Trixeo Aerosphere suspension for inhalation 5/7.2/160 mcg container 120 doses

Instructions for use Trixeo Aerosphere suspension for inhalation 5/7.2/160 mcg container 120 doses

Composition

active ingredients: formoterol fumarate dihydrate, glycopyrronium bromide, budesonide;

1 inhalation (delivered dose) contains 5 μg of micronized formoterol fumarate dihydrate equivalent to 4.8 μg of anhydrous formoterol fumarate; 9 μg of micronized glycopyrronium bromide equivalent to 7.2 μg of glycopyrronium and 160 μg of micronized budesonide;

This corresponds to a metered dose of 5.3 micrograms of micronized formoterol fumarate dihydrate equivalent to 5.1 micrograms of anhydrous formoterol fumarate; 9.6 micrograms of micronized glycopyrronium bromide equivalent to 7.7 micrograms of glycopyrronium and 170 micrograms of micronized budesonide;

excipients: 1,2-distearoyl-sn-glycero-3-phosphocholine, calcium chloride dihydrate, norflurane (HFA-134a).

Dosage form

Pressurized inhalation, suspension.

Main physicochemical properties: white suspension.

Pharmacotherapeutic group

Medicinal products for the treatment of obstructive airway diseases. Adrenergic agents in combination with anticholinergic agents, including ternary combinations with corticosteroids. Formoterol fumarate dihydrate, glycopyrronium bromide, budesonide. ATX code R03A L11.

Pharmacological properties

Pharmacodynamics

Mechanism of action

The drug Trixeo Aerosphere contains budesonide, a glucocorticosteroid, and two bronchodilators - glycopyrronium, a long-acting muscarinic receptor antagonist (anticholinergic drug), and formoterol, a long-acting β2-agonist.

Budesonide is a glucocorticosteroid that, when inhaled, has a rapid (within hours) and dose-dependent anti-inflammatory effect in the respiratory tract.

Glycopyrronium is a long-acting muscarinic receptor antagonist, often referred to as an anticholinergic drug. The primary targets for anticholinergic drugs are muscarinic receptors found in the airways. In the airways, glycopyrronium exerts its pharmacological effects by inhibiting M3 cholinergic receptors in smooth muscle, resulting in bronchodilation. The antagonism is competitive and reversible. In a study, the prevention of bronchoconstrictor effects induced by methylcholine and acetylcholine was dose-dependent and lasted for more than 12 hours.

Formoterol is a selective β2-adrenergic agonist that, when inhaled, produces rapid and sustained relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The bronchodilator effect is dose-dependent; onset of effect occurs within 1–3 minutes after inhalation. The duration of effect after a single dose is at least 12 hours.

Clinical efficacy

The efficacy and safety of Trixeo Aerosphere were evaluated in patients with moderate, severe or very severe COPD in ETHOS and KRONOS, two randomized, parallel-group studies. Both studies were multicenter, double-blind. Patients had a COPD Assessment Test (CAT) symptom score ≥ 10 and were on two or more daily maintenance medications for at least 6 weeks prior to screening.

KRONOS is a 24-week study (N = 1902 randomized participants; 71% were male, mean age 65 years) comparing two inhalations twice daily of Trixeo Aerosphere, GAI FORM/GLI 5/7.2 mcg, GAI FORM/BUD 5/160 mcg and in an open-label comparison with a turbuhaler of formoterol fumarate dihydrate/budesonide (TBH FORM/BUD) 6/200 mcg. Patients had moderate, severe or very severe COPD (FEV1 after bronchodilator use ≥ 25% to 1 in all groups was 1,050–1,193 ml, and at the time of screening, the mean FEV1 after bronchodilator use was 50% of predicted; more than 26% of patients reported one or more moderate or severe COPD exacerbations during the past year and the mean CAT symptom score was 18.3. In a subgroup of participants, treatment was extended for 28 weeks, i.e. up to 52 weeks. The primary endpoints of the KRONOS study were FEV1 values from time 0 to 4 hours after drug administration (according to the area under the pharmaceutical concentration/time curve AUC0-4 FEV1) for the Trixeo Aerosphere drug group compared to the GAI FORM/BUD group and the change in morning minimum FEV1, which measured before the drug was used, compared to the baseline value for the Trixeo Aerosphere drug group compared to the GAI FORM/GLI group at 24 weeks.

