4.1. Therapeutic indications

Maintenance treatment of asthma, in adults not adequately controlled with a maintenance combination of a long-acting beta2-agonist and high dose of inhaled corticosteroid, and who experienced one or more asthma exacerbations in the previous year.

4.2. Posology and method of administration

Posology

The recommended dose is two inhalations twice daily.

The maximum dose is two inhalations twice daily.

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

If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be used for immediate relief.

When choosing the starting dose strength of Trimbow (87/5/9 micrograms or 172/5/9 micrograms), the patients' disease severity, their previous asthma therapy including the inhaled corticosteroid (ICS) dose as well as the patients' current control of asthma symptoms and risk of future exacerbation should be considered.

Stepping-down treatment

Patients should be regularly reassessed by a doctor, so that their doses of beclometasone/formoterol/glycopyrronium remain optimal and are only changed on medical advice. The doses should be titrated to the lowest doses at which effective control of asthma symptoms is maintained.

There are no data on the effect of stepping-down from the high strength (Trimbow 172/5/9 micrograms) to the medium strength beclometasone dipropionate medicinal product (Trimbow 87/5/9 micrograms).

Special populations

Elderly

No dose adjustment is required in elderly patients (65 years of age and older).

Renal impairment

Trimbow can be used at the recommended dose in patients with mild (glomerular filtration rate [GFR] ≥50 to <80 mL/min/1.73 m2) to moderate (GFR ≥30 to <50 mL/min/1.73 m2) renal impairment. Use in patients with severe (GFR <30 mL/min/1.73 m2) renal impairment or end-stage renal (GFR <15 mL/min/1.73 m2) disease requiring dialysis, especially if associated with significant body weight reduction, should be considered only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2).

Hepatic impairment

There are no relevant data on the use of Trimbow in patients with severe hepatic impairment (classified as having Child-Pugh class C) and the medicinal product should be used with caution in these patients (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Trimbow in the paediatric population (under 18 years of age) have not yet been established. No data are available.

Method of administration

For inhalation use.

To ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler correctly by a physician or other healthcare professional, who should also regularly check the adequacy of the patient's inhalation technique (see “Instructions for use” below). The patient should be advised to read the Package Leaflet carefully and follow the instructions for use as given in the leaflet.

This medicinal product is provided with a dose counter on the back of the inhaler, which shows how many actuations are left. Each time the patient presses the container a puff of the solution is released and the counter counts down by one.

The patient should be advised not to drop the inhaler as this may cause the counter to count down.

Instructions for use

Priming the inhaler

Before using the inhaler for the first time, the patient should release one actuation into the air in order to ensure that the inhaler is working properly (priming). Before priming the 60 or 120 actuation pressurised containers, the counter should read 61 or 121, respectively. After priming, the counter should read 60 or 120.

Use of the inhaler

The patient should stand or sit in an upright position when inhaling from the inhaler. The steps below should be followed.

IMPORTANT: steps 2 to 5 should not be performed too quickly:

1. The 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. The patient should breathe out slowly and as deeply as comfortable, in order to empty the lungs.

3. The patient should hold the inhaler vertically with its body upwards and place the mouthpiece between the teeth without biting. The lips should then be placed around the mouthpiece, with the tongue flat under it.

4. At the same time, the patient should breathe in slowly and deeply through the mouth until the lungs are full of air (this should take approximately 4 – 5 seconds). Immediately after starting to breathe in, the patient should firmly press down on the top of the pressurised container to release one puff.

5. The patient should then hold the breath for as long as comfortably possible, then remove the inhaler from the mouth and breathe out slowly. The patients should not breathe out into the inhaler.

6. The patient should then check the dose counter to ensure it has moved accordingly.

To inhale the second puff, the patient should keep the inhaler in a vertical position for approximately 30 seconds and repeat steps 2 to 6.

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

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

After inhaling, the patient should rinse the mouth or gargle with water without swallowing it or brush the teeth (see also section 4.4).

When to get a new inhaler

The patient should be advised to get a new inhaler when the dose counter shows the number 20. He/she 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 actuation.

