Trimbow 100/6/10 and 200/6/10 (2023)

1 Name of Medicine

Beclometasone dipropionate, formoterol (eformoterol) fumarate dihydrate and glycopyrronium bromide (glycopyrrolate).

2 Qualitative and Quantitative Composition

Trimbow 100/6/10.

Each metered dose (the dose leaving the valve) contains 100 micrograms of beclometasone dipropionate (BDP), 6 micrograms of formoterol fumarate dihydrate (FF) and 10 micrograms of glycopyrronium (equivalent to 12.5 micrograms of glycopyrronium bromide) (GB).
Each delivered dose (the dose leaving the mouthpiece) contains 87 micrograms of beclometasone dipropionate (BDP), 5 micrograms of formoterol fumarate dihydrate (FF) and 9 micrograms of glycopyrronium (equivalent to 11 micrograms of glycopyrronium bromide) (GB).

Trimbow 200/6/10.

Each metered dose (the dose leaving the valve) contains 200 micrograms of beclometasone dipropionate (BDP), 6 micrograms of formoterol fumarate dihydrate (FF) and 10 micrograms of glycopyrronium (equivalent to 12.5 micrograms of glycopyrronium bromide) (GB).
Each delivered dose (the dose leaving the mouthpiece) contains 172 micrograms of beclometasone dipropionate (BDP), 5 micrograms of formoterol fumarate dihydrate (FF) and 9 micrograms of glycopyrronium (equivalent to 11 micrograms glycopyrronium bromide) (GB).

List of excipient(s) with known effect.

Ethanol absolute.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pressurised inhalation solution (pressurised inhalation).
Colourless to yellowish liquid solution.
The inhalation solution is contained in a pressurised aluminium container sealed with a metering valve. The canister is inserted into a polypropylene plastic actuator which incorporates a mouthpiece and is fitted with a plastic protective cap. The actuator is grey with a red cap (Trimbow 100/6/10) or green cap (Trimbow 200/6/10). The actuator has a dose counter.

4 Clinical Particulars

4.1 Therapeutic Indications

COPD.

Trimbow 100/6/10 is indicated for 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 (ICS) and a long-acting beta2-agonist (LABA) or a combination of a LABA and a long-acting muscarinic antagonist (LAMA).

Asthma.

Trimbow 100/6/10.

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

Trimbow 200/6/10.

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 Dose and Method of Administration

Dosage.

Trimbow is not to be used as initial therapy but may be considered as step-up from LABA/LAMA or ICS/LABA or for patients already taking ICS+LABA+LAMA. Patients can be changed from their existing inhalers to Trimbow at the next dose. It is important, however, that patients do not take other LABA, LAMA or ICS while taking Trimbow.
A stepwise approach to the management of COPD is recommended, including the cessation of smoking and a pulmonary rehabilitation program.

Adults.

The recommended dose is two inhalations twice daily. The patient should take two inhalations in the morning and two inhalations in the evening at the same time every day.
The maximum dose is two inhalations of Trimbow 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.
Asthma. When choosing the starting dose strength of Trimbow 100/6/10 or Trimbow 200/6/10, 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 Trimbow 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 200/6/10) to the medium strength beclometasone dipropionate medicinal product (Trimbow 100/6/10).

Special populations.

Paediatric population.

COPD.

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

Asthma.

The safety and efficacy of Trimbow in the paediatric population (under 18 years of age) have not yet been established. No data available.
Elderly. No dose adjustment is required in elderly patients (65 years of age and older) (see Section 5.2 Pharmacokinetic Properties, Special patient populations).
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 Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special patient populations).
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 Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special patient populations).

Method of administration.

Trimbow is for oral inhalation only.
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). The patient should be advised to read the Package Leaflet carefully and follow the instructions for use.
Trimbow is provided with a dose counter or dose indicator on the back of the inhaler, which shows how many actuations remain. For the 60 and 120 actuation pressurised containers, each time the patient presses the container a puff of the solution is released and the counter counts down by one.
For the 180 actuation pressurised container, each time the patient presses the pressurised container a puff of the solution is released and the indicator rotates by a small amount. The number of puffs remaining is displayed in intervals of 20.
Patients 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, 120 or 180 actuation pressurised containers, the counter/indicator should read 61, 121 or 180, respectively. After priming, the container the counter/indicator should read 60, 120 or 180.

