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Vylaer Spiromax (budesonide / formoterol fumarate dihydrate) – Summary of product characteristics - R03AK07

Updated on site: 10-Oct-2017

Medication nameVylaer Spiromax
ATC CodeR03AK07
Substancebudesonide / formoterol fumarate dihydrate
ManufacturerTeva Pharma B.V.

1. NAME OF THE MEDICINAL PRODUCT

Vylaer Spiromax 160 micrograms / 4.5 micrograms inhalation powder

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each delivered dose (the dose that leaves the mouthpiece of the Spiromax) contains 160 micrograms of budesonide and 4.5 micrograms of formoterol fumarate dihydrate.

This is equivalent to a metered dose of 200 micrograms budesonide and 6 micrograms of formoterol fumarate dihydrate.

Excipient(s) with known effect:

Each dose contains approximately 5 milligrams of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

 

 

authorised

Inhalation powder.

 

 

 

 

White powder.

 

 

 

 

 

White inhaler with a semi-transparent wine red mouthpiece c ver.

 

 

 

 

 

 

no

longer

 

4.

CLINICAL PARTICULARS

 

 

4.1

Therapeutic indications

 

 

 

 

 

Vylaer Spiromax is indicated in adults 18 years of age and older only.

 

Asthma

 

 

product

 

 

 

Vylaer Spiromax is ind cated

the regular treatment of asthma, where use of a combination (inhaled

corticosteroid and long- ting β2 adrenoceptor agonist) is appropriate:

 

or

 

Medicinal

 

 

 

 

-in patients not ad quately controlled with inhaled corticosteroids and “as needed” inhaled short-acting β2 adrenoceptor agonists.

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

COPD

Symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.

4.2 Posology and method of administration

Vylaer Spiromax is indicated in adults 18 years of age and older only.

Vylaer Spiromax is not indicated for use in children, 12 years of age and younger or adolescents, 13 to 17 years of age.

Posology

Asthma

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

Vylaer Spiromax is not an appropriate treatment for the adult patient with only mild asthma who is not adequately controlled with an inhaled corticosteroid and “as needed” inhaled short-acting β2 adrenoreceptor

agonists.

authorised

 

The dosage of Vylaer Spiromax is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination medicinal products initiated but also when the maintenance dose is adjusted. If an individual patient should require a c mbination of doses other than those available in the combination inhaler, appropriate doses of β2 adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed.

Once asthma symptoms are controlled, consideration maylongerbe given to adually reducing the dose of Vylaer

Spiromax. Patients should be reassessed regularly by their prescrib r/h alth care provider so that the dose of Vylaer Spiromax remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.

When it is appropriate to titrate down to a lower strengthno than is available for Vylaer Spiromax, a change to

an alternative fixed-dose combination of budesonide a d formoterol fumarate containing a lower dose of the inhaled corticosteroid is required.productWhen long- erm control of symptoms is maintained with the lowest recommended dose, then the next step could in lude a test of inhaled corticosteroid alone.

In usual practice when control of symptoms is achieved with the twice daily dose regimen with a lower strength product, titration to a lower effective dose could include once daily dosing when, in the opinion of the prescriber, a long-acting bronchodilator is required to maintain control rather than treatment with an

inhaled corticosteroid alone.

Vylaer SpiromaxMedicinalis taken as regular maintenance treatment with a separate rapid-acting bronchodilator reliever inhaler.

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

Recommended doses:

Adults (18 years and older): 1-2 inhalations twice daily. Some patients may require up to a maximum of 4 inhalations twice daily.

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

Inhalation use.
Method of administration
Paediatric population

COPD

Recommended doses:

Adults (18 years and older): 2 inhalations twice daily.

Special populations:

Elderly patients (≥65 years old)

There are no special dosing requirements for elderly patients.

Patients with renal or hepatic impairment

years of age has not yet been established. No data are availabl .

authorised

There are no data available for use of a fixed-dose combination of budesonide and formoterol fumarate dihydrate in patients with hepatic or renal impairment. As budesonide and formot rol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in pat ents with severe liver cirrhosis.

