4.1. Therapeutic indications

Proxor is indicated in the regular treatment of asthma where use of a combination product (inhaled corticosteroid and long-acting beta2-agonist) is appropriate:

- patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled rapid-acting beta2-agonist or

- patients already adequately controlled on both inhaled corticosteroids and long-acting beta2- agonists.

Proxor is indicated in adults.

4.2. Posology and method of administration

Posology

Proxor is not intended for the initial management of asthma. The dosage of the components of Proxor 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 dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of beta2-agonists and/or corticosteroids by individual inhalers should be prescribed.

Beclometasone dipropionate in Proxor is characterised by an extrafine particle size distribution which results in a more potent effect than formulations of beclometasone dipropionate with a non-extra fine particle size distribution (100 micrograms of beclometasone dipropionate extrafine in Proxor are equivalent to 250 micrograms of beclometasone dipropionate in a non-extrafine formulation). Therefore, the total daily dose of beclometasone dipropionate administered in Proxor should be lower than the total daily dose of beclometasone dipropionate administered in a non-extrafine beclometasone dipropionate formulation.

This should be taken into consideration when a patient is transferred from a beclometasone dipropionate non-extrafine formulation to Proxor; the dose of beclometasone dipropionate should be lower and will need to be adjusted to the individual needs of the patients.

Dose recommendations for adults 18 years and above:

Two inhalations twice daily.

The maximum daily dose is 4 inhalations.

Proxor 200/6 should be used as maintenance therapy only. A lower strength (Proxor 100/6) is available for maintenance and reliever therapy.

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

Patients should be regularly reassessed by a doctor, so that the dosage of Proxor remains optimal and is only changed on medical advice. 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 dosage, then the next step could include a test of inhaled corticosteroid alone. Proxor 200/6 should not be used for step-down treatment but a lower strength of the beclometasone dipropionate component in the same inhaler is available for step-down treatment (Proxor 100/6 micrograms).

Patients should be advised to take Proxor every day even when asymptomatic.

Special patient groups:

There is no need to adjust the dose in elderly patients. There are no data available for use of beclometasone dipropionate/formoterol in patients with hepatic or renal impairment (see section 5.2).

Dose recommendations for children and adolescents under 18 years:

Proxor 200/6 should not be used in children and adolescents less than 18 years.

Method of administration

Proxor is for inhalation use.

To ensure proper administration of the drug, the patient should be shown how to use the medicinal product correctly by a physician or other health professional. Correct use of the pressurised metered dose inhaler is essential in order that treatment is successful. The patient should be advised to read the Patient Information Leaflet carefully and follow the instructions for use as given in the Leaflet.

Proxor inhaler is provided with a counter on the back of the actuator, which shows how many doses are left. For the 120 doses presentation each time the patient press the canister, a puff of medicine is released and the counter counts down by one. For the 180 presentation, each time the patient press the canister the counter rotates by a small amount and the number of puffs remaining is displayed in intervals of 20 (180, 160, 140, 120....). Patients should be advised not to drop the inhaler as this may cause the counter to count down.

Testing the inhaler

Before using the inhaler for the first time or if the inhaler has not been used for 14 days or more, the patient should release one actuation into the air in order to ensure that the inhaler is working properly.

After testing the inhaler for the first time, the counter should read 120 or 180.

Use of the inhaler:

If the inhaler has been exposed to severe cold, patients should warm it with their hands for a few minutes before using it. They should never warm it by artificial means.

Whenever possible patients should stand or sit in an upright position when inhaling from their inhaler.

1. Patients should remove the protective cap from the mouthpiece and check that the mouthpiece is clean and free from dust and dirt or any other foreign objects.

2. Patients should breathe out as slowly and deeply as possible.

3. Patients should hold the canister vertically with its body upwards and put the lips around the mouthpiece without biting the mouthpiece.

4. At the same time, patients should breathe in slowly and deeply through the mouth. After starting to breathe in, they should press down on the top of the inhaler to release one puff.

5. Patients should hold the breath for as long as possible and, finally, they should remove the inhaler from the mouth and breathe out slowly. Patients should not breathe out into the inhaler.

To inhale a further puff, patients should keep the inhaler in a vertical position for about half a minute and repeat steps 2 to 5.

IMPORTANT: patients should not perform steps 2 to 5 too quickly.

After use, patients should close the inhaler with protective cap and check the dose counter.

Patients should be advised to get a new inhaler when the dose counter or indicator shows the number 20. They should stop using the inhaler when the counter shows 0 as any puffs left in the device may not be enough to release a full dose.

