GORESP DIGIHALER Inhalation powder Ref.[109453] Active ingredients: Budesonide Eformoterol

Dosing advice

Patients should be reassessed regularly by their physician/healthcare provider so that the dose of GoResp Digihaler 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 this treatment. When it is appropriate to titrate down to a lower strength than is available for GoResp Digihaler, 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 GoResp Digihaler (for asthma patients using this medicinal product as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for asthma patients using this medicinal product 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 medicinal product maintenance dose as prescribed, even when asymptomatic. The prophylactic use of this medicinal product, e.g. before exercise, has not been studied. The reliever inhalations of GoResp Digihaler 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.

GoResp Digihaler should not be interchanged with other inhalation products containing the combination of the same strength of budesonide and formoterol.

Deterioration of disease

This medicinal product should not be used to treat acute asthma symptoms for which a fast- and short-acting bronchodilator is required. Patients should be advised to have their inhaler to be used for relief in an acute asthma attack available at all times.

Patients should not be initiated on this medicinal product during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse reactions and exacerbations may occur during treatment with GoResp Digihaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with this medicinal product.

If patients find the treatment ineffective, or exceed the highest recommended dose of GoResp Digihaler, 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.

Systemic 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, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (see section 4.8).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

Effects on bone density

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.

Long-term studies with inhaled budesonide in adults at daily doses of 800 micrograms (metered dose) have not shown any significant effects on bone mineral density. No information regarding the effect of a budesonide/formoterol fumarate dihydrate fixed-dose combination at higher doses is available.

Adrenal function

Treatment with supplementary systematic steroids or inhaled budesonide should not be stopped abruptly.

The prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress such as severe infections or elective surgery. Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs which might be seen in acute adrenal crisis may be somewhat vague but may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension and hypoglycaemia.

Paradoxical bronchospasm

Paradoxical bronchospasm may occur, with an immediate increase in wheezing and shortness of breath, after dosing. If the patient experiences paradoxical bronchopasm, treatment with this medicinal product should be discontinued immediately, the patient should be assessed and an alternative therapy instituted, if necessary. Paradoxical bronchopasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway (see section 4.8).

Transfer from oral therapy

If there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy, care should be taken when transferring patients to a budesonide/formoterol fumarate fixeddose combination therapy.

The benefits of inhaled budesonide therapy would normally minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Recovery may take a considerable amount of time after cessation of oral steroid therapy and hence oral steroid-dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.

During transfer from oral therapy to a budesonide/formoterol fumarate fixed-dose combination therapy, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.

Oral infections

To minimise the risk of oropharyngeal candida infection, the patient should be instructed to rinse their mouth out with water after inhaling the dose. If oropharyngeal thrush occurs, patients should also rinse their mouth with water after the as-needed inhalations (see section 4.2).

COPD population

There are no clinical study data on GoResp Digihaler available in COPD patients with a prebronchodilator FEV1 >50% predicted normal and with a post-bronchodilator FEV1 <70% predicted normal (see section 5.1).

Pneumonia

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Interaction with other medicinal products

Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided (see section 4.5). If this is not possible the time interval between administrations of the interacting medicinal products should be as long as possible. In patients using potent CYP3A4 inhibitors, a budesonide/formoterol fumarate fixed-dose combination is not recommended.

Caution with special diseases

A fixed-dose combination of budesonide and formoterol fumarate dihydrate should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

Caution should be observed when treating patients with prolongation of the QTc-interval. Formoterol itself may induce prolongation of the QTc-interval.

The need for, and dose of inhaled corticosteroids should be re-evaluated in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.

Additional blood glucose controls should be considered in diabetic patients.

β₂ adrenoceptor agonists

Potentially serious hypokalaemia may result from high doses of β₂ adrenoceptor agonists. Concomitant treatment of β₂ adrenoceptor agonists with medicinal products which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the β₂ adrenoceptor agonist.

Treatment with β₂ adrenoceptor agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia is increased. It is recommended that serum potassium levels are monitored during these circumstances.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 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.

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 a potentially additive bronchodilating effect.

Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

Hypokalaemia may result from β₂-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, corticosteroids and diuretics (see section 4.4).

Budesonide and formoterol have not been observed to interact with any other medicinal products used in the treatment of asthma.

Paediatric population

Interaction studies have only been performed in adults.

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 breastfeeding 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).

This medicinal product has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Since this medicinal product 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).

Description of selected adverse reactions

Candida infection in the oropharynx is due to active substance deposition. Advising the patient to rinse the mouth out with water after each dose will minimise the risk. Oropharyngeal Candida infection usually responds to topical anti-fungal treatment without the need to discontinue the inhaled corticosteroid. If oropharyngeal thrush occurs, patients should also rinse their mouth with water after the as-needed inhalations.

Paradoxical bronchospasm may occur very rarely, affecting less than 1 in 10,000 people, with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. Treatment with this medicinal product should be discontinued immediately, the patient should be assessed and an alternative therapy is instituted if necessary (see section 4.4).

Systemic effects of inhaled corticosteroids may occur, 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, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. Increased susceptibility to infections and impairment of the ability to adapt to stress may also occur. Effects are probably dependent on dose, exposure time, concomitant and previous steroid exposure and individual sensitivity.

Treatment with β₂ adrenoceptor agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.