The safety and efficacy of Vylaer Spiromax in children, 12 years and younger and adolescents, 13 to 17

This medicinal product is not recommended for use in childrenlongerand adolescents under the age of 18 years.

patients were shown to be able to generate sufficient inspiratory flow rate for Spiromax to deliver the therapeutic dose (see section 5.1).

no Spiromax is a breath actuated, inspiratoryproductflow-driven inhaler, which means that the active substances are delivered into the airways when the patient inhales through the mouthpiece. Moderate and severe asthmatic

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

Vylaer Spiromax should be used correctly in order to achieve effective treatment. As such, the patients should be advisedMedicinalto read the patient information leaflet carefully and follow the instructions for use as detailed in the leaflet.

Open: Hold the Spiromax with the mouthpiece cover at the bottom and open the mouthpiece cover by folding 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 the mouthpiece of the inhaler. Breathe in forcefully and deeply through the mouthpiece. Remove the Spiromax from 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 Vylaer Spiromax due to the lactose excipient.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

General

It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly.

If patients find the treatment ineffective, or exceed the highest recommended dose of Vylaer 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 corticost roi s, e.g. a course of oral corticosteroids, or antibiotic treatment if an infection is present.

Patients should be advised to have their rescue inhaler available at all times.

Patients should be reminded to take their Vylaer Spiromax maintenance dose as prescribed, even when asymptomatic.

authorised

The prophylactic use of Vylaer Spiromax, e.g. before exercise, has not been studied. A separate rapid-acting bronchodilator should be considered for such prophylactic use.

Asthma symptoms

longer

 

Patients should be reassessed regularly by their prescriber/healthcare provider so that the dose of Vylaer

Spiromax remains optimal. The dose should be i rated to the lowest dose at which effective control of

product

no

symptoms is maintained. Once asthma symptoms are controlled, consideration may be given to gradually

reducing the dose of Vylaer Spiromax. When it is appropriate to titrate down to a lower strength than is

available for Vylaer Spiromax, a change to an alternative fixed-dose combination of budesonide and formoterol fumarate containing a lower se of the inhaled corticosteroid is required.

Regular review of patients as treatment is stepped down is important.

Medicinal

Patients should not be

n t ated on Vylaer Spiromax during an exacerbation, or if they have significantly

worsening or acutely deteriorating asthma.

Serious asthma-r lat

adverse reactions and exacerbations may occur during treatment with Vylaer

Spiromax. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with Vylaer Spiromax.

Paradoxical bronchospasm may occur, with an immediate increase in wheezing and shortness of breath, after dosing. If the patient experiences paradoxical bronchopasm Vylaer Spiromax 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).

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.

Adrenal function
Effects on bone density

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).

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid to the lowest dose at which effective control of asthma is maintained, if possible. The benefits 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 inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.

Potential effects on bone density should be considered, particularly in patientsauthorisedon igh doses for prolonged periods that have co-existing risk factors for osteoporosis.

Long-term studies with inhaled budesonide in children at mean daily doses of 400 micrograms (metered dose) or 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.

longer If there is any reason to suppose that adrenal functionnois impaired from previous systemic steroid therapy,

care should be taken when transferring patients to a budesonide/formoterol fumarate fixed-dose combination therapy.

The benefits of inhaled budesonideproducttherapy wo ld 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 am unt of time after cessation of oral steroid therapy and hence oral

High dose corticostero ds

steroid-dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenal function forMedicinalsome considerab e time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.

The prolonged tr atment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may also result 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.

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

Transfer from oral therapy

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,

Caution with special diseases
Interaction with other medicinal products

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.

Pneumonia in patients with COPD

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.authorised

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 includelongercurrent smoking, older age, low body mass index (BMI) and severe COPD.

Concomitant treatment with itraconazole, ritonavirnoor ther potent CYP3A4 inhibitors should be avoided

(see section 4.5). If this is not possible the time i terval between administrations of the interacting medicinal products should be as long as possible.productIn patien s using potent CYP3A4 inhibitors, a budesonide/formoterol fumarate fixed-dose combination is not recommended.

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 Medicinalobstructive rdiomyopathy, 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 adrenoreceptor 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. The excipient lactose contains small amounts of milk proteins which may cause allergic reactions.

