4.1. Therapeutic indications

Asthma

WockAIR is indicated in adults, and adolescents aged 12-17 years, for the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate:

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

or

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

Chronic Obstructive Pulmonary Disease (COPD)

WockAIR is indicated in adults, aged 18 years and older, for the symptomatic treatment of patients with COPD with forced expiratory volume in 1 second (FEV1) <70% predicted normal (post-bronchodilator) and an exacerbation history despite regular bronchodilator therapy (see also section 4.4).

4.2. Posology and method of administration

Route of administration: For inhalation use

Posology

Asthma

WockAIR is not intended for the initial management of asthma. The required dose of the components of WockAIR is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the maintenance dose is adjusted. If an individual patient should require a combination of doses other than that available in the combination inhaler, appropriate doses of β2 adrenoceptor agonists and/or corticosteroids by individual inhalers should be prescribed.

Patients should be regularly reassessed by their prescriber/health care provider, so that the dose of budesonide/formoterol fumarate remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When long-term control of symptoms is maintained with the lowest recommended dose, then the next step could include a test of inhaled corticosteroid alone.

When it is appropriate to titrate down to a lower strength or to prescribe a higher strength than is available for [Nationally competed name], a change to an alternative fixed-dose combination of budesonide and formoterol fumarate containing a lower or a higher dose of the inhaled corticosteroid, respectively, is required.

In usual practice when control of symptoms is achieved with the twice-daily regimen, titration to the lowest effective dose could include budesonide/formoterol fumarate given once daily, when in the opinion of the prescriber, a long-acting bronchodilator in combination with an inhaled corticosteroid would be required to maintain control.

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

WockAIR should be used as maintenance therapy only. Lower strengths are available for the budesonide/formoterol fumarate maintenance and reliever therapy regimen (160 micrograms/4.5 micrograms/inhalation delivered dose).

Recommended doses:

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

Adolescents (12-17 years): 1 inhalation twice daily.

Children under 12 years: as no data are available, WockAIR is not recommended for children younger than 12 years.

COPD

Recommended doses:

Adults: 1 inhalation twice daily.

General information

Special populations:

There are no special dosing requirements for elderly patients. There are no data available for use of WockAIR 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.

Method of administration

Instructions for use:

Patients should be demonstrated how to use the Forspiro inhaler and correct use should be checked regularly.

The inhaler contains 60 doses of powder medicinal product in a coiled strip of foil. It has a dose counter which indicates how many doses are left counting down from 60 to 0. When the last 10 doses have been reached the numbers will be on a red background.

The inhaler is not refillable – it should be disposed of when it is empty and be replaced with a new one.

Before using the inhaler

• The transparent side chamber door should be opened.

• The foil strip should be removed from the side chamber by carefully tearing away the full length of strip against the 'teeth' of the side chamber as shown below. The strip should not be pulled or tugged.

• The side chamber door should be closed and the used strip should be disposed of.

Note: As the inhaler is used the side chamber will gradually fill up with used strip. The foil strips with black bars don't contain medicinal product. Eventually the numbered sections of the strip will appear in the side chamber. There should never be more than 2 sections of foil strip in the side chamber as they may cause the inhaler to jam. The strip should be torn away carefully as shown above, and disposed of safely.

Using the inhaler

The inhaler should be held in hands, as seen in the pictures.

1. Open

• The protective cap should be opened downwards to reveal the mouthpiece.

• The dose counter should be checked to see how many doses are left.

2. Preparation of the dose

• The edge of the white lever should be lifted up. The side chamber should be closed.

Note: The white lever should only be operated when the patient is ready to inhale a dose of the medicinal product. If the patient plays with the white lever he/she will waste doses.

• Open: The white lever should be moved over fully as far as it will go and until it clicks. This action moves a new dose into position with the number at the top.

• Close: Afterwards the white lever should be closed fully so that it clicks back into its original position. The inhaler is now ready for immediate use.

3. Inhalation of the dose

• Away from the inhaler mouthpiece, the patient should breathe out as much as is comfortable. It should never be breathed directly into the inhaler as this could affect the dose.

• The inhaler should be hold level with the protective cap pointing downwards.

• The lips should be closed firmly around the mouthpiece.

• The patient should breathe in as deeply and as hard as possible through the inhaler, not through the nose.

