DUORESP SPIROMAX 320mcg / 9mcg inhalation powder medication leaflet

DuoResp Spiromax 320 micrograms/9 micrograms inhalation powder

Each delivered dose (the dose that leaves the mouthpiece) contains 320 micrograms of budesonide and9 micrograms of formoterol fumarate dihydrate.

This is equivalent to a metered dose of 400 micrograms budesonide and 12 micrograms of formoterolfumarate dihydrate.

Each dose contains approximately 10 milligrams of lactose (as monohydrate) .

For the full list of excipients, see section 6.1.

Inhalation powder.

White powder.

Asthma

DuoResp Spiromax is indicated in adults and adolescents (12 years and older) for the regular treatment ofasthma, where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) isappropriate:

- in patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short-acting β2adrenoceptor agonists.or

- in patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptoragonists.

COPD

DuoResp Spiromax is indicated in adults, aged 18 years and older for the symptomatic treatment of patientswith 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.

Asthma

DuoResp Spiromax is not intended for the initial management of asthma.

DuoResp Spiromax is not an appropriate treatment for the adult or adolescent patient with only mild asthma.

The dosage of DuoResp Spiromax is individual and should be adjusted to the severity of the disease. Thisshould be considered not only when treatment with combination medicinal products is initiated but alsowhen the maintenance dose is adjusted. If an individual patient should require a combination of doses otherthan those available in the combination inhaler, appropriate doses of β2 adrenoceptor agonists and/orcorticosteroids by individual inhalers should be prescribed.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of

DuoResp Spiromax. Patients should be reassessed regularly by their prescriber/health care provider so thatthe dose of DuoResp Spiromax remains optimal. The dose should be titrated to the lowest dose at whicheffective control of symptoms is maintained.

When it is appropriate to titrate down to a lower strength than is available for DuoResp Spiromax, a changeto an alternative fixed-dose combination of budesonide and formoterol fumarate containing a lower dose ofthe inhaled corticosteroid is required. When long-term control of symptoms is maintained with the lowestrecommended dose, then the next step could include a test of inhaled corticosteroid alone.

Patients should be advised to have their separate rapid-acting bronchodilator reliever inhaler available forrescue use at all times.

Recommended doses:

Adults (18 years and older): 1 inhalation twice daily. Some patients may require up to a maximum of 2inhalations twice daily.

Adolescents (12 years and older): 1 inhalation twice daily.

Patients should be regularly reassessed by their prescriber/healthcare provider, so that the dosage of

DuoResp Spiromax remains optimal. The dose should be titrated to the lowest dose at which effectivecontrol of symptoms is maintained. When long-term control of symptoms is maintained with the lowestrecommended dosage, then the next step could include a test of inhaled corticosteroid alone.

In usual practice when control of symptoms is achieved with the twice-daily regimen, titration to the lowesteffective dose could include DuoResp Spiromax given once daily, when in the opinion of the prescriber, along-acting bronchodilator would be required to maintain control.

Increasing use of a separate rapid-acting bronchodilator indicates a worsening of the underlying conditionand warrants a reassessment of the asthma therapy.

DuoResp Spiromax 320 micrograms/9 micrograms should be used as maintenance therapy only. A lowerstrength of DuoResp Spiromax is available for the maintenance and reliever therapy regimen.

COPD

Recommended doses:

Adults (18 years and older):

1 inhalation twice daily

Elderly patients (≥65 years old)

There are no special dosing requirements for elderly patients.

There are no data available for use of a fixed-dose combination of budesonide and formoterol fumaratedihydrate in patients with hepatic or renal impairment. As budesonide and formoterol are primarilyeliminated via hepatic metabolism, an increased exposure can be expected in patients with severe livercirrhosis.

The safety and efficacy of DuoResp Spiromax in paediatric patients below 12 years of age have not beenestablished. No data are available.

This medicinal product is not recommended for use in children under the age of 12 years.

For inhalation use only.

Spiromax is a breath actuated, inspiratory flow-driven inhaler, which means that the active substances aredelivered into the airways when the patient inhales through the mouthpiece.

Moderate and severe asthmatic patients were shown to be able to generate sufficient inspiratory flow rate for

Spiromax to deliver the therapeutic dose (see section 5.1).

