Trixeo Aerosphere · 4.1 Therapeutic indications · 2

HOS-099059 · has-adverse-reaction-information · PDF-Seite 22

Summary of the safety profile The safety profile is characterised by corticosteroid, anticholinergic and β2-adrenergic class effects related to the individual components of the combination. The most commonly reported adverse 22 reactions in patients with asthma were headache (2.2%), dysphonia (1.9%) and urinary tract infection (1.0%). Tabulated list of adverse reactions The tabulated list of adverse reactions is based on the experience with this medicinal product in clinical trials and experience with the individual components. The frequency of adverse reactions is defined using 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) and not known (cannot be estimated from available data). Table 1: Adverse reactions by frequency and system organ class (SOC) System Organ Class Preferred term Frequency Infections and infestations Urinary tract infection Common Oral candidiasis Immune system disorders Hypersensitivity Uncommon Angioedema Not known Endocrine disorders Signs or symptoms of systemic Very rare glucocorticosteroid effects, e.g. hypofunction of the adrenal gland Metabolism and nutrition Hyperglycaemia Common disorders Psychiatric disorders Anxiety Common Insomnia Depression Uncommon Agitation Restlessness Nervousness Abnormal behaviour Very rare Nervous system disorders Headache Common Dizziness Uncommon Tremor Eye disorders Glaucoma Not known Cataract Vision blurred (se

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HOS-099053 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The safety profile is characterised by corticosteroid, anticholinergic and β2-adrenergic class effects related to the individual components of the combination. The most commonly reported adverse 7 reactions in patients receiving this medicinal product were pneumonia (4.6%), oral candidiasis (3.0%), headache (2.7%) and urinary tract infection (2.7%). Tabulated list of adverse reactions The tabulated list of adverse reactions is based on the experience with this medicinal product in clinical trials and experience with the individual components. The frequency of adverse reactions is defined using 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) and not known (cannot be estimated from available data). Table 1: Adverse reactions by frequency and system organ class (SOC) System Organ Class Preferred term Frequency Infections and infestations Pneumonia Common Urinary tract infection Oral candidiasis Immune system disorders Hypersensitivity Uncommon Angioedema Not known Endocrine disorders Signs or symptoms of systemic Very rare glucocorticosteroid effects, e.g. hypofunction of the adrenal gland Metabolism and nutrition Hyperglycaemia Common disorders Psychiatric disorders Anxiety Common Insomnia Depression Uncommon Agitation Restlessness Nervousness Abnormal behaviour Very rare Nervous system disorders Headache Common Dizziness Uncommon Tremor Eye disorders Glaucoma

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HOS-099049 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substances or any of the excipients listed in section 6.1.

HOS-099055 · has-contraindication-information · PDF-Seite 18

Hypersensitivity to the active substances or any of the excipients listed in section 6.1.

HOS-099054 · has-indication-information · PDF-Seite 17

Trixeo Aerosphere is indicated as a maintenance treatment of asthma in patients 12 years of age and older who are not adequately controlled by a combination of a medium dose inhaled corticosteroid and a long-acting beta2-agonist.

HOS-099048 · has-indication-information · PDF-Seite 2

Trixeo Aerosphere is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting beta2-agonist or combination of a long-acting beta2-agonist and a long-acting muscarinic antagonist (for effects on symptoms control and prevention of exacerbations see section 5.1).