If mist appears following inhalation, either from the inhaler or from the sides of the mouth, the procedure should be repeated from step 2.

For patients with weak hands it may be easier to hold the inhaler with both hands. Therefore, the index fingers should be placed on the top of the inhaler canister and both thumbs on the base of the inhaler.

Patients should rinse their mouth or gargle with water or brush the teeth after inhaling (see section 4.4).

The canister contains a pressurised liquid. Patients should be advised not to expose to temperatures higher than 50°C and not to pierce the canister.

Cleaning

Patients should be advised to read the Patient Information Leaflet carefully for cleaning instructions. For the regular cleaning of the inhaler, patients should remove the cap from the mouthpiece and wipe the outside and inside of the mouthpiece with a dry cloth. They should not remove the canister from the actuator and should not use water or other liquids to clean the mouthpiece.

Patients who find it difficult to synchronize aerosol actuation with inspiration of breath, may use the AeroChamber Plus spacer device. They should be advised by their doctor, pharmacist or a nurse in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. This may be obtained by the patients using the AeroChamber Plus by one continuous slow and deep breath through the spacer, without any delay between actuation and inhalation.

4.3. Contraindications

Hypersensitivity to beclometasone dipropionate, formoterol fumarate dihydrate or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Proxor should be used with caution (which may include monitoring) in patients with cardiac arrhythmias, especially third degree atrioventricular block and tachyarrhythmias (accelerated and/or irregular heart beat), idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, severe heart disease, particularly acute myocardial infarction, ischaemic heart disease, congestive heart failure, occlusive vascular diseases, particularly arteriosclerosis, arterial hypertension and aneurysm.

Caution should also be observed when treating patients with known or suspected prolongation of the QTc interval, either congenital or drug induced (QTc > 0.44 seconds). Formoterol itself may induce prolongation of the QTc interval.

Caution is also required when Proxor is used by patients with thyrotoxicosis, diabetes mellitus, phaeochromocytoma and untreated hypokalaemia.

Potentially serious hypokalaemia may result from beta2-agonist therapy. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitant treatment with other medicinal products which can induce hypokalaemia, such as xanthine derivatives, steroids and diuretics (see Section 4.5). Caution is also recommended in unstable asthma when a number of “rescue” bronchodilators may be used. It is recommended that serum potassium levels are monitored in such situations.

The inhalation of formoterol may cause a rise in blood glucose levels. Therefore, blood glucose should be closely monitored in patients with diabetes.

If anaesthesia with halogenated anaesthetics is planned, it should be ensured that Proxor is not administered for at least 12 hours before the start of anaesthesia as there is a risk of cardiac arrhythmias.

As with all inhaled medication containing corticosteroids, Proxor should be administered with caution in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.

It is recommended that treatment with Proxor should not be stopped abruptly.

If patients find the treatment ineffective medical attention must be sought. 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. Consideration should be given to the need for increased treatment with corticosteroids, either inhaled or oral therapy, or antibiotic treatment if an infection is suspected.

Patients should not be initiated on Proxor 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 Proxor. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Proxor.

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and rapidness of breath after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. Proxor should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Proxor should not be used as the first treatment for asthma.

For treatment of acute asthma attacks patients should be advised to have their rapid-acting bronchodilator available at all times, either Proxor (for patients using Proxor as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for patients using Proxor as maintenance therapy only).

Patients should be reminded to take Proxor daily as prescribed even when asymptomatic. The reliever inhalations of Proxor should be taken in response to asthma symptoms but are not intended for regular prophylactic use, e.g. before exercise. For such use, a separate rapid-acting bronchodilator should be considered.

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

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 inhaled than with oral corticosteroids. Possible systemic effects include: Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, 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). Therefore, it is important that the patient is reviewed regularly, and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

Single dose pharmacokinetic data (see section 5.2) have demonstrated that the use of beclometasone dipropionate/formoterol with Aerochamber Plus® spacer device in comparison to the use of standard actuator, does not increase the total systemic exposure to formoterol and reduces the systemic exposure to beclometasone-17-monopropionate, while there is an increase for unchanged beclometasone dipropionate that reaches systemic circulation from the lung; however, since the total systemic exposure to beclometasone dipropionate plus its active metabolite does not change, there is no increased risk of systemic effects when using beclometasone dipropionate/formoterol with the named spacer device.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children aged less than 16 years taking/inhaling higher than recommended doses of beclometasone dipropionate may be at particular risk. Situations which could potentially trigger acute adrenal crisis, include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Care should be taken when transferring patients to Proxor therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.