• The inhaler should be removed from the mouth and the breath should be held for 5-10 seconds or as long as is possible without causing discomfort.

• Afterwards, the patient should breathe out slowly, but not into the inhaler.

• The protective cap should be closed over the mouthpiece.

• The mouth should be rinsed with water, which should be spat out afterwards. This may help to prevent getting fungal infection in the mouth and becoming hoarse.

Cleaning

• The outside of the mouthpiece should be wiped with a clean, dry tissue if necessary.

• The inhaler should not be taken apart to clean it or for any other purpose!

• The inhaler parts must not be cleaned with water or wet wipes as dampness can affect the dose!

• Pins or other sharp objects must never be inserted into the mouthpiece, or any other part, as this may damage the inhaler!

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

4.4. Special warnings and precautions for use

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 WockAIR, medical attention must be sought (see section 4.2). Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy. 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 WockAIR maintenance dose as prescribed, even when asymptomatic.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of WockAIR. Regular review of patients as treatment is stepped down is important. The lowest effective dose of WockAIR should be used (see section 4.2).

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

Serious asthma-related adverse events and exacerbations may occur during treatment with WockAIR . Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of WockAIR.

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

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

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).

Potential effects on bone density should be considered, particularly in patients on high doses for prolonged periods that have coexisting 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 WockAIR at higher doses is available.

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 WockAIR therapy.

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

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

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

During transfer from oral therapy to WockAIR, 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.

To minimise the risk of oropharyngeal candida infection (see section 4.8), the patient should be instructed to rinse their mouth out with water after inhaling the maintenance dose.

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 administration of the interacting medicinal products should be as long as possible.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects.

WockAIR should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

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

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

Potentially serious hypokalaemia may result from high doses of β2 adrenoceptor agonists. Concomitant treatment of β2 adrenoceptor agonists with active substances 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. 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.

As for all β2 adrenoceptor agonists, additional blood glucose controls should be considered in diabetic patients.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR), which have been reported after use of systemic and topical corticosteroids.

Paediatric population

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.

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 patient with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

WockAIR contains lactose (7,9 mg/inhalation).

This amount does not normally cause problems in lactose intolerant people. 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, cobicistat 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 of 3 mg) on average six-fold. When ketoconazole was administered 12 hours after budesonide the concentration was on average increased only three-fold showing that separation of the administration times can reduce the increase in plasma levels. Limited data about this interaction for high-dose inhaled budesonide indicates that marked increase in plasma levels (on average four fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 µg).

Pharmacodynamic interactions

Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. Budesonide/formoterol fumarate should therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine) and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.

In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2-sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors including agents 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 beta-adrenergic active substances or anticholinergics 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

For budesonide/formoterol fumarate 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 effects 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, budesonide/formoterol fumarate should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.

Breastfeeding

Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the suckling child are anticipated. It is not known whether formoterol passes into human breast milk. In rats, small amounts of formoterol have been detected in maternal milk. Administration of budesonide/formoterol fumarate to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Fertility

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

4.7. Effects on ability to drive and use machines

Budesonide/formoterol fumarate has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Since WockAIR contains both budesonide and formoterol, the same pattern of undesirable effects 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 active substance-related adverse reactions are pharmacologically predictable side effects of β2 agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment.

Adverse reactions, which have been associated with budesonide or formoterol, are given below, listed by system organ class and frequency. Frequencies are defined as: very common (☐1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000) and very rare (< 1/10 000).

Table 1

System organ class

Frequency

Adverse Drug 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 disorders

Rare

Hypokalaemia

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

Uncommon

Vision blurred (see also section 4.4)

Very rare

Cataract and glaucoma

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 mediastinal disorders

Common

Mild irritation in the throat, coughing, dysphonia including hoarseness

Rare

Bronchospasm

Gastrointestinal disorders

Uncommon

Nausea

Skin and subcutaneous tissue disorders

Uncommon

Bruises

Musculoskeletal and connective tissue disorders

Uncommon

Muscle cramps

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

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

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged 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.

Paediatric population

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored (see section 4.4).

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

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 during three hours in patients with acute bronchial obstruction raised no safety concerns.

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.

If budesonide/formoterol fumarate therapy has to be withdrawn due to overdose of the formoterol component of the medicinal product, provision of appropriate inhaled corticosteroid therapy must be considered.