Use of the inhaler.

Patients should stand or sit in an upright position when inhaling from their inhaler. The steps below should be followed. Important: steps 2 to 5 should not be performed too quickly:
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 slowly and as deeply as comfortable, in order to empty their lungs.
3. Patients should hold the inhaler vertically with its body upwards and place the mouthpiece between their teeth without biting. Their lips should then be placed around the mouthpiece, with the tongue flat under it.
4. At the same time, patients 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, patients should firmly press down on the top of the pressurised container to release one puff.
5. Patients should then hold their breath for as long as comfortably possible, then remove the inhaler from the mouth and breathe out slowly. Patients should not breathe out into the inhaler.
6. Patients should then check the dose counter or dose indicator to ensure it has moved accordingly.
To inhale the second puff, patients 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, patients should close the inhaler with the protective mouthpiece cover and check the dose counter or dose indicator.
After inhaling, patients should rinse their mouth or gargle with water without swallowing it or brush their teeth (see Section 4.4 Special Warnings and Precautions for Use).

When to get a new inhaler.

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 or indicator 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 a suitable spacer device, properly cleaned as described in the relevant spacer 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 a suitable spacer with one continuous slow and deep breath. Any delays between actuation and inhalation should be kept to a minimum. 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 Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Use with a spacer.

Single dose pharmacokinetic data (see Section 5.2 Pharmacokinetic Properties) have demonstrated that in comparison to routine use without a spacer device, the use of Trimbow with the AeroChamber Plus spacer device increased the total systemic exposure (AUC_0-t) to glycopyrronium. However, available safety data from long-term clinical studies have not raised any significant safety concerns (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).

Cleaning.

For the regular cleaning of the inhaler, patients should remove the cap from the mouthpiece weekly and wipe the outside and inside of the mouthpiece with a dry cloth. They 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 List of Excipients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Not for acute use.

Trimbow 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 trials 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 Adverse Effects (Undesirable Effects)).
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. 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. These factors should be considered when Trimbow is prescribed, and treatment re-evaluated if pneumonia occurs.

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, and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained (see Section 4.2 Dose and Method of Administration).
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.

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 Interactions with Other Medicines and Other Forms of Interactions).

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.

Excipients.

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

Use in 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 Pharmacokinetic Properties). These patients should be monitored for potential adverse reactions.

Use in 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 Pharmacokinetic Properties). These patients should be monitored for potential adverse reactions.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

Interactions with laboratory tests have not been established.

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 Interactions with Other Medicines and Other Forms of Interactions).
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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occur with medicinal products affecting renal excretion mechanisms (see Section 5.2 Pharmacokinetic Properties). 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 (AUC_0-t) by 16% and a slight decrease in renal clearance by 20% due to co administration of cimetidine.
The total formoterol exposure (AUC_0-t) increased by 21% after co administration of Trimbow with cimetidine. This increased exposure was possibly related to inhibition of cytochrome P450 isozymes involved in formoterol metabolism, due to cimetidine co-administration.
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 Special Warnings and Precautions for Use). 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 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific studies on fertility have been performed with Trimbow in humans. Impairment of fertility and inhibition of ovulation were observed in rats treated with beclometasone dipropionate, formoterol fumarate and glycopyrronium bromide in combination (100/6/25 ratio) at oral doses ≥ 2 mg/kg/day. This is attributable to the beclometasone dipropionate component, and occurred only at corticosteroid exposure levels (plasma AUC) far in excess of that in patients receiving Trimbow. Accordingly, impairment of fertility is not expected in patients.
(Category B3)
There are no or limited amount of data from the use of Trimbow in pregnant women.
Studies in rats with beclometasone dipropionate, formoterol fumarate and glycopyrronium bromide in combination (100/6/25 ratio; given orally) showed embryofetal and pup loss, dystocia, decreased fetal/pup weight, increased fetal visceral variations and impaired fetal ossification. These findings are principally attributable to beclometasone dipropionate, and mostly occurred at extremely large multiples of the clinical exposure to the corticosteroid component of Trimbow. The tocolytic effect is due to formoterol fumarate as a beta2-agonist, with effects observed in animals at formoterol exposure levels lower than in patients. 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 fetus. 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 Dose and Method of Administration).
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 into breast-milk.
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.