At the time of study enrollment, the most commonly used COPD treatments reported in the ETHOS and KRONOS studies were inhaled glucocorticosteroid (ICS)+long-acting β2-agonist (LABA)+long-acting muscarinic receptor antagonist (LMRA) (39%, 27%, respectively), ICS+LABA (31%, 38%, respectively), and LABA+LMRA (14%, 20%, respectively).

Impact on exacerbation

Moderate or severe exacerbation

In the 52-week ETHOS study, patients treated with Trixeo Aerosphere experienced a significant reduction in the annual rate of moderate/severe exacerbations during treatment by 24% (95% CI: 17, 31; p < 0.001).

The observed benefit in the annual rate of moderate/severe COPD exacerbations over 24 weeks in the KRONOS study was generally consistent with that observed in the ETHOS study. In the Trixeo Aerosphere group, improvements compared to DAI FORM/GLI were statistically significant, but compared to DAI FORM/BUD and TBH FORM/BUD did not reach statistical significance.

Severe exacerbations (leading to hospitalization or death)

In the ETHOS study, patients treated with Trixeo Aerosphere had a numerical reduction in the annual rate of severe exacerbations during treatment by 16% (95% CI: -3.31; p = 0.0944) compared to GAI FORM/GLI (rate; 0.13 vs. 0.15 events per patient per year) and a significant reduction in the annual rate of severe exacerbations during treatment by 20% (95% CI: 3.34; p = 0.0221) compared to GAI FORM/BUD (rate; 0.13 vs. 0.16 events per patient per year).

In both studies, the benefit of Trixeo Aerosphere in terms of the effect on exacerbations was observed in patients with moderate, severe or very severe COPD.

Impact on lung function

In the ETHOS and KRONOS studies, patients treated with Trixeo Aerosphere demonstrated improvements in lung function (FEV1) during treatment compared to GAI FORM/GLI and GAI FORM/BUD (see Table 1 for ETHOS and Table 2 for KRONOS). In both studies, the effect was sustained over the 24-week treatment period and over 52 weeks in ETHOS.

Table 1

Lung function analysis – ETHOS (spirometry substudy)

# p-value is not adjusted for multiplicity in the hierarchical testing plan.

Least squares method, SD standard error, CI confidence intervals, N number of individuals in the sample “all patients randomized to assigned treatment” (ITT population).

Table 2

Lung function analysis – KRONOS

(52; 95)

p

# p-value is not adjusted for multiplicity in the hierarchical testing plan.

Least squares method, SD standard error, CI confidence intervals, N number of individuals in the sample “all patients randomized to assigned treatment” (ITT population).

Symptom relief

In the ETHOS study, baseline mean dyspnea scores ranged from 5.8 to 5.9 across treatment groups. Patients receiving Trixeo Aerosphere had a significant reduction in dyspnea (as measured by the Dynamic Dyspnea Index (TDI) at 24 weeks) compared with the FORM/GLI GAI (0.40 units; 95% CI: 0.24, 0.55; p

Health-related quality of life

In the ETHOS study, patients treated with Trixeo Aerosphere experienced a significant improvement in disease-related health status (as measured by the St. George's Hospital Respiratory Questionnaire [SGRQ] total score) at 24 weeks compared with GAI FORM/GLI (improvement -1.62; 95% CI: -2.27, -0.97; p

Frequency of use of emergency medicine

In the ETHOS study, patients treated with Trixeo Aerosphere had a significant reduction in the use of rescue medication during treatment over 24 weeks compared with the FORM/GLI GAI (treatment difference: -0.51 inhalations/day; 95% CI: -0.68, -0.34; p FORM/BUD were not statistically significant.

Pharmacokinetics

After inhalation of the combination of formoterol, glycopyrronium and budesonide, the pharmacokinetics of each component were similar to those observed when each active substance was administered separately.