Additional instructions for specific groups of patients

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 pressurised container and both thumbs on the base of the inhaler.

Patients who find it difficult to synchronise aerosol actuation with inspiration of breath may use the AeroChamber Plus spacer device, properly cleaned as described in the relevant leaflet. They should be advised by their doctor or pharmacist about the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled active substance 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. Alternatively, patients may simply breathe in and out (through the mouth) after the actuation, as instructed in the spacer leaflet, to obtain the medicinal product (see sections 4.4 and 5.2).

Cleaning

For the regular cleaning of the inhaler, the patient should remove weekly the cap from the mouthpiece and wipe the outside and inside of the mouthpiece with a dry cloth. He/she should not remove the pressurised container from the actuator and should not use water or other liquids to clean the mouthpiece.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Not for acute use

This medicinal product is not indicated for the treatment of acute episodes of bronchospasm, or to treat an acute disease exacerbation (i.e. as a rescue therapy).

Hypersensitivity

Immediate hypersensitivity reactions have been reported after administration. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips and face), urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted.

Paradoxical bronchospasm

Paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator (reliever). Treatment should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Deterioration of disease

It is recommended that treatment should not be stopped abruptly. If patients find the treatment ineffective, they should continue treatment but medical attention must be sought. Increasing use of reliever bronchodilators indicates a worsening of the underlying condition and warrants a reassessment of the therapy. Sudden or progressive deterioration in symptoms is potentially life-threatening and the patient should undergo urgent medical assessment.

Cardiovascular effects

Due to the presence of a long-acting beta2-agonist and a long-acting muscarinic antagonist, Trimbow should be used with caution in patients with cardiac arrhythmias, especially third degree atrioventricular block and tachyarrhythmias (accelerated and/or irregular heartbeat, including atrial fibrillation), 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 exercised when treating patients with known or suspected prolongation of the QTc interval (QTc > 450 milliseconds for males, or > 470 milliseconds for females), either congenital or induced by medicinal products. Patients diagnosed with the described cardiovascular conditions were excluded from clinical studies with Trimbow. Limited data in asthmatic patients with cardiovascular co-morbidities or risk-factors suggest that these patients are also at higher risk of adverse reactions like local fungal infections or dysphonia (see section 4.8).

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

Caution is also required when treating patients with thyrotoxicosis, diabetes mellitus, pheochromocytoma and untreated hypokalaemia.

Systemic corticosteroid effects

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. The daily dose of Trimbow corresponds to a high dose of inhaled corticosteroid; furthermore, 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, decrease in bone mineral density 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 (see section 4.2).

Trimbow should be administered with caution in patients with active or quiescent pulmonary tuberculosis and in patients with fungal and viral infections in the airways.

Hypokalaemia

Potentially serious hypokalaemia may result from beta2-agonist therapy. This has the potential to produce adverse cardiovascular effects. Particular caution is advised in patients with severe disease 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 when a number of reliever bronchodilators are used. It is recommended that serum potassium levels are monitored in such situations.

Hyperglycaemia

The inhalation of formoterol may cause a rise in blood glucose levels. Therefore, blood glucose should be monitored during treatment following established guidelines in patients with diabetes.

Anticholinergic effect

Glycopyrronium should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or urinary retention. Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop treatment and to contact their doctor immediately should any of these signs or symptoms develop.

Additionally, due to the anticholinergic effect of glycopyrronium, the long-term co-administration with other anticholinergic-containing medicinal products is not recommended (see section 4.5).

Patients with severe renal impairment

In patients with severe renal impairment, including those with end-stage renal disease requiring dialysis, especially if associated with a significant body weight reduction, Trimbow should be used only if the expected benefit outweighs the potential risk (see section 5.2). These patients should be monitored for potential adverse reactions.

Patients with severe hepatic impairment

In patients with severe hepatic impairment, Trimbow should be used only if the expected benefit outweighs the potential risk (see section 5.2). These patients should be monitored for potential adverse reactions.

Prevention of oropharyngeal infections

In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose.

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.