HOS-099051 · has-interaction-information · PDF-Seite 5

Pharmacokinetic interactions Clinical drug-drug interaction studies have not been conducted with this medicinal product, however, the potential for metabolic interactions is considered to be low based on in-vitro studies (see section 5.2). 5 Formoterol does not inhibit the CYP450 enzymes at therapeutically relevant concentrations (see section 5.2). Budesonide and glycopyrronium do not inhibit or induce CYP450 enzymes at therapeutically relevant concentrations. The metabolism of budesonide is primarily mediated by CYP3A4 (see section 5.2). Co-treatment with strong CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products, are expected to increase the risk of systemic side effects, and should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in which case patients should be monitored for systemic corticosteroid adverse reactions. This is of limited clinical importance for short-term (1-2 weeks) treatment. Limited data about this interaction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on average four-fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 micrograms). Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occur with medicinal products affecting renal excretion mechanisms. In vitro, glycopyrronium is a substrate for the renal transporters OCT2 and MATE1/2K. The effect of cimetidine, a probe inhibitor of OCT2 and MATE1, on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC0-t) by 22% and a slight decrease in renal clearance by 23% due to co-administration of cimetidine. Pharmacodynamic interactions Other antimuscarinics and sympathomimetics Co-administration of this medicinal product with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist or β2-adrenergic agonist adverse reactions (see sections 4.4 and 4.9). Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects; therefore, caution is required when other beta-adrenergic medicinal products are prescribed concomitantly with formoterol. Medicinal produc

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HOS-099057 · has-interaction-information · PDF-Seite 20

Pharmacokinetic interactions Clinical drug-drug interaction studies have not been conducted with this medicinal product, however, the potential for metabolic interactions is considered to be low based on in-vitro studies (see section 5.2). 20 Formoterol does not inhibit the CYP450 enzymes at therapeutically relevant concentrations (see section 5.2). Budesonide and glycopyrronium do not inhibit or induce CYP450 enzymes at therapeutically relevant concentrations. The metabolism of budesonide is primarily mediated by CYP3A4 (see section 5.2). Co-treatment with strong CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products, are expected to increase the risk of systemic side effects, and should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in which case patients should be monitored for systemic corticosteroid adverse reactions. This is of limited clinical importance for short-term (1-2 weeks) treatment. Limited data about this interaction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on average four-fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 micrograms). Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occur with medicinal products affecting renal excretion mechanisms. In vitro, glycopyrronium is a substrate for the renal transporters OCT2 and MATE1/2K. The effect of cimetidine, a probe inhibitor of OCT2 and MATE1, on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC0-t) by 22% and a slight decrease in renal clearance by 23% due to co-administration of cimetidine. Pharmacodynamic interactions Other antimuscarinics and sympathomimetics Co-administration of this medicinal product with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist or β2-adrenergic agonist adverse reactions (see sections 4.4 and 4.9). Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects; therefore, caution is required when other beta-adrenergic medicinal products are prescribed concomitantly with formoterol. Medicinal product

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HOS-099052 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no or limited amount of data from the use of budesonide, glycopyrronium and formoterol in pregnant women. Data on the use of inhaled budesonide in more than 2,500 exposed pregnancies indicate no increased teratogenic risk associated with budesonide. Single-dose studies in humans found that very small amounts of glycopyrronium passed the placental barrier. There is no experience with the use of the propellant HFO-1234ze(E) during human pregnancy or lactation. However, studies on the effect of HFO-1234ze(E) on the reproductive function and embryofoetal development in animals revealed no clinically relevant adverse effects. No animal reproductive toxicology studies have been conducted with this medicinal product. Budesonide has been shown to induce embryofoetal toxicity in rats and rabbits, a class effect of glucocorticoids. At very high doses/systemic exposure levels, formoterol caused implantation losses as well as decreases in birth weight and early postnatal survival, whereas glycopyrronium had no significant effects on reproduction (see section 5.3). Administration of this medicinal product to pregnant women should only be considered if the expected benefit to the mother justifies the potential risk to the foetus. Breast-feeding A clinical pharmacology study has shown that inhaled budesonide is excreted in breast milk. However, budesonide was not detected in nursing infant blood samples. Based on pharmacokinetic parameters, the plasma concentration in the child is estimated to be less than 0.17% of the mother’s plasma concentration. Consequently, no effects due to budesonide are anticipated in breast-fed children whose mothers are receiving therapeutic doses of this medicinal product. It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrronium and formoterol into maternal milk in rats has been reported. Administration of this medicinal product to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. Fertility Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximum human exposure to formoterol (see section 5.3). Budesonide and glycopyrronium individually, did not cause any adverse effects on fertility in rats. It is unlikely that this medicinal product administered at the recommended dose will affect fertility in humans.