DuoResp Spiromax should be used correctly in order to achieve effective treatment. As such, the patientsshould be advised to read the patient information leaflet carefully and follow the instructions for use asdetailed in the leaflet.

The use of DuoResp Spiromax follows three steps: open, breathe and close which are outlined below.

Open: Hold the Spiromax with the mouthpiece cover at the bottom and open the mouthpiece cover byfolding it down until it is fully opened when one click is heard.

Breathe: Place the mouthpiece between the teeth with the lips closed around the mouthpiece, do not bite themouthpiece of the inhaler. Breathe in forcefully and deeply through the mouthpiece. Remove the Spiromaxfrom mouth and hold the breath for 10 seconds or as long as comfortable for the patients.

Close: Breathe out gently and close the mouthpiece cover

It is also important to advise patients not to shake the inhaler before use and not to breathe out through the

Spiromax and not to block the air vents when they are preparing the “Breathe” step.

Patients should also be advised to rinse their mouth with water after inhaling (see section 4.4).

The patient may notice a taste when using DuoResp Spiromax due to the lactose excipient.

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

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 ofsymptoms is maintained. Once asthma symptoms are controlled, consideration may be given to graduallyreducing the dose of DuoResp Spiromax. When it is appropriate to titrate down to a lower strength than isavailable for DuoResp Spiromax, a change to an alternative fixed-dose combination of budesonide andformoterol 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 (forasthma patients using DuoResp Spiromax as maintenance and reliever therapy) or a separate rapid-actingbronchodilator (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 stoppedabruptly.

Patients should be reminded to take their DuoResp Spiromax maintenance dose as prescribed, even whenasymptomatic. The prophylactic use of DuoResp Spiromax, e.g. before exercise, has not been studied. Thereliever inhalations of DuoResp Spiromax should be taken in response to symptoms but are not intended forregular prophylactic use, e.g. before exercise. In case of frequent need of bronchodilation withoutcorresponding need for an increased dose of inhaled corticosteroids, an alternative reliever should be used.

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 symptomsremain 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 asthmaor COPD is potentially life-threatening and the patient should undergo urgent medical assessment. In thissituation, consideration should be given to the need for increased therapy with corticosteroids, e.g. a courseof oral corticosteroids, or antibiotic treatment if an infection is present.

Patients should not be initiated on DuoResp Spiromax during an exacerbation, or if they have significantlyworsening or acutely deteriorating asthma.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for longperiods. 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, growthretardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and morerarely, 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 withsymptoms such as blurred vision or other visual disturbances, the patient should be considered for referral toan ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseasessuch as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topicalcorticosteroids.

Effects on bone density

Potential effects on bone density should be considered, particularly in patients on high doses for prolongedperiods that have co-existing risk factors for osteoporosis.

Long-term studies with inhaled budesonide in adults at daily doses of 800 micrograms (metered dose) havenot shown any significant effects on bone mineral density. No information regarding the effect of abudesonide/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 recommendeddoses, may also result in clinically significant adrenal suppression. Therefore additional systemiccorticosteroid cover should be considered during periods of stress such as severe infections or electivesurgery. Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs whichmight 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, hypotensionand hypoglycaemia.

Paradoxical bronchospasm may occur, with an immediate increase in wheezing and shortness of breath, afterdosing. If the patient experiences paradoxical bronchospasm DuoResp Spiromax should be discontinuedimmediately, the patient should be assessed and an alternative therapy instituted, if necessary. Paradoxicalbronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway (seesection 4.8).

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 fixed-dose combinationtherapy.

The benefits of inhaled budesonide therapy would normally minimise the need for oral steroids, but patientstransferring 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 oralsteroid-dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenalfunction 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, agenerally lower systemic steroid action will be experienced which may result in the appearance of allergic orarthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiatedfor 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 temporaryincrease 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 mouthout with water after inhaling the dose. If oropharyngeal thrush occurs, patients should also rinse their mouthwith water after the as-needed inhalations (see section 4.2).

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids isregularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose ofinhaled corticosteroid to the lowest dose at which effective control of asthma is maintained, if possible. Thebenefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed.