Pharmacokinetic interactions

4.5 Interaction with other medicinal products and other forms of interactionauthorised

Potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, voriconazole, posac nazole, 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).

interaction for high-dose inhaled budesonide indicates thatlongermarked increases in plasma levels (on average four fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled

The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, incr ased 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 average increased only three-fold showing

that separation of the administration times can reduce the increase in plasma levels. Limited data about this

budesonide (single dose of 1000 micrograms).

no

 

Pharmacodynamic interactions

 

β adrenergic blockers can weakenproductinhibit 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 (includingMedicinaleye drops) un ess there are compelling reasons.

Concomitant treatment w th quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoam ne oxidase inhibitors 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.

Breast-feeding

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.

4.6 Fertility, pregnancy and lactation

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.

authorised

 

There are no adequate data from use of formoterol in pregnant women. In animal stud es 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 tera ogenic 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 excesslongerprenatal 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.

should only be used when the benefits outweigh thenopotential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.

During pregnancy, a fixed-dose combination therapy f budesonid and formoterol fumarate dihydrate

anticipated. It is not known whetherproductformoterol passes into human breast milk. In rats, small amounts of formoterol haveMedicinalbeen detected maternal milk. Administration of a fixed-dose combination therapy of budesonide and formoterol fum rate dihydrate to women who are breast-feeding should only be considered

Budesonide is excreted in breast milk. H wever, at therapeutic doses no effects on the suckling child are

if the expected benefit to the mother is greater than any possible risk to the child.

Fertility

No data on fertility are available.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

Since Vylaer 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).

Vylaer Spiromax is not indicated in children and adolescents under the age of 18 years (see section 4.2).

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)

authorised

 

 

 

 

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions,

 

 

e.g. exanthema, urticaria, prur tu ,

dermatitis,

 

 

angioedema and anaphylactic eaction

Endocrine disorders

Very rare

Cushing´s syndrome, adrenal

suppression,

 

 

growth retardation, decrease in bone mineral

 

 

density

 

 

Metabolism and nutrition

Rare

Hypokalaemia

 

 

disorders

 

 

longer

 

 

Very rare

Hyperglycaemia

 

 

Psychiatric disorders

Uncommon

Aggression, psychomotor hyperactivity, anxiety,

 

 

sleep disorders

 

 

 

Very rare

Depressi n, behavioural changes

 

 

 

(predominantly in children)

 

Nervous system disorders

Common

no

 

 

 

Headache, tremor

 

 

 

Uncommon

Dizziness

 

 

 

product

Taste disturbances

 

 

 

Very rare

 

 

Eye disorders

Very rare

Cataract and glaucoma

 

Cardiac disorders

Common

Palpitations

 

 

 

Uncomm n

Tachycardia

 

 

 

Rare

Cardiac arrhythmias, e.g. atrial fibrillation,

Skin and subcutaneousMedicinal

 

supraventricular tachycardia, extrasystoles

Uncommon

Bruises

 

 

 

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, hoarseness

mediastinal disor ers

Rare

Bronchospasm

 

 

 

Very rare

Paradoxical bronchospasm

 

Gastrointestinal disorders

Uncommon

Nausea

 

 

tissue disorders

 

 

 

 

 

Musculoskeletal and

Uncommon

Muscle cramps

 

 

connective tissue disorders

 

 

 

 

 

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.

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 bronchopasm responds to a rapid-

Reporting of suspected adverse reactions

acting inhaled bronchodilator and should be treated straightaway. Vylaer Spiromax 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 suspected adverse reactions after authorisation of the medicinalauthorisedproduct mportant. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthca e p ofessionals are asked

to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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 symptomatic treatment may be indicated. A dose of 90 micrograms admi istered during three hours in patients with acute

bronchial obstruction raised no safety concerns.

longer

 

Acute overdose with budesonide, even in excessive doses, is not expected to be a clinical problem. When

used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal

suppression, may appear.

product

no

 

 

 

 

If Vylaer Spiromax therapy has to be with rawn due to overdose of the formoterol component of the

medicinal product, provision of app iate inhaled corticosteroid therapy must be considered.

5.

Medicinal

 

 

PHARMACOLOGICAL PROPERTIES

 

5.1

Pharmacodynamic properties

 

Pharmacotherap utic group: Drugs for obstructive airway diseases, adrenergics and other drugs for obstructive airway diseases.