Stepping-down treatment

Patients should be regularly reassessed by a doctor, so that their doses of beclometasone/formoterol/glycopyrronium remain optimal and are only changed on medical advice. The doses should be titrated to the lowest doses at which effective control of asthma symptoms is maintained.

There are no data on the effect of stepping-down from the high strength (Trimbow 172/5/9 micrograms) to the medium strength beclometasone dipropionate medicinal product (Trimbow 87/5/9 micrograms) (see section 4.2).

Ethanol contents

This medicinal product contains 8.856 mg of ethanol per actuation, which is equivalent to 17.712 mg per dose of two actuations. There is a theoretical potential for interaction in particularly sensitive patients taking disulfiram or metronidazole.

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

Pharmacokinetic interactions

Since glycopyrronium is eliminated mainly by the renal route, interaction could potentially occur with medicinal products affecting renal excretion mechanisms (see section 5.2). The effect of organic cation transport inhibition (using cimetidine as a probe inhibitor of OCT2 and MATE1 transporters) in the kidneys on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC0-t) by 16% and a slight decrease in renal clearance by 20% due to co administration of cimetidine.

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 medicinal products.

Pharmacodynamic interactions

Related to formoterol

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

Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects; therefore, caution is required when other beta-adrenergic medicinal products are prescribed concomitantly with formoterol.

Concomitant treatment with quinidine, disopyramide, procainamide, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants and phenothiazines can prolong the QT 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 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 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.

Related to glycopyrronium

The long-term co-administration of Trimbow with other anticholinergic-containing medicinal products has not been studied and is therefore not recommended (see section 4.4).

4.6. Fertility, pregnancy and lactation

There is no experience with or evidence of safety issues on the use of the propellant norflurane (HFA134a) during human pregnancy or lactation. However, studies on the effect of HFA134a on the reproductive function and embryofoetal development in animals revealed no clinically relevant adverse effects.

Pregnancy

There are no or limited amount of data from the use of Trimbow in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). Glucocorticoids are known to cause effects in the early gestation phase, while beta2-sympathomimetics like formoterol have tocolytic effects. Therefore, as a precautionary measure, it is preferable to avoid the use of Trimbow during pregnancy and during labour.

Trimbow should only be used during pregnancy if the expected benefit to the patient outweighs the potential risk to the foetus. Infants and neonates born to mothers receiving substantial doses should be observed for adrenal suppression.

If treatment during pregnancy is necessary, the lowest effective dose should be used (see section 4.2).

Breast-feeding

There are no relevant clinical data on the use of Trimbow during breast-feeding in humans.

Glucocorticoids are excreted in human milk. It is reasonable to assume that beclometasone dipropionate and its metabolites are also excreted in human milk.

It is unknown whether formoterol or glycopyrronium (including their metabolites) are excreted in human milk but they have been detected in the milk of lactating animals. Anticholinergics like glycopyrronium could suppress lactation.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Trimbow therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No specific studies have been performed with Trimbow with regard to the safety in human fertility. Animal studies have shown impairment of fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions in patients with COPD or asthma are respectively: dysphonia (0.3% and 1.5%) and oral candidiasis (0.8% and 0.3%), which are normally associated with inhaled corticosteroids; muscle spasms (0.4% and 0.2%), which can be attributed to the long-acting beta2-agonist component; and dry mouth (0.4% and 0.5%), which is a typical anticholinergic effect.

In asthmatic patients, adverse reactions tend to cluster during the first 3 months following initiation of therapy and become less frequent with longer-term use (after 6 months of treatment).

Tabulated list of adverse reactions

Adverse reactions associated to beclometasone dipropionate/formoterol/glycopyrronium occurred during clinical studies and post-marketing experience as well as adverse reactions listed for the marketed individual components are provided 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); very rare (<1/10,000) and not known (cannot be estimated from available data).