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 Adverse Effects (Undesirable Effects)

Clinical trial data.

COPD.

The most frequently reported adverse events in the three Phase III, 52 week active controlled studies in COPD using BDP/FF/GB 100/6/12.5 (TRILOGY, TRINITY and TRIBUTE) are presented in Table 1, Table 2 and Table 3.
The TRILOGY study included 687 patients with COPD who received Trimbow pressurised metered dose inhaler (pMDI) 100/6/12.5 micrograms two inhalations twice daily for up to 52 weeks, which were compared to 680 patients with COPD treated with an active comparator, a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms pMDI two inhalations twice daily.
The TRINITY study included 1077 patients with COPD who received Trimbow pMDI 100/6/12.5 micrograms two inhalations twice daily for up to 52 weeks, which were compared to 1076 patients with COPD treated with tiotropium bromide 18 micrograms inhalation powder, hard capsule, once daily. The third arm included 537 patients with COPD treated with a two-inhaler triple therapy consisting of a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms (corresponding to a delivered dose of 84.6/5.0 micrograms) pMDI two inhalations twice daily plus tiotropium bromide 18 micrograms inhalation powder, hard capsule, once daily.
The TRIBUTE study included 764 patients with COPD who received Trimbow pMDI 100/6/12.5 micrograms two inhalations twice daily for up to 52 weeks, which were compared to 768 patients with COPD treated with an active comparator, indacaterol/glycopyrronium 110/50 micrograms inhalation powder, hard capsule, once daily.

Summary of the safety profile.

The most frequently reported adverse reactions in patients with COPD or asthma with Trimbow were respectively: dysphonia (0.3% and 1.5%) and oral candidiasis (0.8% and 0.3%), which are normally associated with ICS; muscle spasms (0.4% and 0.2%), which can be attributed to the LABA component; and dry mouth (0.4% and 0.5%), which is a typical anticholinergic effect, which can be attributed to the LAMA component.
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 with Trimbow occurred during clinical trials and post-marketing experience as well as adverse reactions listed for the marketed individual components are provided in Table 4, 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).

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 suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

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 Special Warnings and Precautions for Use). If overdose occurs, the patient's symptoms should be treated supportively with appropriate monitoring as necessary.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

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.

Trimbow contains beclometasone dipropionate, formoterol and glycopyrronium (BDP/FF/GB) in a solution formulation resulting in an aerosol with extrafine particles with an average mass median aerodynamic diameter (MMAD) of around 1.1 micrometres 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 non-extrafine 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 ismediated 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. It shows greater than 4-fold selectivity for the human M3 receptors over the human M2 receptor.

Clinical trials.

COPD. All patients included in the below described clinical studies were required to have a clinical diagnosis of COPD, a smoking history of at least 10 pack years; a post-salbutamol FEV₁/ FVC ratio < 0.70 and FEV₁ of < 50% predicted normal; evidence of symptoms with a COPD Assessment Test (CAT) score of 10 or above; and a history of ≥ 1 COPD exacerbation in the previous 12 months at screening.

Study 1 (TRILOGY).