ATC code: R03AK07

Mechanism of action and pharmacodynamic effects

Vylaer Spiromax contains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma exacerbations. The specific properties of budesonide and formoterol allow the combination to be used as maintenance treatment of asthma. The mechanisms of action of the two substances respectively are discussed below.

Budesonide

Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has less

severe adverse reactions than systemic corticosteroids. The exact mechanism responsible for the anti- inflammatory effect of glucocorticosteroids is unknown.
Formoterol
Formoterol is a selective β2 adrenoceptor agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose-dependant, with an onset of effect within 1-3 minutes. The duration of effect is at least 12 hours after a single dose.
Clinical efficacy and safety
Asthma

Budesonide/formoterol maintenance therapy

effect over time.

authorised

Clinical studies in adults have shown that the addition of formoterol to budesonide improved asthma symptoms 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 free combination of budesonide and formoterol, and exceeded that of budesonide alone. All treatment arms used a short-acting β2 adrenoceptor agonist as needed. There was no sign of ttenuation of the anti-asthmatic

Two 12-week paediatric studies have been performed in which 265 children aged 6-11 years were treated with a maintenance dose of budesonide/formoterol (2 inhalati s of 80 micrograms

/4.5 micrograms/inhalation twice daily), and a short acting β2 adrenoceptor agonist as needed. In both

studies, lung function was improved and the treatment waslongerwell tolerated compared to the corresponding dose of budesonide alone.

COPD

product

no

In two 12-month studies, the effect on lung function and the rate of exacerbation (defined as courses of oral steroids and/or course of antibiotics and/ 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 per

year (as defined above) was significantly reduced with budesonide/formoterol as compared with treatment with formoterolMedicinalalone or pl cebo (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 the

budesonide/formoterol group (7-8 days/patient/year compared with 11-12 and 9-12 days in the placebo and formoterol groups, respectively). For changes in lung-function parameters, such as FEV1, budesonide/formot rol 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 6-17 years), 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(containing placebo). The impact of enhanced training in dry powder inhaler inhalation technique on inhalation speed and volume was also assessed in these subject groups. The data from the study indicated that regardless of age 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 to those generated through the marketed multi-dose dry powder inhaler device. The mean PIFR achieved by patients with asthma or COPD was over 60L/min, a flow rate at which both devices studied are known to

deliver comparable amounts of drug to the lungs. Very few patients had PIFRs below 40L/min; when PIFRs were less than 40L/min there appeared to be no clustering by age or disease severity.

5.2 Pharmacokinetic properties

Absorption

The fixed-dose combination of budesonide and formoterol, and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively. In spite of this, a small increase in cortisol suppression was seen after administration of fixed-dose combination compared 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 comparableauthorisedafter the administration of budesonide and formoterol as monoproducts or as the fixed-dose combination. For bude onide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was similar after administration of the fixed combination. Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalation via the powder inhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is

approximately 49% of the delivered dose. In children 6-16longeryears of age the lung deposition falls in the same range as in adults for the same given dose. The resulting plasma conc ntrations were not determined.

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

Distribution

no

Plasma protein binding is approximatelyproduct50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for form te l and 3 L/kg for budesonide. Formoterol is inactivated via

conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first p ss ge through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid act v ty 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 or any displacement reactions between formoterol and budesonide.

Elimination

Medicinal

 

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-life averages 17 hours.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are eliminated in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide 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.

Pharmacokinetic/pharmacodynamic relationship(s)

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.

Vylaer Spiromax pharmacokinetic profile

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

5.3 Preclinical safety data

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 beenauthorisedshown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not eem to be relevant

in humans at the recommended doses. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures an those reached during clinical use. However, these animal experimental results do not seem to be relevant in humans.

6.

PHARMACEUTICAL PARTICULARS

 

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6.1

List of excipients

 

 

Lactose monohydrate.

 

no

6.2

Incompatibilities

product

 

Not applicable.

 

 

6.3

Shelf life

 

 

3 years.

 

 

After opening the foil wrap: 6 months.

 

 

6.4

Special precautions for storage

 

 

Keep the mouthpieceMedicinalcover closed after removal of the foil wrap.

Do not store above 25 C.