MedDRA system organ class

Adverse reaction

Frequency

Infections and infestations

Pneumonia (in COPD patients), pharyngitis, oral candidiasis, urinary tract infection1, nasopharyngitis1

Common

Influenza1, oral fungal infection, oropharyngeal candidiasis, oesophageal candidiasis, fungal (oro)pharyngitis, sinusitis1, rhinitis1, gastroenteritis1, vulvovaginal candidiasis1

Uncommon

Lower respiratory tract infection (fungal)

Rare

Blood and lymphatic system disorders

Granulocytopenia1

Uncommon

Thrombocytopenia1

Very rare

Immune system disorders

Dermatitis allergic1

Uncommon

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

Rare

Endocrine disorders

Adrenal suppression1

Very rare

Metabolism and nutrition disorders

Hypokalaemia, hyperglycaemia

Uncommon

Decreased appetite

Rare

Psychiatric disorders

Restlessness1

Uncommon

Psychomotor hyperactivity1, sleep disorders1, anxiety, depression1, aggression1, behavioural changes (predominantly in children) 1

Frequency not known

Insomnia

Rare

Nervous system disorders

Headache

Common

Tremor, dizziness, dysgeusia1, hypoaesthesia1

Uncommon

Hypersomnia

Rare

Eye disorders

Vision, blurred1 (see also section 4.4)

Frequency not known

Glaucoma1, cataract1

Very rare

Ear and labyrinth disorders

Otosalpingitis1

Uncommon

Cardiac disorders

Atrial fibrillation, electrocardiogram QT prolonged, tachycardia, tachyarrhythmia1, palpitations

Uncommon

Angina pectoris (stable1 and unstable), extrasystoles (ventricular1 and supraventricular), nodal rhythm, sinus bradycardia

Rare

Vascular disorders

Hyperaemia1, flushing1, hypertension

Uncommon

Extravasation blood

Rare

Respiratory, thoracic and mediastinal disorders

Dysphonia

Common

Asthmatic crisis1, cough, productive cough1, throat irritation, epistaxis1, pharyngeal erythema

Uncommon

Bronchospasm paradoxical1, exacerbation of asthma, oropharyngeal pain, pharyngeal inflammation, dry throat

Rare

Dyspnoea1

Very rare

Gastrointestinal disorders

Diarrhoea1, dry mouth, dysphagia1, nausea, dyspepsia1, burning sensation of the lips1, dental caries1, (aphthous) stomatitis

Uncommon

Skin and subcutaneous tissue disorders

Rash1, urticaria, pruritus, hyperhidrosis1

Uncommon

Angioedema1

Rare

Musculoskeletal and connective tissue disorders

Muscle spasms, myalgia, pain in extremity1, musculoskeletal chest pain1

Uncommon

Growth retardation1

Very rare

Renal and urinary disorders

Dysuria, urinary retention, nephritis1

Rare

General disorders and administration site conditions

Fatigue1

Uncommon

Asthenia

Rare

Oedema peripheral1

Very rare

Investigations

C-reactive protein increased1, platelet count increased1, free fatty acids increased1, blood insulin increased1, blood ketone body increased1, cortisol decreased1

Uncommon

Blood pressure increased1, blood pressure decreased1

Rare

Bone density decreased1

Very rare

1 Adverse reactions reported in the SmPC of at least one of the individual components, but not observed as adverse reactions in the clinical development of Trimbow

Among the observed adverse reactions the following are typically associated with:

Beclometasone dipropionate

Pneumonia, oral fungal infections, lower respiratory tract infection fungal, dysphonia, throat irritation, hyperglycaemia, psychiatric disorders, cortisol decreased, blurred vision.

Formoterol

Hypokalaemia, hyperglycaemia, tremor, palpitations, muscle spasms, electrocardiogram QT prolonged, blood pressure increased, blood pressure decreased, atrial fibrillation, tachycardia, tachyarrhythmia, angina pectoris (stable and unstable), ventricular extrasystoles, nodal rhythm.

Glycopyrronium

Glaucoma, atrial fibrillation, tachycardia, palpitations, dry mouth, dental caries, dysuria, urinary retention, urinary tract infection.

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:

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

An overdose of Trimbow may produce signs and symptoms due to the individual component's pharmacological actions, including those seen with overdose of other beta2-agonists or anticholinergics and consistent with the known inhaled corticosteroid class effects (see section 4.4). If overdose occurs, the patient's symptoms should be treated supportively with appropriate monitoring as necessary.