The efficacy of the single-inhaler fixed triple combination of beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB 100/6/12.5 micrograms) pMDI administered as a two inhalations twice-daily treatment in patients with a clinical diagnosis of COPD has been evaluated in this multicentre, randomised double-blind, parallel group 52-week active-controlled study compared to the fixed combination pMDI - beclomethasone dipropionate, formoterol fumarate (BDP/FF 100/6 micrograms) two inhalations twice-daily.
At screening, the mean post-bronchodilator FEV₁ was 36.5% predicted, the mean reversibility was 10.40%, and the mean CAT score was 20.8. In the year prior to study entry, 80.2% of the patients had one moderate or severe COPD exacerbation, while 19.8% of the patients had experienced more than one exacerbation.
BDP/FF/GB demonstrated a statistically significant improvement in lung function (as defined by change from baseline in pre-dose FEV₁ at Week 26 and change from baseline in 2-hour post-dose FEV₁; co-primary endpoints) compared with BDP/FF (see Table 5).
BDP/FF/GB showed a numerical improvement compared with BDP/FF at Week 26 for dyspnea severity measured by the transition dyspnea index (TDI) focal score (co-primary endpoint) and health-related quality of life measured by the St. George's Respiratory Questionnaire (SGRQ) total score. BDP/FF/GB also demonstrated a reduction in the annual rate of moderate/severe exacerbations (i.e. requiring treatment with antibiotics or corticosteroids or hospitalisation) compared with BDP/FF (see Table 5).
The lung function, TDI and SGRQ outcomes at Week 52 (data not shown) were consistent with the results observed at Week 26 (see Table 5).

Study 2 (TRINITY).

The efficacy of the single-inhaler fixed triple combination of beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB 100/6/12.5 micrograms) pMDI administered as two inhalations, twice-daily treatment in patients with a clinical diagnosis of COPD has been evaluated in this multicentre, double-blind, double-dummy, parallel group 52-week active-controlled study. It was compared to tiotropium bromide (TIO 18 micrograms) inhalation powder once-daily, and a two-inhaler triple therapy containing the fixed combination beclomethasone dipropionate, formoterol fumarate (BDP/FF 100/6 micrograms) pMDI two inhalations twice-daily and tiotropium bromide inhalation powder (TIO 18 micrograms) once-daily [BDP/FF + TIO].
At screening, the mean post-bronchodilator FEV₁ was 36.6% predicted, the mean reversibility was 7.75%, and the mean CAT score was 21.6. In the year prior to study entry, 79.7% of the patients had one moderate or severe COPD exacerbation, while 20.3% of the patients had experienced more than one exacerbation.
BDP/FF/GB demonstrated a statistically significant reduction in the annual rate of moderate/severe exacerbations (i.e. requiring treatment with antibiotics or corticosteroids or hospitalisation) compared with TIO (primary endpoint), as well as a statistically significant improvement in lung function (as defined by change from baseline in pre-dose FEV₁ at Week 52; key secondary endpoint) compared with TIO (see Table 6).
In addition, no relevant differences were observed between BDP/FF/GB and BDP/FF+TIO in terms of change from baseline in pre-dose FEV₁ at Week 52 (key secondary endpoint) and moderate/severe exacerbation rate. BDP/FF/GB showed improvement compared with TIO at Week 52 in health-related quality of life measured by the SGRQ total score.

Study 3 (TRIBUTE).

The efficacy of the single-inhaler fixed triple combination of beclomethasone dipropionate, formoterol, glycopyrronium bromide (BDP/FF/GB 100/6/12.5 micrograms) pMDI administered as a two inhalations twice-daily treatment in patients with a clinical diagnosis of COPD has been evaluated in this 52-week active-controlled study compared to the fixed combination indacaterol/glycopyrronium (IND/GLY 110/50 micrograms) inhalation powder once-daily.
At screening, the mean post-bronchodilator FEV₁ was 36.4% predicted, and the mean reversibility was 8.58%. The mean CAT score was 21.2. In the year prior to study entry, 80.8% of the patients had one moderate or severe COPD exacerbation, while 19.2% of the patients experienced more than one exacerbation.
BDP/FF/GB demonstrated a statistically significant reduction in the annual rate of moderate/severe exacerbations (i.e. requiring treatment with antibiotics or corticosteroids or hospitalisation) compared with IND/GLY (primary endpoint) (see Table 7). Time to first moderate/severe COPD exacerbation, as well as the analyses of moderate and severe COPD exacerbations (considered separately) showed a trend toward a delay in time to the first event and a reduction of the rate of exacerbation.
BFP/FF/GB improved average pre-dose FEV₁ over the 52-week treatment period compared to IND/GLY. A similar improvement was observed at Week 52 (data not shown).
Treatment with BDP/FF/GB showed an improvement compared with IND/GLY in health-related quality of life measured by the SGRQ total score at Week 52.
The lung function and SGRQ total score outcomes at Week 26 were consistent with the results observed at Week 52 (data not shown).