Use with spacer

Following administration of this medicinal product with the Aerochamber Plus Flow-Vu spacer to healthy volunteers, the total systemic exposure (measured by AUC0-t) of budesonide and glycopyrronium increased by 33% and 55%, respectively, while the exposure of formoterol remained unchanged.

Absorption

Budesonide

Following inhalation of this medicinal product in COPD patients, peak concentrations (Cmax) of budesonide were observed within 20–40 minutes. Steady state is reached after approximately 1 day of repeated administration of this medicinal product, with exposure approximately 1.3 times higher than after the first dose.

Glycopyrronium

After inhalation of this medicinal product in COPD patients, glycopyrronium Cmax was reached within 6 minutes. Steady state is reached within 3 days of repeated administration of this medicinal product, and the exposure is approximately 1.8 times higher than after the first dose.

Formoterol

After inhalation of this medicinal product in patients with COPD, Cmax of formoterol was observed within 40–60 minutes. Steady state is reached within 2 days of repeated administration of this medicinal product, and the exposure is approximately 1.4 times higher than after the first dose.

Distribution

Budesonide

According to a population pharmacokinetic analysis, the estimated apparent volume of distribution of budesonide at steady state is 1200 L. The binding of budesonide to plasma proteins is approximately 90%.

Glycopyrronium

According to a population pharmacokinetic analysis, the estimated apparent volume of distribution of glycopyrronium at steady state is 5500 L. In the concentration range of 2–500 nmol/L, the binding of glycopyrronium to plasma proteins ranged from 43–54%.

Formoterol

According to population pharmacokinetic analysis, the estimated apparent volume of distribution of formoterol at steady state is 2400 L. In the concentration range of 10–500 nmol/L, the binding of formoterol to plasma proteins ranged from 46–58%.

Biotransformation

Budesonide

Budesonide undergoes extensive (approximately 90%) first-pass metabolism to form metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6-β-hydroxy-budesonide and 16-α-hydroxy-prednisolone, is less than 1% of the glucocorticosteroid activity of budesonide.

Glycopyrronium

Based on the literature and in vitro studies in human hepatocytes, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

Formoterol

The primary metabolism of formoterol is by direct glucuronidation and O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been shown to be primarily responsible for O-demethylation.

Breeding

Budesonide is eliminated by metabolism, mainly catalyzed by the enzyme CYP3A4. Budesonide metabolites are excreted in the urine in pure or conjugated form. Only minor amounts of unchanged budesonide were detected in the urine. The effective terminal elimination half-life of budesonide, determined by a population pharmacokinetic analysis, was 5 hours.

Glycopyrronium

Following intravenous administration of 0.2 mg of radiolabeled glycopyrronium, 85% of the dose was excreted in the urine within 48 hours of administration; some radioactivity was also excreted in the bile. The effective terminal elimination half-life of glycopyrronium, determined by population pharmacokinetic analysis, was 15 hours.

Formoterol

The elimination of formoterol was studied in six healthy subjects after simultaneous oral and intravenous administration of radiolabeled formoterol. In this study, 62% of the radioactivity was excreted in the urine and 24% in the feces. The effective elimination half-life of formoterol, determined by population pharmacokinetic analysis, was 10 hours.

Special patient groups

Age, gender, race/ethnicity, and body weight

No dose adjustment is necessary due to the lack of influence of age, gender or body weight of the patient on the pharmacokinetic parameters of budesonide, glycopyrronium and formoterol. No significant differences in total systemic exposure (AUC) of all components of the drug were found among healthy subjects of Japanese, Chinese and European/American origin. There are insufficient pharmacokinetic data for other ethnic groups or races.

Liver failure

Pharmacokinetic studies of this medicinal product in patients with hepatic impairment have not been conducted. However, since budesonide and formoterol are eliminated primarily by hepatic metabolism, increased plasma concentrations of the medicinal product may be expected in patients with severe cirrhosis. Glycopyrronium is primarily cleared from the systemic circulation by renal excretion, and hepatic impairment is not expected to affect its systemic exposure.

