DuoResp Spiromax · 4.4 Special warnings and precautions for use · 1

HOS-155417 · has-adverse-reaction-information · PDF-Seite 25

Summary of the safety profile Since DuoResp Spiromax contains both budesonide and formoterol, the same pattern of adverse reactions as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common adverse reactions are pharmacologically predictable adverse reactions of β2 adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment. In a 3-year clinical trial with budesonide in COPD, skin bruises and pneumonia occurred at a frequency of 10% and 6%, respectively, compared with 4% and 3% in the placebo group (p<0.001 and p<0.01, respectively). 25 Tabulated list of adverse reactions Adverse reactions, which have been associated with budesonide or formoterol, are given below and listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, < 1/100), rare (≥1/10,000, < 1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). System Organ Class Frequency Adverse reaction Infections and infestations Common Candida infections in the oropharynx, pneumonia (in COPD patients) Immune system disorders Rare Immediate and delayed hypersensitivity reactions, e.g. exanthema, urticaria, pruritus, dermatitis, angioedema and anaphylactic reaction Endocrine disorders Very rare Cushing´s syndrome, adrenal suppression, growth retardation, decrease in bone mineral density Metabolism and nutrition Rare Hypokalaemia disorders Very rare Hyperglycaemia Psychiatric disorders Uncommon Aggression, psychomotor hyperactivity, anxiety, sleep disorders Very rare Depression, behavioural changes (predominantly in children) Nervous system disorders Common Headache, tremor

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HOS-155411 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Since DuoResp Spiromax contains both budesonide and formoterol, the same pattern of adverse reactions as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common adverse reactions are pharmacologically predictable adverse reactions of β2 adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment. In a 3-year clinical trial with budesonide in COPD, skin bruises and pneumonia occurred at a frequency of 10% and 6%, respectively, compared with 4% and 3% in the placebo group (p<0.001 and p<0.01, respectively). Tabulated list of adverse reactions Adverse reactions, which have been associated with budesonide or formoterol, are given below and listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, < 1/100), rare (≥1/10,000, < 1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). System Organ Class Frequency Adverse reaction Infections and infestations Common Candida infections in the oropharynx, pneumonia (in COPD patients) 10  Immune system disorders Rare Immediate and delayed hypersensitivity reactions, e.g. exanthema, urticaria, pruritus, dermatitis, angioedema and anaphylactic reaction Endocrine disorders Very rare Cushing´s syndrome, adrenal suppression, growth retardation, decrease in bone mineral density Metabolism and nutrition Rare Hypokalaemia disorders Very rare Hyperglycaemia Psychiatric disorders Uncommon Aggression, psychomotor hyperactivity, anxiety, sleep disorders Very rare Depression, behavioural changes (predominantly in children) Nervous system disorders

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HOS-155407 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substances or the excipient listed in section 6.1.

HOS-155413 · has-contraindication-information · PDF-Seite 20

Hypersensitivity to the active substances or the excipient listed in section 6.1.

HOS-155406 · has-indication-information · PDF-Seite 2

Asthma DuoResp Spiromax is indicated in adults and adolescents (12 years and older) for the regular treatment of asthma, where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate: -in patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short-acting β2 adrenoceptor agonists. or -in patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptor agonists. COPD DuoResp Spiromax is indicated in adults, aged 18 years and older for the symptomatic treatment of patients with COPD with forced expiratory volume in 1 second (FEV1) < 70% predicted normal (post bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long- acting bronchodilators.

HOS-155412 · has-indication-information · PDF-Seite 18

Asthma DuoResp Spiromax is indicated in adults and adolescents (12 years and older) for the regular treatment of asthma, where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate: - in patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short-acting β2 adrenoceptor agonists. or - in patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptor agonists. COPD DuoResp Spiromax is indicated in adults, aged 18 years and older for the symptomatic treatment of patients with COPD with forced expiratory volume in 1 second (FEV1) < 70% predicted normal (post bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long- acting bronchodilators.

HOS-155409 · has-interaction-information · PDF-Seite 8

Pharmacokinetic interactions Potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors) are likely to markedly increase plasma levels of budesonide and concomitant use should be avoided. If this is not possible the time interval between administration of the inhibitor and budesonide should be as long as possible (see section 4.4). In patients 8 using potent CYP3A4 inhibitors, a fixed-dose combination of budesonide and formoterol fumarate dihydrate maintenance and reliever therapy is not recommended. The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, increased plasma levels of concomitantly orally administered budesonide (single dose 3 mg) on average six-fold. When ketoconazole was administered 12 hours after budesonide the concentration was on average increased only three-fold showing that separation of the administration times can reduce the increase in plasma levels. 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). Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects. Pharmacodynamic interactions β adrenergic blockers can weaken or inhibit the effect of formoterol. A fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate should therefore not be given together with β adrenergic blockers (including eye drops) unless there are compelling reasons. Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine) and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias. In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2 sympathomimetics. Concomitant treatment with monoamine oxidase inhibitors including medicinal products with similar properties such as furazolidone and procarbazine may precipitate hypertensive reactions

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HOS-155415 · has-interaction-information · PDF-Seite 24