Patients transferring from oral to inhaled corticosteroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past or have received prolonged treatment with high doses of inhaled corticosteroids may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.

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 (BMI) and severe COPD.

Patients should be advised to rinse the mouth or gargle with water or brush the teeth after inhaling the prescribed dose to minimise the risk of oropharyngeal candida infection.

Visual disturbance

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

Alcohol content

Proxor contains 9 mg of alcohol (ethanol) in each actuation which is equivalent to 0.25 mg/kg per dose of two actuations. The amount in two actuations of this medicine is equivalent to less than 1 ml of wine or beer. The small amount of alcohol in this medicine will not have any noticeable effects.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes.

Beclometasone is less dependent on CYP3A metabolism than some other corticosteroids, and in general interactions are unlikely; however, the possibility of systemic effects with concomitant use of strong CYP3A inhibitors (e.g. ritonavir, cobicistat) cannot be excluded, and therefore caution and appropriate monitoring is advised with the use of such agents.

Pharmacodynamic interactions

Beta- blockers (including eye drops) should be avoided in asthmatic patients. If beta-blockers are administered for compelling reasons, the effect of formoterol will be reduced or abolished.

On the other hand, concomitant use of other beta-adrenergic medicinal products can have potentially additive effects, therefore caution is required when theophylline or other beta-adrenerigic drugs are prescribed concomitantly with formoterol.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, monoamine 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 beta2- 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 treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalaemic effect of beta2-agonists (see section 4.4.). Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

Proxor contains a small amount of ethanol. There is a theoretical potential for interaction in particularly sensitive patients taking disulfiram or metronidazole.

4.6. Fertility, pregnancy and lactation

There is no experience with or evidence of safety of propellant HFA-134a in human pregnancy or lactation. However studies of the effect of HFA-134a on reproductive function and embryofetal development in animals have revealed no clinically relevant adverse effects.

Pregnancy

There are no relevant clinical data on the use of Proxor in pregnant women. Animal studies using beclometasone dipropionate and formoterol combination showed evidence of toxicity to reproduction after high systemic exposure (see 5.3 Preclinical safety data). Because of the tocolytic actions of beta2- sympathomimetic agents particular care should be exercised in the run up to delivery. Formoterol should not be recommended for use during pregnancy and particularly at the end of pregnancy or during labour unless there is no other (safer) established alternative.

Proxor should only be used during pregnancy if the expected benefits outweigh the potential risks.

Breast-feeding

There are no relevant clinical data on the use of Proxor in lactation in humans.

Although no data from animal experiments are available, it is reasonable to assume that beclometasone dipropionate is secreted in milk, like other corticosteroids.

While it is not known whether formoterol passes into human breast milk, it has been detected in the milk of lactating animals.

Administration of Proxor to women who are breast-feeding should only be considered if the expected benefits outweigh the potential risks.

Fertility

There are no data in humans. In animal studies in rats, the presence of beclometasone dipropionate at high doses in the combination was associated with reduced female fertility and embryotoxicity (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

As Proxor contains beclometasone dipropionate and formoterol fumarate dihydrate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds.

Undesirable effects which have been associated with beclometasone dipropionate and formoterol administered as a fixed combination (Proxor) and as single agents are given below, listed by system organ class. 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 < 1/1,000) and very rare (≤1/10,000), not known (cannot be estimated from the available data).

Common and uncommon ADRs were derived from clinical trials in asthmatic and COPD patients.

System Organ Class

Adverse Reaction

Frequency

Infections and Infestations

Pharyngitis, oral candidiasis, pneumonia* (in COPD patients)

Common

Influenza, oral fungal infection, oropharyngeal candidiasis, oesophageal candidiasis, vulvovaginal candidiasis, gastroenteritis, sinusitis, rhinitis,

Uncommon

Blood and lymphatic system disorders

Granulocytopenia

Uncommon

Thrombocytopenia

Very rare

Immune system disorders

Dermatitis allergic

Uncommon

Hypersensitivity reactions, including erythema, lips, face, eye and pharyngeal oedema

Very rare

Endocrine disorders

Adrenal suppression

Very rare

Metabolism and nutrition disorders

Hypokalaemia, Hyperglycaemia

Uncommon

Psychiatric disorders

Restlessness

Uncommon

Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)

Unknown

Nervous system disorders

Headache

Common

Tremor, dizziness

Uncommon

Eye disorders

Glaucoma, cataract

Very rare

Vision, blurred (see also section 4.4)