Kidney failure

Studies evaluating the effect of renal insufficiency on the pharmacokinetics of budesonide, glycopyrronium and formoterol have not been conducted.

The effect of renal impairment on the exposure of budesonide, glycopyrronium and formoterol over a period of up to 24 weeks was assessed in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) ranged from 31 to 192 mL/min, corresponding to a range from moderate renal impairment to no renal impairment. Modelling of systemic exposure (AUC0-12) in COPD patients with moderate renal impairment (eGFR 45 mL/min) indicated an approximate 68% increase in glycopyrronium levels compared to COPD patients with normal renal function (eGFR > 90 mL/min). Renal function was found to have no effect on the exposure of budesonide or formoterol. In COPD patients with low body weight and moderate or severe renal impairment, systemic exposure to glycopyrronium may be approximately doubled.

Indication

Trixeo Aerosphere is indicated as maintenance therapy for adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are inadequately responsive to therapy with a combination of an inhaled corticosteroid and a long-acting β2-agonist or a combination of a long-acting β2-agonist and a long-acting muscarinic receptor antagonist (for information on the effect on symptom control and prevention of exacerbations, see section "Pharmacodynamics").

Contraindication

Hypersensitivity to the active substances or to any of the excipients listed in the "Composition" section.

Interaction with other medicinal products and other types of interactions

Pharmacokinetic interactions

Clinical studies of the interaction of this medicinal product with other medicinal products have not been conducted, however, the likelihood of metabolic interactions is considered low based on in vitro studies (see section "Pharmacokinetics").

Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations (see section 5.2). Budesonide and glycopyrronium do not inhibit or induce CYP450 enzymes at therapeutically relevant concentrations.

Limited data on the above-mentioned interactions with high doses of inhaled budesonide indicate that a significant increase in plasma levels (on average 4-fold) is possible when itraconazole 200 mg once daily is used together with inhaled budesonide (single dose 1000 mcg).

Since glycopyrronium is primarily excreted by the kidneys, interactions with drugs that affect renal excretion mechanisms are possible. In vitro, glycopyrronium is a substrate for the renal transporters OCT2 and MATE1/2K. A study of the effect of cimetidine, a marker inhibitor of OCT2 and MATE1, on the disposition of inhaled glycopyrronium showed a limited increase in total systemic exposure (AUC0-t) of 22% and a slight decrease in renal clearance of 23% due to co-administration of cimetidine.

Pharmacodynamic interactions

Other antimuscarinics and sympathomimetics

The concomitant use of this medicinal product with other medicinal products containing anticholinergics and/or long-acting β2-agonists has not been studied and is not recommended, as it may potentiate the known adverse reactions to inhaled muscarinic receptor antagonists or β2-agonists (see sections 4.4 and 4.8).

Potentially additive effects may occur when other β-adrenergic medicinal products are used concomitantly; therefore, caution should be exercised when prescribing other β-adrenergic medicinal products concomitantly with formoterol.

Drug-induced hypokalemia

Initial hypokalemia is possible and may be exacerbated by concomitant use of medicinal products including xanthine derivatives, corticosteroids and non-potassium-sparing diuretics (see section 4.4). Hypokalemia may increase the susceptibility to arrhythmias in patients receiving digitalis glycosides.

β-blockers

β-blockers (including eye drops) may weaken or inhibit the effect of formoterol. Concomitant use of β-blockers should be avoided unless the expected benefit outweighs the potential risks. If β-blockers are required, cardioselective agents of this class are preferred.

Other pharmacodynamic interactions

Concomitant use of quinidine, disopyramide, procainamide, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants and phenothiazines may prolong the QT interval and increase the risk of ventricular arrhythmias. In addition, L-dopa, L-thyroxine, oxytocin and alcohol may impair cardiac tolerance to β2-sympathomimetics.

Concomitant use of monoamine oxidase inhibitors, including drugs with similar properties such as furazolidone and procarbazine, may provoke hypertensive reactions.

Patients receiving concomitant anesthesia using halogenated hydrocarbons are at increased risk of arrhythmia.

Application features

This medicine is not intended for the treatment of acute conditions.

