TRIMBOW 88 MICROGRAMS / 5 MICROGRAMS / 9 MICROGRAMS INHALATION POWDER - summary of medicine characteristics

Trimbow 88 micrograms/5 micrograms/9 micrograms inhalation powder

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each delivered dose (the dose leaving the mouthpiece) contains

88 micrograms of beclometasone dipropionate, 5 micrograms of formoterol fumarate dihydrate and 9 micrograms of glycopyrronium (as 11 micrograms glycopyrronium bromide).

Each metered dose contains 100 micrograms of beclometasone dipropionate, 6 micrograms of formoterol fumarate dihydrate and 10 micrograms of glycopyrronium (as 12.5 micrograms glycopyrronium bromide).

Excipient with known effect

Each inhalation contains 9.9 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Inhalation powder.

White or almost white powder in a white inhaler (NEXThaler).

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 to moderate renal impairment. Use in patients with severe renal impairment or end-stage renal 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 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 inhaling, patients should rinse their mouth or gargle with water without swallowing it or brush their 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 person 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

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

1. 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. Patients should breathe out slowly and as deeply as comfortable, in order to empty their lungs.

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

4. Patients should breathe in forcefully and deeply through the mouth. They may notice a taste or hear or feel a click when taking the dose.

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

6. After use, patients 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, patients 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. Patients 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 lifethreatening 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 trials 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 longterm 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.

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 anticholinergic­containing 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 breastfeeding in humans.

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

It is unknown whether formoterol or glycopyrronium (including their metabolites) pass into human breast-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 mothers.

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 trials 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).

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 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics incl. triple combinations with corticosteroids. ATC code: R03AL09.

Mechanism of action and pharmacodynamic effects

Trimbow contains beclometasone dipropionate, formoterol and glycopyrronium (BDP/FF/G) in a dry powder formulation resulting in an extrafine aerosol with extrafine particles and co-deposition of the three components. The aerosol particles of Trimbow are on average much smaller than the particles delivered in non-extrafine formulations. For beclometasone dipropionate, this results in a more potent effect than formulations with a nonextrafine particle size distribution (100 micrograms of beclometasone dipropionate extrafine in Trimbow are equivalent to 250 micrograms of beclometasone dipropionate in a non-extrafine formulation).

Beclometasone dipropionate

Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases of the airways. Their action is mediated by the binding to glucocorticoid receptors in the cytoplasm resulting in the increased transcription of genes coding for anti-inflammatory proteins.

Formoterol

Formoterol is a selective beta2-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1–3 minutes after inhalation, and has a duration of 12 hours after a single dose.

Glycopyrronium

Glycopyrronium is a high-affinity, long-acting muscarinic receptor antagonist (anticholinergic) used for inhalation as bronchodilator treatment.

Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways. Glycopyrronium bromide is a high affinity muscarinic receptor antagonist with a greater than 4-fold selectivity for the human M3 receptors over the human M2 receptor as it has been demonstrated.

Clinical efficacy and safety

Trimbow inhalation powder

The development programme of Trimbow inhalation powder was conducted with BDP/FF/G 88/5/9 and included one 4-week non-inferiority study. Study TRI-D was a multicentre, randomized, double-blind, double-dummy, active controlled, 3-way cross-over trial that compared 3 treatment periods of 4 weeks each with BDP/FF/G inhalation powder, BDP/FF/G pressurised inhalation, solution or a fixed-dose combination of beclometasone dipropionate and formoterol 100/6 micrograms pressurised inhalation solution, each delivered as 2 inhalations twice daily, separated by 2-week wash-outs in patients with stable, moderate-to-severe COPD. The co-primary efficacy endpoints were the change from baseline in FEV1 AUC0–12h normalised by time and in trough FEV1 at 24 hours on Day 28.

Effects on lung function

366 patients were randomized. Non-inferiority of BDP/FF/G inhalation powder versus BDP/FF/G pressurised inhalation solution was demonstrated for both co-primary endpoints, with the lower limits of confidence interval of the adjusted mean differences falling above the non-inferiority threshold of –50 mL: the adjusted mean differences (95% CI) were –20 mL (-35; –6) for FEV1 AUC0–12h, and 3 mL (-15; 20) for trough FEV1 at 24 hours on Day 28.

Both BDP/FF/G powder inhalation and pressurised inhalation solution significantly improved FEV1 AUC0–12h versus the fixed-dose combination of beclometasone dipropionate and formoterol pressurised inhalation solution by 85 mL (95% CI: 70; 99) and 105 mL (95% CI: 90; 120), respectively (p < 0.001 for both).

