4.1. Therapeutic indications

Maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting beta2-agonist or a combination of a long-acting beta2-agonist and a long-acting muscarinic antagonist (for effects on symptoms control and prevention of exacerbations see section 5.1).

4.2. Posology and method of administration

Posology

The recommended dose is two inhalations twice daily.

The maximum dose is two inhalations twice daily.

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

There is no relevant use of Trimbow in the paediatric population (under 18 years of age) for the indication of COPD.

Method of administration

For inhalation use.

The inhaler is a breath-operated inhaler. 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.

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

Instructions for use

Inform the patient when using a new inhaler

• If the pouch is not sealed or is damaged or if the inhaler looks broken or damaged, the patient should return it to the pharmacist who supplied it and get a new one.

• The patient should write down the date the pouch is opened to the label on the box.

• The dose counter window has to show “120”. If the number shown is less than “120”, the patient should return the inhaler to the person who supplied it and get a new one.

Use of the inhaler

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

1. The patients should hold the inhaler in the upright position, check the number of doses (any number between “1” and “120” shows that there are doses left) and open the cover fully.

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

3. The patient should place the lips around the mouthpiece, without covering the air vent or inhaling into the air vent.

4. The patient should breathe in forcefully and deeply through the mouth. He/she may notice a taste or hear or feel a click when taking the dose.

5. The patient should then remove the inhaler from the mouth, hold the breath as long as comfortably (5-10 seconds) and then breathe out slowly. The patient should not breathe out into the inhaler.

6. After use, the patient should move the inhaler back to the upright position, close the cover fully and check the dose counter to ensure it has gone down by one.

7. If another dose has to be taken, the patient should repeat steps 1-6.

NOTE: The number of inhalations shown in the window on the shell does not decrease on closing the cover if the patient has not inhaled through the inhaler. The patient should be instructed to only open the inhaler's cover when needed. In the event that the patient has opened the inhaler but not inhaled, and the cover is closed, the dose is moved back to the powder reservoir within the inhaler; the following dose can be safely inhaled.

Cleaning

Regular cleaning of the inhaler is normally not necessary. The patient may clean the inhaler after use with a dry cloth or tissue, but not with water or other liquids.

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.

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.

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.

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 medium 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.

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.

Lactose contents

This medicinal product contains lactose.

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

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

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.

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 women.

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

In a 4-week study, the safety profile of Trimbow inhalation powder was similar to the one observed for Trimbow pressurised solution.

The most frequently reported adverse reactions in patients with COPD or asthma with Trimbow pressurised solution 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. Similarly, dry mouth was reported in 2 patients (0.6%) with Trimbow inhalation powder. 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.