Pharmacokinetic interactions Potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors) are likely to markedly increase plasma levels of budesonide and concomitant use should be avoided. If this is not possible the time interval between administration of the inhibitor and budesonide should be as long as possible (see section 4.4). The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, increased plasma levels of concomitantly orally administered budesonide (single dose 3 mg) on average six-fold. When ketoconazole was administered 12 hours after budesonide the concentration was on average increased only three-fold showing that separation of the administration times can reduce the increase in plasma levels. 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). Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.1 Pharmacodynamic interactions β adrenergic blockers can weaken or inhibit the effect of formoterol. A fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate should therefore not be given together with β adrenergic blockers (including eye drops) unless there are compelling reasons. Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine) and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias. In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2 sympathomimetics. Concomitant treatment with monoamine oxidase inhibitors including medicinal products with similar properties such as furazolidone and procarbazine may precipitate hypertensive reactions. There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons. Concomitant use of other β adrenergic medicinal products and anticholinergic medicinal products can have

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HOS-155416 · has-pregnancy-information · PDF-Seite 25

Pregnancy For a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate or the concomitant treatment with formoterol and budesonide, no clinical data on exposed pregnancies are available. Data from an embryo-fetal development study in the rat, showed no evidence of any additional effect from the combination. There are no adequate data from use of formoterol in pregnant women. In animal studies formoterol has caused adverse reactions in reproduction studies at very high systemic exposure levels (see section 5.3). Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies glucocorticosteroids have been shown to induce malformations (see section 5.3). This is not likely to be relevant for humans given recommended doses. Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range. During pregnancy, a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used. Breast-feeding Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the suckling child are anticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate 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 There is no data available on the potential effect of budesonide on fertility. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure (see section 5.3).

HOS-155410 · has-pregnancy-information · PDF-Seite 9

Pregnancy For a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate or the concomitant treatment with formoterol and budesonide, no clinical data on exposed pregnancies are available. Data from an embryo-fetal development study in the rat, showed no evidence of any additional effect from the combination. 9 There are no adequate data from use of formoterol in pregnant women. In animal studies formoterol has caused adverse reactions in reproduction studies at very high systemic exposure levels (see section 5.3). Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies glucocorticosteroids have been shown to induce malformations (see section 5.3). This is not likely to be relevant for humans given recommended doses. Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range. During pregnancy, a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used. Breast-feeding Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the suckling child are anticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate 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 There is no data available on the potential effect of budesonide on fertility. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure (see section 5.3).

HOS-155414 · has-warning-information · PDF-Seite 20

Dosing advice Patients should be reassessed regularly by their prescriber/healthcare provider so that the dose of DuoResp Spiromax remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of DuoResp Spiromax. When it is appropriate to titrate down to a lower strength than is available for DuoResp Spiromax, a change to an alternative fixed-dose combination of budesonide and formoterol fumarate containing a lower dose of the inhaled corticosteroid is required. 20 Regular review of patients as treatment is stepped down is important. Patients should be advised to have their rescue inhaler available at all times, either DuoResp Spiromax (for asthma patients using DuoResp Spiromax as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for asthma patients using DuoResp Spiromax as maintenance therapy only). It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly. Patients should be reminded to take their DuoResp Spiromax maintenance dose as prescribed, even when asymptomatic. The prophylactic use of DuoResp Spiromax, e.g. before exercise, has not been studied. The reliever inhalations of DuoResp Spiromax should be taken in response to symptoms but are not intended for regular prophylactic use, e.g. before exercise. In case of frequent need of bronchodilation without corresponding need for an increased dose of inhaled corticosteroids, an alternative reliever should be used. Deterioration of disease Serious asthma-related adverse reactions and exacerbations may occur during treatment with DuoResp Spiromax. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with DuoResp Spiromax. If patients find the treatment ineffective, or exceed the highest recommended dose of DuoResp Spiromax, medical attention must be sought (see section 4.2). Sudden and progressive deterioration in control of asthma or COPD is potentially life-threatening and the patient should undergo urgent medical assessment. In this situation, consideration should be given to the need for increased therapy with corticosteroids, e.g. a course of oral corticosteroids, or antibiotic treatment if an infection is present. Patien

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HOS-155408 · has-warning-information · PDF-Seite 5

Dosing advice Patients should be reassessed regularly by their prescriber/healthcare provider so that the dose of DuoResp Spiromax remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of DuoResp Spiromax. When it is appropriate to titrate down to a lower strength than is available for DuoResp Spiromax, a change to an alternative fixed-dose combination of budesonide and formoterol fumarate containing a lower dose of the inhaled corticosteroid is required. Regular review of patients as treatment is stepped down is important.. Patients should be advised to have their rescue inhaler available at all times, either DuoResp Spiromax (for asthma patients using DuoResp Spiromax as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for asthma patients using DuoResp Spiromax as maintenance therapy only). It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly. Complete withdrawal of inhaled corticosteroids should not be considered unless it is temporarily required to confirm diagnosis of asthma. Patients should be reminded to take their DuoResp Spiromax maintenance dose as prescribed, even when asymptomatic. The prophylactic use of DuoResp Spiromax, e.g. before exercise, has not been studied. The reliever inhalations of DuoResp Spiromax should be taken in response to symptoms but are not intended for regular prophylactic use, e.g. before exercise. In case of frequent need of bronchodilation without corresponding need for an increased dose of inhaled corticosteroids, an alternative reliever should be used. Deterioration of disease 5 Serious asthma-related adverse reactions and exacerbations may occur during treatment with DuoResp Spiromax. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with DuoResp Spiromax. If patients find the treatment ineffective, or exceed the highest recommended dose of DuoResp Spiromax, medical attention must be sought (see section 4.2). Sudden and progressive deterioration in control of asthma or COPD is potentially life-threatening and the patient should undergo urgent medical assessment. In this situation, consideration should be given to the need fo

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