This medicine is not indicated for the treatment of acute episodes of bronchospasm, i.e. for emergency care.

Paradoxical bronchospasm

The use of formoterol/glycopyrronium/budesonide may cause paradoxical bronchospasm with sudden wheezing and dyspnea after dosing; this condition may be life-threatening. Therapy with this medicinal product should be discontinued immediately if paradoxical bronchospasm occurs. Patients experiencing paradoxical bronchospasm should be evaluated and alternative therapy instituted if necessary.

Worsening of the disease

Abrupt discontinuation of this medicinal product is not recommended. If patients consider treatment ineffective, treatment should be continued while seeking medical advice. If the patient is increasingly requiring bronchodilators to relieve symptoms, this indicates a worsening of the underlying disease and the need to review the treatment regimen. Sudden and progressive worsening of COPD symptoms is potentially life-threatening, so the patient should undergo an urgent medical examination.

Effects on the cardiovascular system

Cardiovascular effects such as cardiac arrhythmias, such as atrial fibrillation and tachycardia, may occur following administration of muscarinic receptor antagonists and sympathomimetics, including glycopyrronium and formoterol. This medicinal product should be used with caution in patients with clinically significant uncontrolled and severe cardiovascular disease, such as unstable ischemic heart disease, acute myocardial infarction, cardiomyopathy, cardiac arrhythmias and severe heart failure.

Caution should also be exercised when treating patients with known or suspected QTc prolongation (QTc > 450 ms in males or > 470 ms in females), whether congenital or drug-induced.

Systemic effects may occur with any inhaled corticosteroid, especially at high doses for long periods. The likelihood of such effects is much lower with inhaled corticosteroids than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decreased bone mineral density, cataracts, and glaucoma. The potential effect of the drug on bone mineral density should be considered, especially in patients receiving high doses for long periods and who have concomitant risk factors for osteoporosis.

Vision impairment

Visual disturbances have been reported with systemic and topical corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, such as cataracts, glaucoma or rare conditions such as central serous chorioretinopathy; such visual disturbances have been reported with systemic and topical corticosteroids (see section 4.8).

Switching from oral therapy

Particular care should be taken when treating patients who are being transferred from oral corticosteroids, as they may remain at risk of adrenal insufficiency for a significant period of time. Patients requiring high-dose corticosteroid therapy or long-term treatment with inhaled corticosteroids at the highest recommended dose may also be at risk. Such patients may develop symptoms of adrenal insufficiency during periods of severe stress. Additional systemic corticosteroid therapy should be considered during periods of stress or elective surgery.

Pneumonia in patients with COPD

An increased incidence of pneumonia, including pneumonia requiring hospitalization, has been observed in patients with chronic obstructive pulmonary disease (COPD) receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing corticosteroid dose, but this has not been conclusively demonstrated in any of the studies.

For inhaled corticosteroids, there is no conclusive clinical evidence of differences in the magnitude of the risk of pneumonia.

Physicians need to be alert to the possible development of pneumonia in patients with COPD, as the clinical signs of this infectious disease overlap with the symptoms of COPD exacerbation.

Risk factors for developing pneumonia in patients with COPD include smoking, older age, low body mass index (BMI), and severe COPD.

Hypokalemia

Potentially serious hypokalaemia may develop during β2-agonist therapy. This may lead to adverse cardiovascular reactions. Particular caution is recommended in severe COPD, as this effect may be exacerbated by hypoxia. Hypokalaemia may also be exacerbated by concomitant use of this medicinal product with other medicinal products that may cause hypokalaemia, such as xanthine derivatives, steroids and diuretics (see section 4.5).

Hyperglycemia

Inhaled β2-agonists in high doses may lead to an increase in plasma glucose levels. Therefore, during treatment, blood glucose levels should be monitored in accordance with established recommendations for patients with diabetes mellitus.

Comorbidities

This drug should be used with caution in patients with thyrotoxicosis.

Anticholinergic activity

Due to its anticholinergic activity, this medicinal product should be used with caution in patients with symptomatic prostatic hyperplasia, urinary retention or angle-closure glaucoma. Patients should be informed of the signs and symptoms of acute angle-closure glaucoma and of the need to discontinue use of this medicinal product and seek immediate medical attention if any of these signs or symptoms develop.