Inspiratory flow

An open-label placebo study was conducted to verify that the inspiratory flow which could be generated through the inhaler is not influenced by patient’s age, disease and disease severity, and therefore the activation and delivery of active substances from the device could be achieved in all patients. The primary endpoint was the percentage of patients in each age and disease group able to activate the inhaler. Eighty-nine patients, in the age range 5–84 years, including patients with moderate and severe asthma (FEV1 > 60% and < 60% predicted, respectively), and patients with moderate and severe COPD (FEV1 > 50% and < 50% predicted, respectively) participated in the trial. All patients, irrespective of age, disease and disease severity, were able to generate sufficient inspiratory flow to activate the inhaler. In an additional open label placebo study, patients with mild to severe COPD, regardless of their functional limitation, were able to effectively activate and use the inhaler.

Trimbow pressurised solution

The development programme of Trimbow pressurised solution in COPD was conducted with BDP/FF/G 87/5/9 and included two 52-week active-controlled studies. The TRILOGY study compared BDP/FF/G with a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms two inhalations twice daily (1,368 randomised patients). The TRINITY study compared BDP/FF/G with tiotropium 18 micrograms inhalation powder, hard capsule, one inhalation once daily; in addition, effects were compared with an extemporary triple combination made of a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms (corresponding to a delivered dose of 84.6/5.0 micro­grams) two inhalations twice daily plus tiotropium 18 micrograms inhalation powder, hard capsule, one inhalation once daily (2,691 randomised patients). The TRIBUTE study compared BDP/FF/G with a fixed combination of indacaterol/gly­copyrronium 85/43 micrograms inhalation powder, hard capsule, one inhalation once daily (1,532 randomised patients).

Reduction of COPD exacerbations

BDP/FF/G reduced the rate of moderate/severe exacerbations over 52 weeks by 23% compared with a fixed combination of beclometasone dipropionate and formoterol (rate: 0.41 versus 0.53 events per patient/year; p = 0.005), by 20% compared with tiotropium (rate: 0.46 versus 0.57 events per patient/year; p = 0.003) and by 15% compared with a fixed combination of indacaterol and glycopyrronium (rate: 0.50 versus 0.59 events per patient/year; p = 0.043). No differences were observed when comparing BDP/FF/G with the extemporary triple combination made of beclometasone dipropionate and formoterol fixed combination plus tiotropium (moderate/severe exacerbation rate: 0.46 versus 0.45 events per patient/year).

Effects on lung function

Compared with a fixed combination of beclometasone dipropionate and formoterol, BDP/FF/G improved pre-dose FEV1 by 71 mL after 28 days, by 81 mL after 26 weeks of treatment and by 63 mL after 52 weeks of treatment. Compared with tiotropium, BDP/FF/G improved pre-dose FEV1 by 51 mL after 26 weeks of treatment and by 61 mL after 52 weeks of treatment. These improvements were statistically significant (p < 0.001). Compared with a fixed combination of indacaterol and glycopyrronium, BDP/FF/G improved average pre-dose FEV1 over the 52-week treatment period by 22 mL (p=0.018).

Similar improvements, although not statistically significant, were observed at weeks 26 and 52.

No differences were observed when comparing BDP/FF/G and the extemporary triple combination made of a fixed combination of beclometasone dipropionate and formoterol plus tiotropium (difference of 3 mL in pre-dose FEV1 after 52 weeks of treatment).

Symptomatic outcomes

BDP/FF/G was statistically significantly superior to a fixed combination of beclometasone dipropionate and formoterol, to tiotropium and to a fixed combination of indacaterol and glycopyrronium in terms of improvement in quality of life (measured by the Saint George Respiratory Questionnaire -SGRQ – total score).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Trimbow in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Trimbow – fixed combination

The pharmacokinetic of beclometasone dipropionate (and its active metabolite beclometasone 17-monopropionate), formoterol and glycopyrronium bromide has been investigated in a pharmacokinetic study conducted in healthy subjects comparing Trimbow inhalation powder with the pressurised solution formulation, both delivering beclometasone dipropionate, formoterol fumarate and glycopyrronium bromide at a strength of 100/6/12.5 Lig/in­halation, (8 inhalations corresponding to a total dose of 800/48/100 |ig). The relative total systemic exposure was assessed without the use of charcoal blockade to account for both the active substance absorbed from the lung and from the gastrointestinal tract, while the relative lung availability was investigated by using a charcoal blockade to exclude active substance absorption from the gastrointesti­nal tract.

Beclometasone dipropionate was rapidly absorbed showing a peak in plasma concentration at 10 min post-dose for both Trimbow inhalation powder and the pressurised inhalation solution. Administration of the inhalation powder resulted in an increased total systemic exposure (1.2-fold for Cmax and 2.4-fold for AUC0-t) and lung availability (1.3-fold for Cmax and 2.5-fold for AUC0-t) when compared to the pressurised solution. Beclometasone 17-monopropionate was rapidly formed showing a peak in plasma concentration at about 15–30 min after administration of the medicinal product.

