Drugs that lower blood potassium

Concomitant use with methylxanthine derivatives, steroids, and non-potassium-sparing diuretics may potentiate the hypokalemic effect of beta2-adrenergic agonists.

Interactions related to drug metabolism and transport

Inhibition of two important components of indacaterol elimination, CYP3A4, and P-gp, did not affect the safety of indacaterol at therapeutic doses. Drug interaction studies have been performed with potent and specific inhibitors of CYP3A4 and P-gp (such as ketoconazole, erythromycin, verapamil, and ritonavir). Verapamil used as a P-gp inhibitor resulted in a 1.4 to 2-fold increase in the area under the curve (AUC) and a 1.5-fold increase in indacaterol Cmax. Co-administration of indacaterol with erythromycin resulted in a 1.4 to 1.6-fold increase in AUC and 1.2-fold in Cmax. Ketoconazole strongly inhibits P-gp and CYP3A4 simultaneously, resulting in a 2-fold increase in AUC and a 1.4-fold increase in Cmax. Concomitant treatment with indacaterol and ritonavir, a concomitant inhibitor of both P-gp and CYP3A4, resulted in a 1.6 to 1.8-fold increase in AUC but no effect on Cmax. In summary, the data suggest that total clearance is affected by the activity of both P-gp and CYP3A4 and the 2-fold increase in AUC induced by ketoconazole, a potent inhibitor of copper time of P-gp and CYP3A4, reflecting the maximum effect of dual inhibition of these two agents. Increased drug exposure due to drug interactions did not have any effect on drug safety as demonstrated by safety experience during indacaterol treatment in clinical trials using the drug above. a year at a dose of 600 micrograms.

Interactions related to glycopyrronium

In vitro studies have shown that glycopyrronium does not inhibit or induce the metabolism of other drugs, including drug delivery systems. Metabolism, with the participation of many enzymes, plays a secondary role in the elimination of glycopyrronium. Inhibition or induction of the metabolism of glycopyrrinium does not change the concentration of the drug in circulation.

Anticholinergic drugs

Concomitant use of Ultibro Breezhaler with inhaled anticholinergics has not been studied, therefore, like other anticholinergics, the concomitant use of Ultibro Breezhaler with these agents is not recommended.

Cimetidine and other organocation transporter system inhibitors

In a clinical study in healthy volunteers, cimetidine, an organocation transporter system inhibitor thought to be involved in renal excretion of glycopyrronium, increased glycopyrrinium concentrations by 22% during the week. complete and 23% decrease in renal clearance. Based on this changing trend, no drug interactions are expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport system.

Side effects

The safety profile presentation is based on experience with Ultibro Breezhaler and individual components.

Safety experience with Ultibro Breezhaler includes use for up to 15 months at recommended therapeutic doses.

Ultibro Breezhaler has shown similar adverse reactions for each individual ingredient. Since the drug contains indacaterol and glycopyrronium, the type and severity of adverse reactions associated with each of these ingredients can be expected in combination.

The safety profile is characterized by typical anticholinergic and beta-adrenergic symptoms associated with each individual component of the combination. The other most common adverse reactions associated with the product (at least 3% of patients receiving Ultibro Breezhaler and also higher than placebo) were cough, nasopharyngitis, and headache.

Adverse reactions detected in clinical trials and from postmarketing sources are listed by MedDRA system organ class. Within each organ system group, adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency group, adverse reactions are presented in order of decreasing severity. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); unknown (cannot be estimated from the available data).

Cough is common but usually mild in intensity.

Preservation

Do not store the drug above 30oC. Avoid moisture.

Presentation and packaging

Inhalation powder contained in hard capsules: box of 5 blisters x 6 tablets (with 1 inhaler), a box of 1 blister x 6 tablets (with 1 inhaler), a box of 2 blisters x 6 tablets (with 1 inhaler).