Relvar Ellipta · 4.6 Fertility, pregnancy and lactation · 1

HOS-096564 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with fluticasone furoate/vilanterol. In the asthma clinical development programme a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development programme a total of 6,237 subjects were included in an integrated assessment of adverse reactions. The most commonly reported adverse reactions with fluticasone furoate and vilanterol were headache and nasopharyngitis. With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD. Tabulated list of adverse reactions Adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of frequencies: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. System organ class Adverse reaction(s) Frequency Infections and infestations Pneumonia* Common Upper respiratory tract infection Bronchitis Influenza Candidiasis of mouth and throat Immune system disorders Hypersensitivity reactions including Rare anaphylaxis, angioedema, rash, and urticaria. Metabolism and nutrition Hyperglycaemia Uncommon disorders Psychiatric disorders Anxiety Rare Nervous system disorders Headache Very common Tremor Rare Eye disorders Vision blurred (see section 4.4) Uncommon Cardiac disorders Extrasystoles

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HOS-096570 · has-adverse-reaction-information · PDF-Seite 32

Summary of the safety profile Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with fluticasone furoate/vilanterol. In the asthma clinical development programme a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development programme a total of 6,237 subjects were included in an integrated assessment of adverse reactions. The most commonly reported adverse reactions with fluticasone furoate and vilanterol were headache and nasopharyngitis. With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD. Tabulated list of adverse reactions Adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of frequencies: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 32  System organ class Adverse reaction(s) Frequency Infections and infestations Pneumonia* Common Upper respiratory tract infection Bronchitis Influenza Candidiasis of mouth and throat Immune system disorders Hypersensitivity reactions including Rare anaphylaxis, angioedema, rash, and urticaria. Metabolism and nutrition Hyperglycaemia Uncommon disorders Psychiatric disorders Anxiety Rare Nervous system disorders Headache Very common Tremor Rare Eye disorders Vision blurred (see section 4.4) Uncommon Cardiac disorders Extrasystoles Uncommon Palpitations

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HOS-096566 · has-contraindication-information · PDF-Seite 29

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

HOS-096560 · has-contraindication-information · PDF-Seite 6

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

HOS-096565 · has-indication-information · PDF-Seite 25

Asthma Relvar Ellipta is indicated for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate: • patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta2-agonists. • patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist.

HOS-096559 · has-indication-information · PDF-Seite 2

Asthma Relvar Ellipta is indicated for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate: • patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta2-agonists. • patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist. COPD (Chronic Obstructive Pulmonary Disease) Relvar Ellipta is indicated for the symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy.

HOS-096568 · has-interaction-information · PDF-Seite 31

Clinically significant drug interactions mediated by fluticasone furoate/vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing. Interaction with beta-blockers Beta2-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Concurrent use of both non-selective and selective beta2-adrenergic blockers should be avoided unless there are compelling reasons for their use. Interaction with CYP3A4 inhibitors Fluticasone furoate and vilanterol are both rapidly cleared by extensive first pass metabolism mediated by the liver enzyme CYP3A4. Caution is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid undesirable effects, in which case patients should be monitored for systemic corticosteroid undesirable effects. A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and the strong CYP3A4 inhibitor ketoconazole (400 mg). Co-administration increased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta2-agonist related systemic effects on heart rate, blood potassium or QTcF interval. Interaction with P-glycoprotein inhibitors Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). A clinical pharmacology study in healthy subjects with co-administered vilanterol and the potent P-gp and moderate CYP3A4 inhibitor verapamil did not show any significant effect on the pharmacokinetics of vilanterol. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted. Sympathomimetic medicinal products Concomitant administration of other sympathomimetic medicinal prod

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HOS-096562 · has-interaction-information · PDF-Seite 8