6.5Nature and contents of container

The inhaler is white with a semi-transparent wine red mouthpiece cover. The inhaler is made of acrylonitrile butadiene styrene (ABS), polyethylene terephthalate (PT) , and polypropylene (PP). Each inhaler contains 120 doses and is foil-wrapped.

Pack sizes of 1 or 3 inhalers.

Not all pack-sizes may be marketed.

6.6Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swensweg 5, 2031GA HaarlemThe Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/949/001

EU/1/14/949/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19th November 2014

authorised

 

Date of latest renewal:

 

10. DATE OF REVISION OF THE TEXT

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.com

 

 

no

longer

 

product

 

Medicinal

 

 

 

 

 

1. NAME OF THE MEDICINAL PRODUCT

Vylaer Spiromax 320 micrograms/9 micrograms inhalation powder

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each delivered dose (the dose that leaves the mouthpiece of the Spiromax) contains 320 micrograms of budesonide and 9 micrograms of formoterol fumarate dihydrate.

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

Excipient(s) with known effect:

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

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

 

 

authorised

Inhalation powder.

 

 

 

White powder.

 

 

 

 

 

 

 

White inhaler with a semi-transparent wine red mouthpiece cover.

 

4.

CLINICAL PARTICULARS

no

longer

 

 

 

4.1

Therapeutic indications

 

 

 

 

 

 

 

Vylaer Spiromax is indicated in adults 18 years of age and older only.

 

Asthma

product

 

 

 

 

 

 

 

 

Vylaer Spiromax is indicated in the regular treatment of asthma, where use of a combination (inhaled

corticosteroid and long-act g β2 adrenoceptor agonist) is appropriate:

 

or

- in patients notMedicinalequately controlled with inhaled corticosteroids and “as needed” inhaled short-acting β2 adrenoceptor agonists.

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

COPD

Symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.

4.2Posology and method of administration

Vylaer Spiromax is indicated in adults 18 years of age and older only.

Vylaer Spiromax is not indicated for use in children, 12 years of age and younger or adolescents, 13 to 17 years of age.

Posology

Asthma

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

Vylaer Spiromax is not an appropriate treatment for the adult patient with only mild asthma who is not adequately controlled with an inhaled corticosteroid and “as needed” inhaled short-acting β2 adrenoreceptor agonists.

The dosage of Vylaer Spiromax is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination medicinal products is initiated but also

than those available in the combination inhaler, appropriate doses of β2 adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed.

when the maintenance dose is adjusted. If an individual patient should require a combination of doses other authorised

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Vylaer Spiromax . Patients should be reassessed regularly by their prescriber/health care provider so that the dose of Vylaer Spiromax remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.

an alternative fixed–dose combination of budesonide and formoterol fumarate containing a lower dose of the inhaled corticosteroid is required. When long-term control of symptoms is maintained with the lowest recommended dose, then the next step could include a test f inhaled corticosteroid alone.

When it is appropriate to titrate down to a lower strengthlongerthan is available for Vylaer Spiromax, a change to

the prescriber, a long-acting bronchodilator is requiredno to maintain control rather than treatment with an inhaled corticosteroid alone.

In usual practice when control of symptoms is achieved with the twice daily dose regimen with a lower strength product, titration to a lower effective dose could include once daily dosing when, in the opinion of

Recommended doses:

product

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

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

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

Vylaer Spiromax 320 micrograms/9 micrograms should be used as maintenance therapy only.

COPD

Recommended doses:

Adults (18 years and older):

1 inhalation twice daily

Special populations:

Elderly patients (≥65 years old)

There are no special dosing requirements for elderly patients.

Patients with renal or hepatic impairment

There are no data available for use of a fixed-dose combination of budesonide and formoterol fumarate dihydrate in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.

Paediatric population

The safety and efficacy of Vylaer Spiromax in children, 12 years and younger and adolescents, 13 to 17 years of age has not yet been established. No data are available.

This medicinal product is not recommended for use in children and adolescents under the age of 18 years.

Method of administration

Inhalation use.