Study 4 (TRISTAR).

The effect on health-related quality of life of the single-inhaler fixed triple combination of beclomethasone dipropionate, formoterol, glycopyrronium bromide (BDP/FF/GB 100/6/12.5 micrograms) pMDI administered as a two inhalations twice-daily treatment in patients with a clinical diagnosis of COPD has been evaluated in this multicentre, randomised, open-label, parallel group, 26-week active-controlled study compared to a two-inhaler triple therapy with the fixed combination of fluticasone furoate, vilanterol (FLU/VI 92/22 micrograms) inhalation powder, pre-dispensed once-daily and tiotropium (TIO 18 micrograms) inhalation powder hard capsule once-daily.
At screening, the mean post-bronchodilator FEV₁ was 36.3% predicted, the mean reversibility was 7.27%, and the mean CAT score was 22.8. In the year prior to study entry, 84.1% of the patients had one moderate or severe COPD exacerbation, while 15.9% of the patients had experienced more than one exacerbation.
BDP/FF/GB was non-inferior to FLU/VI+TIO at Week 26 in health-related quality of life measured by the St. George's Respiratory Questionnaire (SGRQ) total score, with the upper limit of the 95% CI for the adjusted mean difference between treatments being below the non-inferiority margin of 4 units (primary endpoint). The responder analysis on the same outcome showed similar results.
No relevant differences were observed in the secondary endpoints (see Table 8).

Asthma. The Phase III clinical development programme in asthma included two randomised, double-blind, active-controlled studies of 52 weeks duration, one performed with the medium ICS dose strength (BDP/FF/GB 100/6/12.5; TRIMARAN) and another one with the high ICS dose strength (BDP/FF/GB 200/6/12.5; TRIGGER).
Both studies were conducted in adult patients with a clinical diagnosis of asthma who were uncontrolled on dual maintenance treatment using a medium dose (TRIMARAN) or high dose (TRIGGER) ICS/LABA combination (ACQ-7 score ≥ 1.5). In order to be eligible, patients had to have experienced at least one asthma exacerbation requiring treatment with systemic corticosteroids or emergency department visit or in-patient hospitalisation in the previous year.
The TRIMARAN study compared two twice-daily doses of BDP/FF/GB 100/6/12.5 (N=579) with two twice-daily doses of a fixed combination of beclometasone dipropionate (BDP) and formoterol (FF) 100/6 micrograms (delivered dose of 84.6/5.0) (N=576). The TRIGGER study compared two twice-daily doses of BDP/FF/GB 200/6/12.5 (N=573) with two twice-daily doses of a fixed combination of BDP and FF 200/6 micrograms alone (delivered dose 177.7/5.1) (N=576) or on top of two once-daily doses of tiotropium 2.5 micrograms (N=288) as an open-label triple combination arm.
The primary objective of the studies was to demonstrate superiority of either BDP/FF/GB 100/6/12.5 or BDP/FF/GB 200/6/12.5 (two inhalations twice daily) over the respective fixed dual combination product (medium or high dose ICS/LABA) in terms of the co-primary endpoints (change from baseline in pre-dose FEV₁ at Week 26 and the rate of moderate and severe exacerbation rate over 52 weeks).
The TRIGGER study was not powered to evaluate the comparative efficacy of BDP/FF/GB 200/6/12.5 vs. BDP/FF + tiotropium 2.5 micrograms. Descriptive results are included in Table 9.
Median age of patients enrolled in the two pivotal trials was 54 years. Less than 20% of patients were aged 65 years or more and approximately 60% of patients were female. During the study, about 16% (TRIMARAN) and 23% (TRIGGER) of patients used an AeroChamber Plus spacer.

Reduction of asthma exacerbations.