Clinically significant drug interactions mediated by fluticasone furoate/vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing. Interaction with beta-blockers Beta2-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Concurrent use of both non-selective and selective beta2-adrenergic blockers should be avoided unless there are compelling reasons for their use. Interaction with CYP3A4 inhibitors Fluticasone furoate and vilanterol are both rapidly cleared by extensive first pass metabolism mediated by the liver enzyme CYP3A4. Caution is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid undesirable effects, in which case patients should be monitored for systemic corticosteroid undesirable effects. A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and the strong CYP3A4 inhibitor ketoconazole (400 mg). Co-administration increased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax 65% and 22%, 8  respectively. The increase in vilanterol exposure was not associated with an increase in beta2-agonist related systemic effects on heart rate, blood potassium or QTcF interval. Interaction with P-glycoprotein inhibitors Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). A clinical pharmacology study in healthy subjects with co-administered vilanterol and the potent P-gp and moderate CYP3A4 inhibitor verapamil did not show any significant effect on the pharmacokinetics of vilanterol. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted. Sympathomimetic medicinal products Concomi

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HOS-096569 · has-pregnancy-information · PDF-Seite 32

Pregnancy Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant (see section 5.3). There are no or limited data from the use of fluticasone furoate and vilanterol trifenatate in pregnant women. Administration of fluticasone furoate/vilanterol to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. Breast-feeding There is insufficient information on the excretion of fluticasone furoate or vilanterol trifenatate and/or metabolites in human milk. However, other corticosteroids and beta2-agonists are detected in human milk (see section 5.3). A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue fluticasone furoate/vilanterol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no fertility data in humans. Animal studies showed no effect of fluticasone furoate/vilanterol trifenatate on fertility (see section 5.3).

HOS-096563 · has-pregnancy-information · PDF-Seite 9

Pregnancy Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant (see section 5.3). There are no or limited data from the use of fluticasone furoate and vilanterol trifenatate in pregnant women. Administration of fluticasone furoate/vilanterol to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. Breast-feeding There is insufficient information on the excretion of fluticasone furoate or vilanterol trifenatate and/or metabolites in human milk. However, other corticosteroids and beta2-agonists are detected in human milk (see section 5.3). A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue fluticasone furoate/vilanterol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no fertility data in humans. Animal studies showed no effect of fluticasone furoate/vilanterol trifenatate on fertility (see section 5.3).

HOS-096567 · has-warning-information · PDF-Seite 29

Deterioration of disease Fluticasone furoate/vilanterol should not be used to treat acute asthma symptoms, for which a short- acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician. Patients should not stop therapy with fluticasone furoate/vilanterol in asthma, without physician supervision since symptoms may recur after discontinuation. Asthma-related adverse events and exacerbations may occur during treatment with fluticasone furoate/vilanterol. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with Relvar Ellipta. Paradoxical bronchospasm Paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short-acting inhaled bronchodilator. Relvar Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Cardiovascular effects Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinal products including Relvar Ellipta. In a placebo- controlled study in subjects with moderate COPD and a history of, or an increased risk of cardiovascular disease, there was no increase in the risk of cardiovascular events in patients receiving fluticasone furoate/vilanterol compared with placebo. However, fluticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease or heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium. 29 Patients with hepatic impairment For patients with moderate to severe hepatic impairment, the 92/22 micrograms dose should be used and patients should be monitored for systemic corticosteroid-related adverse reactions (see section 5.2). 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 than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid f

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HOS-096561 · has-warning-information · PDF-Seite 6

Deterioration of disease Fluticasone furoate/vilanterol should not be used to treat acute asthma symptoms or an acute exacerbation in COPD, for which a short-acting bronchodilator is required. Increasing use of short- acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician. 6 Patients should not stop therapy with fluticasone furoate/vilanterol in asthma or COPD, without physician supervision since symptoms may recur after discontinuation. Asthma-related adverse events and exacerbations may occur during treatment with fluticasone furoate/vilanterol. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of treatment with Relvar Ellipta. Paradoxical bronchospasm Paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short-acting inhaled bronchodilator. Relvar Ellipta should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Cardiovascular effects Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic medicinal products including Relvar Ellipta. In a placebo- controlled study in subjects with moderate COPD and a history of, or an increased risk of cardiovascular disease, there was no increase in the risk of cardiovascular events in patients receiving fluticasone furoate/vilanterol compared with placebo (see section 5.1). However, fluticasone furoate/vilanterol should be used with caution in patients with severe cardiovascular disease or heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium. Patients with hepatic impairment For patients with moderate to severe hepatic impairment, the 92/22 micrograms dose should be used and patients should be monitored for systemic corticosteroid-related adverse reactions (see section 5.2). 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 than with oral corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease i

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