In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Limited data from long-term studies suggest that most children and adolescents treated with inhaledbudesonide will ultimately achieve their adult target height. However, an initial small but transient reductionin growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.

COPD population

There are no clinical study data on DuoResp Spiromax available in COPD patients with a pre-bronchodilator

FEV1 >50% predicted normal and with a post-bronchodilator FEV1 <70% predicted normal (see section 5.1).

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

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

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as theclinical 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 medicinalproducts should be as long as possible. In patients using potent CYP3A4 inhibitors, a budesonide/formoterolfumarate fixed-dose combination is not recommended.

Caution with special diseases

A fixed-dose combination of budesonide and formoterol fumarate dihydrate should be administered withcaution 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 orsevere heart failure.

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

The need for, and dose of inhaled corticosteroids should be re-evaluated in patients with active or quiescentpulmonary 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. Concomitanttreatment of β2 adrenoceptor agonists with medicinal products which can induce hypokalaemia or potentiatea hypokalaemic effect, e.g. xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemiceffect 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 acutesevere asthma as the associated risk may be augmented by hypoxia and in other conditions when thelikelihood for hypokalaemia is increased. It is recommended that serum potassium levels are monitoredduring these circumstances.

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

Potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin,telithromycin, nefazodone and HIV protease inhibitors) are likely to markedly increase plasma levels ofbudesonide and concomitant use should be avoided. If this is not possible the time interval betweenadministration 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 concomitantlyorally administered budesonide (single dose 3 mg) on average six-fold. When ketoconazole wasadministered 12 hours after budesonide the concentration was on average increased only three-fold showingthat separation of the administration times can reduce the increase in plasma levels. Limited data about thisinteraction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on averagefour fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaledbudesonide (single dose of 1000 micrograms).

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase therisk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increasedrisk of systemic corticosteroid side-effects, in which case patients should be monitored for systemiccorticosteroid side-effects.1

Pharmacodynamic interactionsβ adrenergic blockers can weaken or inhibit the effect of formoterol. A fixed-dose combination therapy ofbudesonide and formoterol fumarate dihydrate should therefore not be given together with β adrenergicblockers (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 ventriculararrhythmias.

In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors including medicinal products with similarproperties such as furazolidone and procarbazine may precipitate hypertensive reactions.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenatedhydrocarbons.

Concomitant use of other β adrenergic medicinal products and anticholinergic medicinal products can have apotentially additive bronchodilating effect.

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

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

Interaction studies have only been performed in adults.

For a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrate or the concomitanttreatment with formoterol and budesonide, no clinical data on exposed pregnancies are available. Data froman embryo-fetal development study in the rat, showed no evidence of any additional effect from thecombination.

There are no adequate data from use of formoterol in pregnant women. In animal studies formoterol hascaused 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 theuse 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 forintrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoidreceptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.

During pregnancy, a fixed-dose combination therapy of budesonide and formoterol fumarate dihydrateshould only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonideneeded to maintain adequate asthma control should be used.

Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the suckling child areanticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts offormoterol have been detected in maternal milk. Administration of a fixed-dose combination therapy ofbudesonide and formoterol fumarate dihydrate to women who are breast-feeding should only be consideredif the expected benefit to the mother is greater than any possible risk to the child.

There is no data available on the potential effect of budesonide on fertility. Animal reproduction studies withformoterol have shown a somewhat reduced fertility in male rats at high systemic exposure (see section 5.3).

DuoResp Spiromax has no or negligible influence on the ability to drive and use machines.

Since DuoResp Spiromax contains both budesonide and formoterol, the same pattern of adverse reactions asreported for these substances may occur. No increased incidence of adverse reactions has been seenfollowing concurrent administration of the two compounds. The most common adverse reactions arepharmacologically predictable adverse reactions of β2 adrenoceptor agonist therapy, such as tremor andpalpitations. These tend to be mild and usually disappear within a few days of treatment. In a 3-year clinicaltrial 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).