The simultaneous use of this medicinal product with other medicinal products containing anticholinergics is not recommended (see section “Interaction with other medicinal products and other types of interactions”).

Kidney failure

Since glycopyrronium is excreted primarily by the kidneys, patients with severe renal impairment (creatinine clearance

Liver failure

Patients with severe hepatic impairment should be given this medicine only if the expected benefit outweighs the potential risk (see section 5.2). Such patients should be monitored for possible adverse reactions.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of inhaled budesonide in more than 2500 pregnant women indicate no increased teratogenic risk associated with budesonide. Single-dose clinical studies have shown that very small amounts of glycopyrronium cross the placental barrier.

There is no experience or data on safety issues with the use of norflurane propellant (HFA 134a) during pregnancy or lactation. However, studies of the effects of HFA 134a on reproductive function and embryo-fetal development in animals have not revealed clinically significant adverse reactions.

Animal reproductive toxicity studies have not been conducted with this medicinal product. Budesonide has been shown to cause embryo-fetal toxicity in rats and rabbits, an effect common to the glucocorticoid class of medicinal products. At very high doses/systemic exposure levels, formoterol caused miscarriages and reduced birth weight and early postnatal survival, while glycopyrronium had no significant effect on reproductive function.

The administration of this medicinal product to pregnant women should be considered only if the expected benefit to the mother justifies the potential risk to the foetus.

Breast-feeding

A clinical pharmacology study has shown that budesonide is excreted in breast milk. However, it was not detected in the blood plasma of infants. Based on pharmacokinetic parameters, the concentration of budesonide in the infant's blood plasma is less than 0.17% of the concentration in the maternal blood plasma. Therefore, no effects of budesonide are expected in breast-fed infants whose mothers receive therapeutic doses of this medicinal product. It is not known whether glycopyrronium and formoterol are excreted in breast milk. There is evidence of the penetration of glycopyrronium and formoterol into breast milk in rats.

The use of this medicinal product in breastfeeding women should only be considered

if the expected benefit to the mother outweighs any possible risk to the child.

Fertility

Studies in rats have shown adverse effects of formoterol on fertility only at doses exceeding the maximum human dose. Budesonide and glycopyrronium alone did not have any adverse effects on fertility in rats. This medicinal product is unlikely to affect fertility in humans when administered at recommended doses.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug Trixeo Aerosphere has no or negligible influence on the ability to drive and use machines. However, dizziness is an uncommon side effect that should be taken into account when driving or using machines.

Method of administration and doses

Dosage

The recommended and maximum dose is two inhalations twice a day (two inhalations in the morning and two inhalations in the evening).

If you miss a dose, take it as soon as possible and take the next dose at the usual time. There is no need to take an extra dose to make up for the missed dose.

Special patient groups

Elderly patients

No dose adjustment is required for elderly patients (see section "Pharmacokinetics").

Kidney failure

This medicinal product may be administered at the recommended dose to patients with mild to moderate renal impairment. It may also be administered at the recommended dose to patients with severe renal impairment or end-stage renal disease requiring dialysis only if the expected benefit outweighs the potential risks (see sections 4.4 and 5.2).

Liver failure

This medicinal product can be administered at the recommended dose in patients with mild to moderate hepatic impairment. It can also be administered at the recommended dose in patients with severe hepatic impairment only if the expected benefit outweighs the potential risks (see sections 4.4 and 5.2).

Method of administration and doses

For inhalation use.

Instructions for use

To ensure correct administration of Trixeo Aerosphere, a doctor or other healthcare professional should show the patient how to use the inhaler correctly; this professional should also regularly check the patient's inhalation technique. The patient should be advised to read the instructions for use carefully and follow the instructions for use given in it.

Note: It is important to inform the patient:

· Do not use the inhaler if the desiccant inside the foil pouch has spilled out of its packaging. For best results, the inhaler should be allowed to stand at room temperature for a period of time before use.

· Prepare the inhaler by shaking it and pointing it