Spiromax is a breath actuated, inspiratory flow-driven inhaler, which me ns that the active substances are

delivered into the airways when the patient inhales through the mouthpiece. Moderate and severe asthmatic

 

 

authorised

patients were shown to be able to generate sufficient inspiratory flow rate for Spiromax to deliver the

therapeutic dose (see section 5.1).

longer

 

 

 

Vylaer Spiromax should be used correctly in order to achieve effective treatment. As such, the patients should be advised to read the patient information leaf et carefully and follow the instructions for use as detailed in the leaflet.no

folding it down until it is fully opened when one click is heard.

The use of Vylaer Spiromax followsproductthree simple s eps: open, breathe and close which are outlined below. Open: Hold the Spiromax with the mo thpiece cover at the bottom and open the mouthpiece cover by

Breathe: Place the mouthpiece between the teeth with the lips closed around the mouthpiece, do not bite the

Close: Breathe out gently and close the mouthpiece cover

mouthpiece ofMedicinalthe inhaler. Breathe in forcefully and deeply through the mouthpiece. Remove the Spiromax from mouth and hold the bre th for 10 seconds or as long as comfortable for the patients.

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 Vylaer Spiromax due to the lactose excipient.

4.3Contraindications

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

4.4Special warnings and precautions for use

General

It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly.

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

Patients should be advised to have their rescue inhaler available at all times.

Patients should be reminded to take their Vylaer Spiromax maintenance dose as prescribed, even when asymptomatic.

The prophylactic use of Vylaer Spiromax , e.g. before exercise, has not been studied. A separate rapid- acting bronchodilator should be considered for such prophylactic use .

Asthma symptoms

Patients should be reassessed regularly by their prescriber/healthcare provider so t at the dose of Vylaer 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, consider tion may be given to gradually

reducing the dose of Vylaer Spiromax . When it is appropriate to tit ate down to lower strength than is

 

authorised

available for Vylaer 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.

 

longer

 

Patients should not be initiated on Vylaer Spiromax during an exacerbation, or if they have significantly

worsening or acutely deteriorating asthma.

no

Spiromax . Patients should be askedproductto continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with Vylaer Spiromax .

Serious asthma-related adverse reactions and exacerbations may occur during treatment with Vylaer

Paradoxical bronchospasm may occur, with an immediate increase in wheezing and shortness of breath, after dosing. If the patient experiences paradoxical bronchopasm Vylaer Spiromax should be discontinued

bronchopasmMedicinalresponds to rapid-acting inhaled bronchodilator and should be treated straightaway (see section 4.8).

immediately, the patient should be assessed and an alternative therapy instituted, if necessary. Paradoxical

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).

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid to the lowest dose at which effective control of asthma is maintained, if possible. The benefits 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.

High dose corticosteroids
Adrenal function

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

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 children at mean daily doses of 400 micrograms (metered dose) or 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.

combination therapy.

If there is any reason to suppose that adrenal function is impaired from previousauthorisedsystemic steroid therapy, care should be taken when transferring patients to a budesonide/formoterol fumarate fixed- dose

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 impairedlongeradrenal eserve for 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.

product no 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 uring periods of stress such as severe infections or elective surgery. Rapid reduction in the dose f 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,

Treatment with supplementary systematic steroids or inhaled budesonide should not be stopped abruptly. Transfer from oral therapy

weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension and hypoglycaemia.Medicinal

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.

Caution with special diseases

Pneumonia in patients with COPD

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

Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4authorisedinhibit rs should be avoided

(BMI) and severe COPD.

Interaction with other medicinal products

(see section 4.5). If this is not possible the time interval between administra ions of the interacting medicinal products should be as long as possible. In patients using potent CYP3A4 inhibitors, budesonide/formoterol fumarate fixed-dose combination is not recommended.

A fixed-dose combination of budesonide and formoterol fumarate dihydrate should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia,

longer hypertrophic obstructive cardiomyopathy, idiopathicnosubvalvular aortic stenosis, severe hypertension,

aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

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

Additional blood glucose co trols should be considered in diabetic patients. β2 adrenoreceptor agonists

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

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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. The excipient lactose contains small amounts of milk proteins which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

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

four fold) may occur if itraconazole, 200 mg once daily, is administeredauthorisedc nc mitantly with inhaled budesonide (single dose of 1000 micrograms).

administered 12 hours after budesonide the concentration was on average increased only thr e-fold showing

that separation of the administration times can reduce the increase in plasma levels. Limit data about this

interaction for high-dose inhaled budesonide indicates that marked increases in plasma levels (on average

Pharmacodynamic interactions

β adrenergic blockers can weaken or inhibit the effect of formot ol. 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 reas s.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines

 

 

longer

(terfenadine), monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QTc-interval and

increase the risk of ventricular arrhythmias.

no

 

 

 

In addition L-Dopa, L-thyroxine, oxyto in 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 rocarbazine may precipitate hypertensive reactions.

product

There is an Medicinalelevated risk of rrhythmias 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.