Adverse reactions, which have been associated with budesonide or formoterol, are given below and listed bysystem 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, growthretardation, decrease in bone mineral density

Metabolism and nutrition Rare Hypokalaemiadisorders 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

Uncommon Dizziness

Very rare Taste disturbances

Eye disorders Very rare Cataract and glaucoma

Uncommon Vision, blurred (see also section 4.4)

Cardiac disorders Common Palpitations

Uncommon Tachycardia

Rare Cardiac arrhythmias, e.g. atrial fibrillation,supraventricular tachycardia, extrasystoles

Very rare Angina pectoris. Prolongation of QTc-interval

Vascular disorders Very rare Variations in blood pressure

Respiratory, thoracic and Common Mild irritation in the throat, coughing, Dysphoniamediastinal disorders including hoarseness

Rare Bronchospasm

Very rare Paradoxical bronchospasm

Gastrointestinal disorders Uncommon Nausea

Skin and subcutaneous Uncommon Bruisestissue disorders

Musculoskeletal and Uncommon Muscle crampsconnective tissue disorders

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

Paradoxical bronchospasm may occur very rarely, affecting less than 1 in 10,000 people, with an immediateincrease in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. DuoResp Spiromax should be discontinuedimmediately, the patient should be assessed and an alternative therapy is instituted if necessary (see section4.4).

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 andadolescents, decrease in bone mineral density, cataract and glaucoma. Increased susceptibility to infectionsand 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 suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

An overdose of formoterol would likely lead to effects that are typical for β2 adrenoceptor agonists: tremor,headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia,hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and vomiting. Supportive and symptomatictreatment may be indicated. A dose of 90 micrograms administered during three hours in patients with acutebronchial obstruction raised no safety concerns.

Acute overdose with budesonide, even in excessive doses, is not expected to be a clinical problem. Whenused chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenalsuppression, may appear.

If DuoResp Spiromax therapy has to be withdrawn due to overdose of the formoterol component of themedicinal product, provision of appropriate inhaled corticosteroid therapy must be considered.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics and other drugs forobstructive airway diseases.

ATC code: R03AK07

Mechanism of action and pharmacodynamic effects

DuoResp Spiromax contains formoterol and budesonide, which have different modes of action and showadditive effects in terms of reduction of asthma exacerbations

Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action inthe airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has lesssevere adverse reactions than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.

Formoterol is a selective β2 adrenoceptor agonist that when inhaled results in rapid and long-acting relaxationof bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect isdose-dependent, with an onset of effect within 1-3 minutes. The duration of effect is at least 12 hours after asingle dose.

Asthma

Budesonide/formoterol maintenance therapy

Clinical studies in adults have shown that the addition of formoterol to budesonide improved asthmasymptoms and lung function, and reduced exacerbations.

In two 12-week studies the effect on lung function of budesonide/formoterol was equal to that of the freecombination of budesonide and formoterol, and exceeded that of budesonide alone. All treatment arms useda short-acting β2 adrenoceptor agonist as needed. There was no sign of attenuation of the anti-asthmaticeffect over time.

COPD

In two 12-month studies, the effect on lung function and the rate of exacerbation (defined as courses of oralsteroids and/or course of antibiotics and/or hospitalisations) in patients with severe COPD was evaluated.

Median FEV1 at inclusion in the trials was 36% of predicted normal. The mean number of exacerbations peryear (as defined above) was significantly reduced with budesonide/formoterol as compared with treatmentwith formoterol alone or placebo (mean rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group).

The mean number of days on oral corticosteroids/patient during the 12 months was slightly reduced in thebudesonide/formoterol group (7-8 days/patient/year compared with 11-12 and 9-12 days in the placebo andformoterol groups, respectively). For changes in lung-function parameters, such as FEV1,budesonide/formoterol was not superior to treatment with formoterol alone.

Peak Inspiratory Flow Rate through the Spiromax Device

A randomised, open-label placebo study was performed in children and adolescents with asthma (aged 6-17years), adults with asthma (aged 18-45 years), adults with chronic obstructive pulmonary disease (COPD -aged >50 years) and healthy volunteers (aged 18-45 years) to evaluate the peak inspiratory flow rate (PIFR)and other related inhalation parameters following inhalation from a Spiromax device (containing placebo)compared with inhalation from an already marketed multi-dose dry powder inhaler device (containingplacebo). The impact of enhanced training in dry powder inhaler inhalation technique on inhalation speedand volume was also assessed in these subject groups. The data from the study indicated that regardless ofage and underlying disease severity, children, adolescents and adults with asthma as well as patients with

COPD were able to able to achieve inspiratory flow rates through the Spiromax device that were similar tothose generated through the marketed multi-dose dry powder inhaler device. The mean PIFR achieved bypatients with asthma or COPD was over 60L/min, a flow rate at which both devices studied are known todeliver comparable amounts of drug to the lungs. Very few patients had PIFRs below 40L/min; when PIFRswere less than 40L/min there appeared to be no clustering by age or disease severity.