HOS-099058 · has-pregnancy-information · PDF-Seite 22

Pregnancy There are no or limited amount of data from the use of budesonide, glycopyrronium and formoterol in pregnant women. Data on the use of inhaled budesonide in more than 2 500 exposed pregnancies indicate no increased teratogenic risk associated with budesonide. Single-dose studies in humans found that very small amounts of glycopyrronium passed the placental barrier. There is no experience with or evidence of safety issues on the use of the propellant norflurane (HFA-134a) during human pregnancy or lactation. However, studies on the effect of HFA-134a on the reproductive function and embryofoetal development in animals revealed no clinically relevant adverse effects. No animal reproductive toxicology studies have been conducted with this medicinal product. Budesonide has been shown to induce embryofoetal toxicity in rats and rabbits, a class effect of glucocorticoids. At very high doses/systemic exposure levels, formoterol caused implantation losses as well as decreases in birth weight and early postnatal survival, whereas glycopyrronium had no significant effects on reproduction (see section 5.3). Administration of this medicinal product to pregnant women should only be considered if the expected benefit to the mother justifies the potential risk to the foetus. Breast-feeding A clinical pharmacology study has shown that inhaled budesonide is excreted in breast milk. However, budesonide was not detected in nursing infant blood samples. Based on pharmacokinetic parameters, the plasma concentration in the child is estimated to be less than 0.17% of the mother’s plasma concentration. Consequently, no effects due to budesonide are anticipated in breast-fed children whose mothers are receiving therapeutic doses of this medicinal product. It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrronium and formoterol into maternal milk in rats has been reported. Administration of this medicinal product to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child. Fertility Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximum human exposure to formoterol (see section 5.3). Budesonide and glycopyrronium individually, did not cause any adverse effects on fertility in rats. It is unlikely that this medicinal product administered at the recommended dose will affect fer

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HOS-099050 · has-warning-information · PDF-Seite 3

Not for acute use This medicinal product is not indicated for the treatment of acute episodes of bronchospasm, i.e. as a rescue therapy. Paradoxical bronchospasm Administration of formoterol/glycopyrronium/budesonide may produce paradoxical bronchospasm with an immediate wheezing and shortness of breath after dosing and may be life-threatening. Treatment with this medicinal product should be discontinued immediately if paradoxical bronchospasm occurs. The patient should be assessed, and alternative therapy instituted if necessary. 3 Deterioration of disease It is recommended that treatment with this medicinal product should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment, but medical attention must be sought. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden and progressive deterioration in the symptoms of COPD is potentially life-threatening and the patient should undergo urgent medical assessment. Cardiovascular effects Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen after the 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 prolongation of the QTc interval (QTc >450 milliseconds for males, or >470 milliseconds for females), either congenital or induced by medicinal products. Systemic corticosteroid effects Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma. Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have co-existing risk factors for osteoporosis. Visual disturbances Visual disturbance may

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HOS-099056 · has-warning-information · PDF-Seite 18

Not for acute use This medicinal product is not indicated for the treatment of acute episodes of bronchospasm, i.e. as a rescue therapy. Paradoxical bronchospasm Administration of formoterol/glycopyrronium/budesonide may produce paradoxical bronchospasm with an immediate wheezing and shortness of breath after dosing and may be life-threatening. Treatment with this medicinal product should be discontinued immediately if paradoxical bronchospasm occurs. The patient should be assessed, and alternative therapy instituted if necessary. 18 Deterioration of disease It is recommended that treatment with this medicinal product should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment, but medical attention must be sought. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden and progressive deterioration in the symptoms of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. Cardiovascular effects Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen after the 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 ischaemic heart disease, acute myocardial infarction, cardiomyopathy, cardiac arrhythmias, and severe heart failure. Caution should also be exercised when treating patients with known or suspected prolongation of the QTc interval (QTc >450 milliseconds for males, or >470 milliseconds for females), either congenital or induced by medicinal products. Systemic corticosteroid effects Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma. Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have co-existing risk factors for osteoporosis. Visual disturbances Visual disturbance ma

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