In the TRIMARAN study, BDP/FF/GB 100/6/12.5 significantly reduced the rate of moderate/severe exacerbations compared with the fixed combination of BDP/FF 100/6 micrograms (adjusted rate ratio 0.846, 95% CI [0.725; 0.987]).
In the TRIGGER study, BDP/FF/GB 200/6/12.5 also reduced the rate of moderate/severe exacerbations more than the fixed combination of BDP/FF 200/6 micrograms but this effect did not achieve statistical significance (adjusted rate ratio 0.880, 95% CI [0.751;1.030], p=0.11). Due to the hierarchical testing, all TRIGGER efficacy endpoints and the pre-specified analysis of severe exacerbations (data pooled across TRIMARAN and TRIGGER studies) resulted in nominal p-values only (Table 9).
Data of TRIMARAN and TRIGGER studies suggest that the time to first moderate/severe exacerbation (secondary endpoint) was prolonged in the triple combination arm when compared with the respective dual combination arm.

Effects on lung function.

In both studies, BDP/FF/GB 100/6/12.5 and BDP/FF/GB 200/6/12.5 improved the lung function parameters of pre-dose FEV₁ (co-primary endpoint), peak_0-3h FEV₁, and morning peak expiratory flow (key secondary endpoints), compared with a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms and 200/6 micrograms, respectively, after 26 weeks of treatment. All improvements were statistically significant (see Table 9).

Co-primary endpoints (pre-dose FEV₁ at Week 26 and the rate of moderate and severe exacerbation rate over 52 weeks) and the key secondary endpoints (peak_0-3h FEV₁ at Week 26, morning PEF over 26 weeks and the rate of severe exacerbations [pooled analysis of TRIMARAN and TRIGGER] over 52 weeks) were part of the step-down, closed confirmatory testing strategy and thus controlled for multiplicity.
Since the superiority test of one of the co-primary endpoints in the TRIGGER study did not achieve statistical significance, results for TRIGGER efficacy endpoints and the rate of severe exacerbations (pooled analysis) are nominal p-values and presented for descriptive purposes.
Since the TRIGGER trial was not powered to evaluate the comparative efficacy of BDP/FF/GB 200/6/12.5 vs. BDP/FF 200/6 plus tiotropium 2.5, it is not clear whether the observed differences are real or a random result.

5.2 Pharmacokinetic Properties

Trimbow - fixed combination.

The systemic exposure to beclometasone dipropionate, formoterol and glycopyrronium has been investigated in a pharmacokinetic study conducted in healthy subjects. The study compared data obtained after treatment with a single dose of Trimbow (4 inhalations of 100/6/25 micrograms, a non-marketed formulation containing twice the approved strength of glycopyrronium) or a single dose of the extemporary combination of beclometasone dipropionate/formoterol (4 inhalations of 100/6 micrograms) plus glycopyrronium (4 inhalations of 25 micrograms). The maximum plasma concentration and systemic exposure of beclometasone dipropionate main active metabolite (beclometasone 17 monopropionate) and formoterol were similar after administration of the fixed or extemporary combination. For glycopyrronium, the maximum plasma concentration was similar after administration of the fixed or extemporary combination, while the systemic exposure was slightly higher after administration of Trimbow than with the extemporary combination. This study also investigated the potential pharmacokinetic interaction between the active components of Trimbow by comparing the pharmacokinetic data obtained after a single dose of the extemporary combination or after a single dose of the single components beclometasone dipropionate/formoterol or glycopyrronium. There was no clear evidence of pharmacokinetic interaction, however, the extemporary combination showed formoterol and glycopyrronium levels transiently slightly higher immediately after dosing compared with the single components. It is noted that single component glycopyrronium, formulated as pressurised metered dose inhaler, which was used in the PK studies, is not available on the market.
The dose proportionality of systemic and lung exposure to beclometasone dipropionate has been investigated in a pharmacokinetic study conducted in healthy subjects with non-marketed Trimbow. The study compared data obtained after treatment with a single dose (4 inhalations) of Trimbow 200/6/25 micrograms or a single dose (4 inhalations) of Trimbow 100/6/25 micrograms (both are non-marketed formulations containing twice the approved strength of glycopyrronium). Trimbow 200/6/25 micrograms treatment resulted in a two times higher systemic and lung exposure to beclometasone dipropionate and to its main active metabolite (beclometasone 17-monopropionate) in comparison to Trimbow 100/6/25 micrograms, which is consistent with the different strengths of the two formulations. The systemic and lung exposure to glycopyrronium and formoterol was similar after the two treatments, although a high variability was observed for glycopyrronium bromide C_max.
A comparison across studies showed that the pharmacokinetics of beclometasone 17 monopropionate, formoterol and glycopyrronium is similar in COPD patients, in patients with asthma and in healthy subjects.