Administration of the inhalation powder resulted in a slightly lower total systemic exposure compared to the pressurised solution (-17% for Cmax and –16% for AUC0-t) while the lung availability was equivalent for AUC0-t but slightly lower for Cmax (-13%).

Formoterol was rapidly absorbed showing a peak in plasma concentration at 10 min post-dose for both the inhalation powder and the pressurised inhalation solution. Administration of the inhalation powder resulted in an increased total systemic exposure (1.6-fold for Cmax and 1.2-fold for AUC0-t) and lung availability (1.8-fold for Cmax and 1.9-fold for AUC0-t) when compared to the pressurised solution.

The pharmacokinetic profile of glycopyrronium bromide was characterised by a rapid absorption with plasma peak concentration at 10 min post-dose for both the inhalation powder and the pressurised inhalation solution. The total systemic exposure resulted equivalent for the inhalation powder in comparison to the pressurised solution but was 2.2-fold higher when assessed as maximum concentration. The lung availability was higher for the inhalation powder, with a 2.9-fold increase in Cmax and a 1.2-fold increase in AUC0-t.

Effect of renal impairment

Systemic exposure (AUC0-t) to beclometasone dipropionate, to its metabolite beclometasone 17-monopropionate and to formoterol was not affected by mild to severe renal impairment. For glycopyrronium, there was no impact in subjects with mild and moderate renal impairment. However, an increase in total systemic exposure of up to 2.5-fold was observed in subjects with severe renal impairment (glomerular filtration rate below 30 mL/min/1.73 m2), as a consequence of a significant reduction of the amount excreted in urine (approximately 90% reduction of glycopyrronium renal clearance).

Simulations performed with a pharmacokinetic model showed that even when covariates had extreme values (body weight less than 40 kg and concomitant glomerular filtration rate below 27 mL/min/1.73 m2), exposure to Trimbow active substances remains in approximately a 2.5-fold range compared to the exposure in a typical patient with median covariate values.

Beclometasone dipropionate

Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone 17-monopropionate which has a more potent topical antiinflammatory activity compared with the pro-drug beclometasone dipropionate.

Absorption, distribution and biotransformation

Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there is extensive conversion to beclometasone 17-monopropionate via esterase enzymes that are found in most tissues. The systemic availability of the active metabolite arises from lung (36%) and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible; however, pre-systemic conversion to beclometasone 17-monopropionate results in 41% of the dose being absorbed as the active metabolite. There is an approximately linear increase in systemic exposure with increasing inhaled dose. The absolute bioavailability following inhalation is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone 17-monopropionate respectively. Following intravenous dosing, the disposition of beclometasone dipropionate and its active metabolite is characterised by high plasma clearance (150 and 120 L/h respectively), with a small volume of distribution at steady state for beclometasone dipropionate

(20 L) and larger tissue distribution for its active metabolite (424 L). Plasma protein binding is moderately high.

Elimination

Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polar metabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible. The terminal elimination halflives are 0.5 hours and 2.7 hours for beclometasone dipropionate and beclometasone 17-monopropionate respectively.

Patients with hepatic impairment

The pharmacokinetics of beclometasone dipropionate in patients with hepatic impairment has not been studied, however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver to form the more polar products beclometasone 21-monopropionate, beclometasone 17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.

Formoterol

Absorption and distribution

Following inhalation, formoterol is absorbed from both the lung and the gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler may range between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Peak plasma concentrations of the unchanged active substance occur within 0.5 to 1 hours after oral administration. Plasma protein binding of formoterol is 61–64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. The elimination half-life determined after oral administration is 23 hours. Absorption of formoterol is linear following inhalation of 12 to 96 micrograms of formoterol.

Biotransformation

Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. Liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.

Elimination

The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12–96 micrograms dose range. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on plasma concentrations measured following inhalation of a single 120 micrograms dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. The (R,R)- and

(S,S)-enantiomers represented about 40% and 60% of unchanged active substance excreted in the urine, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing. After oral administration (40 to 80 micrograms), 6% to 10% of the dose was recovered in urine as unchanged active substance in healthy subjects; up to 8% of the dose was recovered as the glucuronide. A total 67% of an oral dose of formoterol is excreted in urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 mL/min.

Patients with hepatic impairment

The pharmacokinetics of formoterol has not been studied in patients with hepatic impairment; however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.