The fixed-dose combination of budesonide and formoterol, and the corresponding monoproducts have beenshown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively. Inspite of this, a small increase in cortisol suppression was seen after administration of fixed-dose combinationcompared to the monoproducts. The difference is considered not to have an impact on clinical safety.

There was no evidence of pharmacokinetic interactions between budesonide and formoterol.

Pharmacokinetic parameters for the respective substances were comparable after the administration ofbudesonide and formoterol as monoproducts or as the fixed-dose combination. For budesonide, AUC wasslightly higher, rate of absorption more rapid and maximal plasma concentration higher after administrationof the fixed combination. For formoterol, maximal plasma concentration was similar after administration ofthe fixed combination. Inhaled budesonide is rapidly absorbed and the maximum plasma concentration isreached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalationvia the powder inhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability isapproximately 49% of the delivered dose. In children 6-16 years of age the lung deposition falls in the samerange as in adults for the same given dose. The resulting plasma concentrations were not determined.

Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutesafter inhalation. In studies the mean lung deposition of formoterol after inhalation via the powder inhalerranged from 28% to 49% of the delivered dose. The systemic bioavailability is about 61% of the delivereddose.

Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume ofdistribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated viaconjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seenmainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) ofbiotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. Theglucocorticosteroid activity of the major metabolites, 6-beta-hydroxy-budesonide and 16-alfa-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any metabolic interactions orany displacement reactions between formoterol and budesonide.

The major part of a dose of formoterol is transformed by liver metabolism followed by renal elimination.

After inhalation, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine.

Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination half-lifeaverages 17 hours.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites ofbudesonide are eliminated in urine as such or in conjugated form. Only negligible amounts of unchangedbudesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2

L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.

The pharmacokinetics of budesonide or formoterol in children and patients with renal failure are unknown.

The exposure of budesonide and formoterol may be increased in patients with liver disease.

DuoResp Spiromax pharmacokinetic profile

In pharmacokinetic studies with and without a charcoal blockage, DuoResp Spiromax was evaluated bycomparing it with an alternative authorised fixed-dose combination inhaled product containing the sameactive substances, budesonide and formoterol and has been shown to be equivalent in both systemic exposure(safety) and pulmonary deposition (efficacy).

Systemic exposure for both budesonide and formoterol correlates in a linear fashion to administered dose.

The toxicity observed in animal studies with budesonide and formoterol, given in combination or separately,were effects associated with exaggerated pharmacological activity.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations(cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevantin humans at the recommended doses. Animal reproduction studies with formoterol have shown a somewhatreduced fertility in male rats at high systemic exposure and implantation losses as well as decreased earlypostnatal survival and birth weight at considerably higher systemic exposures than those reached duringclinical use. However, these animal experimental results do not seem to be relevant in humans.

Lactose monohydrate (which contains milk proteins).

Not applicable.

3 years.

After opening the foil wrap: 6 months.

Do not store above 25°C.

Keep the mouthpiece cover closed after removal of the foil wrap.

The inhaler is white with a semi-transparent wine red mouthpiece cover. The drug/mucosal contact parts ofthe inhaler are made of acrylonitrile butadiene styrene (ABS), polyethylene (PE), and polypropylene (PP).

Each inhaler contains 60 doses and is foil-wrapped.

Pack sizes of 1, 2 or 3 inhalers.

Not all pack-sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements..

Teva Pharma B.V.

Swensweg 5, 2031GA Haarlem, The Netherlands

EU/1/14/920/004

EU/1/14/920/005

EU/1/14/920/006

Date of first authorisation: 28th April 2014

Date of latest renewal: 8th April 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.com