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.

4.6Fertility, pregnancy and lactation

Pregnancy

Breast-feeding

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 authorisedand formoterol fumarate dihydrate

should only be used when the benefits outweigh the potential risks. The lowest effect ve dose of budesonide needed to maintain adequate asthma control should be used.

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 p ssible risk to the child.

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 intolongerhuman b east milk. In rats, small amounts of

Fertility

No data on fertility are available.

no

4.7 Effects on ability to drive and use machines

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

pharmacologicallyMedicinalpredictable adverse reactions of β2 adrenoceptor agonist therapy, such as tremor and

4.8 Undesirable effects

product

Summary of safety prof le

Since Vylaer Spiromax contains both budesonide and formoterol, the same pattern of adverse reactions as reported for th se 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

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).

Vylaer Spiromax is not indicated in children and adolescents under the age of 18 years (see section 4.2).

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

 

 

Uncommon

Dizziness

 

 

Very rare

Taste disturbances

 

Eye disorders

Very rare

Cataract and glaucoma

Cardiac disorders

Common

Palpitations

 

 

Uncommon

Tachycardia

 

 

Rare

Cardiac arrhythmias, .g. atrial fibrillation,

 

 

 

authorised

 

 

supraventricular tachycardia, extrasystoles

 

Very rare

Angina pectoris. Prolongation of QTc-interval

Vascular disorders

Very rare

Variati s in blood pressure

Respiratory, thoracic and

Common

Mi d irritation in the throat, coughing, hoarseness

mediastinal disorders

 

longer

 

Rare

Br nchospasm

 

 

Very rare

Paradoxical bronchospasm

 

 

no

 

Gastrointestinal disorders

Uncommon

Nausea

 

Skin and subcutaneous

Uncommon

Bruises

 

tissue disorders

 

 

 

Musculoskeletal and

Uncomm n

Muscle cramps

 

connective tissue disorders

product

 

 

Description ofMedicinalselected adverse reactions

Candida infection 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.

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 bronchopasm responds to a rapid- acting inhaled bronchodilator and should be treated straightaway. Vylaer Spiromax 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.

Pharmacotherapeutic group: obstructive airway diseases.
ATC code: R03AK07

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.

4.9 Overdose

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 symptomatic

treatment may be indicated. A dose of 90 micrograms administered duringauthorisedthree hours in patients with acute bronchial obstruction raised no safety concerns.

Acute overdose with budesonide, even in excessive doses, is not expected to be cl n cal problem. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.

If Vylaer Spiromax therapy has to be withdrawn due to overdose of the formoterol component of the medicinal product, provision of appropriate inhaled corticosteroidlongerthe apy must be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action and pharmacodynamic effects

no Drugsproductfor obs ruc ive airway diseases, adrenergics and other drugs for

substances respectively are discussed below.

Vylaer SpiromaxMedicinalcontains formoterol and budesonide, which have different modes of action and show additive effects in terms of reduction of asthma exacerbations. The mechanisms of action of the two

Budesonide

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

Formoterol

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

Clinical efficacy and safety

Asthma

Budesonide/formoterol maintenance therapy

Clinical studies in adults have shown that the addition of formoterol to budesonide improved asthma symptoms 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 free combination of budesonide and formoterol, and exceeded that of budesonide alone. All treatment arms used a short-acting β2 adrenoceptor agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.

Two 12-week paediatric studies have been performed in which 265 children aged 6-11 years were treated

with a maintenance dose of budesonide/formoterol (2 inhalations of

authorised

 

80 micrograms/4.5 micrograms/inhalation twice daily), and a short acting β2 adrenoceptor agonist as needed. In both studies, lung function was improved and the treatment was well tolerated compared to the corresponding dose of budesonide alone.