Glycopyrronium

Absorption and distribution

Glycopyrronium has a quaternary ammonium structure which limits its passage across biological membranes and produces slow, variable and incomplete gastrointestinal absorption. Following glycopyrronium inhalation, the lung bioavailability was 10.5% (with activated charcoal ingestion) while the absolute bioavailability was 12.8% (without activated charcoal ingestion) confirming the limited gastrointestinal absorption and indicating that more than 80% of glycopyrronium systemic exposure was from lung absorption. After repeated inhalation of twice daily doses ranging from 12.5 to 50 micrograms via pressurised metered dose inhaler in COPD patients, glycopyrronium showed linear pharmacokinetics with little systemic accumulation at steady state (median accumulation ratio 2.2–2.5).

The apparent volume of distribution (Vz) of inhaled glycopyrronium was increased compared to intravenous infusion (6,420 L versus 323 L), reflecting the slower elimination after inhalation.

Biotransformation

The metabolic pattern of glycopyrronium in vitro (humans, dogs, rats, mice and rabbits liver microsomes and hepatocytes) was similar among species and the main metabolic reaction was the hydroxylation on the phenyl or ciclopentyl rings. CYP2D6 was found to be the only enzyme responsible for glycopyrronium metabolism.

Elimination

The mean elimination half-life of glycopyrronium in healthy volunteers was approximately 6 hours after intravenous injection while after inhalation in COPD patients it ranged from 5 to 12 hours at steady state. After a glycopyrronium single intravenous injection, 40% of the dose was excreted in the urine within 24 hours. In COPD patients receiving repeated twice daily administration of inhaled glycopyrronium, the fraction of the dose excreted in urine ranged from 13.0% to 14.5% at steady state. Mean renal clearance was similar across the range of doses tested and after single and repeated inhalation (range 281–396 mL/min).

5.3 Preclinical safety data

Safety pharmacology

In an inhalation study in telemetered dogs, the cardiovascular system was a major target system for acute effects of Trimbow (increase in heart rate, decrease in blood pressure, ECG changes at higher doses), effects probably mainly related to the beta2-adrenergic activity of formoterol and the anti-muscarinic activity of glycopyrronium. There was no evidence for overadditive effects of the triple combination when compared with the single components.

Repeat dose toxicity

In repeat dose inhalation studies with Trimbow in rats and dogs of up to 13 weeks duration, the main observed alterations were related to effects on the immune system (probably due to systemic corticosteroid effects of beclometasone dipropionate and its active metabolite beclometasone-17-monopropionate) and on the cardiovascular system (probably related to the beta2-adrenergic activity of formoterol and the anti-muscarinic activity of glycopyrronium). The toxicological profile of the triple combination reflected that of the single active components without a relevant increase in toxicity and without unexpected findings.

Reproductive and development toxicity

Beclometasone dipropionate/be­clometasone-17-monopropionate was considered responsible for reproductive toxicity effects in rats such as reduction of the conception rate, fertility index, early embryonic development parameters (implantation loss), delay in ossification and increased incidence of visceral variations; while tocolytic and anti-muscarinic effects, attributed to the beta2-adrenergic activity of formoterol and the anti-muscarinic activity of glycopyrronium, affected pregnant rats in the late phase of gestation and/or early phase of lactation, leading to loss of pups.

Genotoxicity

Genotoxicity of Trimbow has not been evaluated, however, the single active components were devoid of genotoxic activity in the conventional test systems.

Carcinogenicity

Carcinogenicity studies have not been performed with Trimbow. However, in a 104-week rat inhalation carcinogenicity study and an oral 26-week

carcinogenicity study in transgenic Tg.rasH2 mice, glycopyrronium bromide showed no carcinogenic potential and published data concerning long-term studies conducted with beclometasone dipropionate and formoterol fumarate in rats do not indicate a clinically relevant carcinogenic potential.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate (may contain milk proteins)

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

21 months.

After first opening the pouch, the medicinal product should be used within 6 weeks and stored in a dry place.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the inhaler in the original package in order to protect from moisture and only remove from the pouch immediately before first use.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

The inhaler is a white inhaler with a grey mouthpiece cover and a counter for the inhalations. It consists of a casework comprising of a lower shell with window to display number of inhalations left and an integral cover. When opened, the cover, which also drives the dose counter mechanism, reveals a mouthpiece through which the medicinal product is inhaled.

The lower shell and mouthpiece are made from acrylonitrile butadiene styrene and the cover is made from polypropylene.

The inhaler is packed into a thermo welded Polyamide/Alu­minium/Polyet­hylene (PA/Al/PE) or Polyethylene-Terephthalate/A­luminium/ Polyethylene (PET/Al/PE) pouch.

Pack sizes:

Pack of 1 inhaler containing 120 inhalations

Multipack containing 240 inhalations (2 inhalers of 120 inhalation­s each).

Multipack containing 360 inhalations (3 inhalers of 120 inhalation­s each).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

7   MARKETING AUTHORISATION HOLDER