Not known

Ear and labyrinth disorders

Otosalpingitis

Uncommon

Cardiac disorders

Palpitations, electrocardiogram QT corrected interval prolonged, electrocardiogram change, tachycardia, tachyarrhythmia, atrial fibrillation*,

Uncommon

Ventricular extrasystoles, angina pectoris

Rare

Vascular disorders

Hyperaemia, flushing

Uncommon

Respiratory, thoracic and mediastinal disorders

Dysphonia

Common

Cough, productive cough, throat irritation, asthmatic crisis

Uncommon

Bronchospasm paradoxical

Rare

Dyspnoea, exacerbation of asthma

Very rare

Gastrointestinal disorders

Diarrhoea, dry mouth, dyspepsia, dysphagia, burning sensation of the lips, nausea, dysgeusia

Uncommon

Skin and subcutaneous tissue disorders

Pruritus, rash, hyperhidrosis, urticaria

Uncommon

Angioedema

Rare

Musculoskeletal and connective tissue disorders

Muscle spasms, myalgia

Uncommon

Growth retardation in children and adolescents

Very rare

Renal and urinary disorders

Nephritis

Rare

General disorders and administration site conditions

Oedema peripheral

Very rare

Investigations

C-reactive protein increased, platelet count increased, free fatty acids increased, blood insulin increased, blood ketone body increased, blood cortisol decrease*

Uncommon

Blood pressure increased, blood pressure decreased

Rare

Bone density decreased

Very rare

* One related non serious case of pneumonia was reported by one patient treated with beclometasone dipropionate/formoterol in a pivotal clinical trial in COPD patients. Other adverse reactions observed with beclometasone dipropionate/formoterol in COPD clinical trials were: reduction of blood cortisol and atrial fibrillation.

As with other inhalation therapy, paradoxical bronchospasm may occur (see 4.4 'Special Warnings and Precautions for Use').

Among the observed adverse reactions those typically associated with formoterol are:

hypokalemia, headache, tremor, palpitations, cough, muscle spasms and prolongation of QTc interval.

Adverse reactions typically associated with the administration of beclomethasone dipropionate are:

oral fungal infections, oral candidiasis, dysphonia, throat irritation.

Dysphonia and candidiasis may be relieved by gargling or rinsing the mouth with water or brushing the teeth after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing the treatment with Proxor.

Systemic effects of inhaled corticosteroids (e.g. beclometasone dipropionate) may occur particularly when administered at high doses prescribed for prolonged periods, these may include adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma (see also 4.4).

Hypersensitivity reactions including rash, urticaria pruritus, erythema and oedema of the eyes, face, lips and throat may also occur.

Paediatric Population

In a 12-week study in adolescent asthma patients, the safety profile of a medicinal containing beclometasone dipropionate and formoterol was not different to that of beclomethasone dipropionate monotherapy.

Beclometasone/Formoterol paediatric experimental formulation of beclometasone dipropionate and formoterol fumarate 50/6 micrograms per actuation administered to asthmatic children aged 5-11 years over 12 weeks tratement period, showed a safety profile similar to the approved marketed formoterol and beclometasone dipropionate single agents.

However, the same paediatric formulation of Beclometasone/Formoterol 50/6 micrograms administered to asthmatic children aged 5-11 years over 2 weeks did not demonstrate non-inferiority to the free combination of marketed formoterol and beclometasone dipropionate single agents in terms of lower leg growth rate.

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.

4.9. Overdose

Inhaled doses of beclometasone dipropionate/formoterol up to twelve cumulative actuations (total beclometasone dipropionate 1200 micrograms, formoterol 72 micrograms) have been studied in asthmatic patients. The cumulative treatments did not cause abnormal effect on vital signs and neither serious nor severe adverse events were observed.

Excessive doses of formoterol may lead to effects that are typical of beta2-adrenergic agonists: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, prolongation of QTc interval, metabolic acidosis, hypokalaemia, hyperglycaemia.

In case of overdose of formoterol, supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective beta-adrenergic blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm. Serum potassium should be monitored.

Acute inhalation of beclometasone dipropionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function recovers in a few days, as verified by plasma cortisol measurements. In these patients treatment should be continued at a dose sufficient to control asthma.

Chronic overdose of inhaled beclometasone dipropionate: risk of adrenal suppression (see section 4.4.). Monitoring of adrenal reserve may be necessary. Treatment should be continued at a dose sufficient to control asthma.