COPD

In two 12-month studies, the effect on lung function and the rate of ex cerbation (defined as courses of oral steroids and/or course of antibiotics and/or hospitalisations) in pati nts with severe COPD was evaluated. Median FEV1 at inclusion in the trials was 36% of predicted normal. The mean number of exacerbations per year (as defined above) was significantly reduced with budeso ide/formoterol as compared with treatment with formoterol alone or placebo (mean rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group).

A randomised, open-label placebo study was performed in children and adolescents with asthma (aged 6-17

The mean number of days on oral corticosteroids/patient during the 12 months was slightly reduced in the

budesonide/formoterol group (7-8 days/patient/year c

 

longer

mpared with 11-12 and 9-12 days in the placebo and

formoterol groups, respectively).

For cha ges

 

in lung-function parameters, such as FEV1,

 

 

no

 

budesonide/formoterol was not superior to trea ment with formoterol alone.

Peak Inspiratory Flow Rate through the Spiromax Device

 

product

 

 

 

years), adults with asthma (aged 18-45 years), adults with chronic obstructive pulmonary disease (COPD – aged >50 years)Medicinaland healthy vo unteers (aged 18-45 years) to evaluate the peak inspiratory flow rate (PIFR) and other related inhalation par meters following inhalation from a Spiromax device (containing placebo)

compared with inhalat on from an already marketed multi-dose dry powder inhaler device (containing placebo). The impact of enhanced training in dry powder inhaler inhalation technique on inhalation speed and volume was also assessed these subject groups. The data from the study indicated that regardless of age 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 to those generated through the marketed multi-dose dry powder inhaler device. The mean PIFR achieved by patients with asthma or COPD was over 60L/min, a flow rate at which both devices studied are known to deliver comparable amounts of drug to the lungs. Very few patients had PIFRs below 40L/min; when PIFRs were less than 40L/min there appeared to be no clustering by age or disease severity.

5.2 Pharmacokinetic properties

Absorption

The fixed-dose combination of budesonide and formoterol, and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively. In spite of this, a small increase in cortisol suppression was seen after administration of fixed-dose combination compared 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 of budesonide and formoterol as monoproducts or as the fixed-dose combination. For budesonide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was similar after administration of the fixed combination. Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalation via the powder inhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children 6-16 years of age the lung deposition falls in the same range 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 minutes after inhalation. In studies the mean lung deposition of formoterol after inhalation via the powder inhaler

ranged from 28% to 49% of the delivered dose. The systemic bioavailability is about 61% of the delivered

dose.

authorised

 

Distribution

Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolit s of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6-beta-hydroxy-budesonide and 16-alfa-hydroxy-

prednisolone, is less than 1% of that of budesonide. There are

indications of any metabolic interactions or

any displacement reactions between formoterol and budes nide.

 

Elimination

longer

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

budesonide are eliminated

urineproductas such or in conjugated form. Only negligible amounts of unchanged

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-life averages 17 hours.

Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of

Pharmacokinetic/pharmacodynamic relationship(s)

budesonide haveMedicinalbeen detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma el m ation 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.

Vylaer Spiromax pharmacokinetic profile

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

5.3 Preclinical safety data

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 relevant in humans at the recommended doses. Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results do not seem to be relevant in humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate.

 

 

authorised

After opening the foil wrap: 6 months.

 

6.2

Incompatibilities

 

 

 

Not applicable.

 

 

 

6.3

Shelf life

 

 

 

3 years.

 

 

illongerwrap.

Keep the mouthpiece cover closed after removal of the f

6.4

Special precautions for storage

 

 

Do not store above 25 C.

 

no

 

6.5

Nature and contents of container

 

Pack sizes of 1 or 3 inhalers.

product

 

 

The inhaler is white with a semi-transparent wine red mouthpiece cover. The inhaler is made of acrylonitrile butadiene styrene (ABS), polyethylene terephthalate (PT) , and polypropylene (PP). Each inhaler contains 60 doses and is foil-w apped.

Not all pack-sizesMedicinalmay be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swensweg 5, 2031GA Haarlem

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/14/949/002

EU/1/14/949/004

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