Effect of a spacer.

In patients with COPD the use of Trimbow with the AeroChamber Plus spacer increased the lung delivery of beclometasone 17 monopropionate, formoterol and glycopyrronium (maximum plasma concentration increased by 15%, 58% and 60% respectively). The total systemic exposure (as measured by AUC_0-t) was slightly reduced for beclometasone 17 monopropionate (by 37%) and formoterol (by 24%), while it was increased for glycopyrronium (by 45%). Also see Section 4.4 Special Warnings and Precautions for Use.
In patients with asthma, the use of Trimbow with a spacer increased the lung delivery of beclometasone 17-monopropionate, formoterol and glycopyrronium (maximum plasma concentration increased by 7%, 23% and 34% respectively). The total systemic exposure (as measured by AUC_0-t) was slightly reduced for beclometasone 17-monopropionate (by 34%) and formoterol (by 30%), while it was increased for glycopyrronium (by 36%). (See Section 4.2 Dose and Method of Administration).

Effect of renal impairment.

Systemic exposure (AUC_0-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 anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.

Absorption, distribution and metabolism.

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.

Excretion.

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 half-lives 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 2-3 hours. Absorption of formoterol is linear following inhalation of 12 to 96 micrograms of formoterol.

Metabolism.

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.

Excretion.

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% to10% 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 (i.v.) infusion (6420 L versus 323 L), reflecting the slower elimination after inhalation.

Metabolism.

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.

Excretion.

The mean elimination half-life of glycopyrronium in healthy volunteers was approximately 6 hours after i.v. injection while after inhalation in COPD patients it ranged from 5 to 12 hours at steady state. After a glycopyrronium single i.v. 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

Genotoxicity.

Individually, beclometasone dipropionate, formoterol fumarate and glycopyrronium bromide were devoid of genotoxic activity in assays for bacterial mutagenicity, chromosomal aberrations in vitro (human lymphocytes) and in vivo clastogenicity (rat bone marrow micronucleus test).

Carcinogenicity.

Carcinogenicity studies have not been performed with beclometasone dipropionate, formoterol fumarate and glycopyrronium bromide in combination. Data for the individual active components are described below:

Beclometasone dipropionate.

The potential carcinogenicity of beclometasone dipropionate has not been adequately investigated in animal studies. Other glucocorticoids (budesonide, prednisolone and triamcinolone acetate) have been shown to increase the incidence of hepatocellular tumours in rats by a non-genotoxic mechanism.

Formoterol fumarate.

In 2-year studies in mice and rats, treatment with formoterol fumarate, given via the diet or drinking water at very high doses, was associated with increases in several tumour types. In mice, these included hepatocellular adenoma and carcinomas (≥ 2 mg/kg/day), leiomyomas and leiomyosarcomas in the female reproductive tract (≥ 2 mg/kg/day) and adrenal subcapsular cell tumours (≥ 66 mg/kg/day). In rats, treatment was associated with benign granulosa/theca cell tumours in the ovaries (≥ 0.5 mg/kg/day), mesovarian leiomyomas (≥ 18 mg/kg/day), mammary adenocarcinomas (≥ 36 mg/kg/day) and thyroid C-cell neoplasms (46 mg/kg/day). A mesovarian leiomyoma was also observed in a female rat dosed by inhalation at 130 microgram/kg/day for two years (almost 60 times the maximum recommended human dose for Trimbow, adjusted for body surface area). Mammary adenocarcinomas, smooth muscle tumours in the female reproductive tract and effects on the ovary have been reported in rats and mice treated with other β2-adrenergic agonists and are likely to be secondary to prolonged stimulation of β2-adrenoceptors in these tissues.

Glycopyrronium bromide.

No carcinogenic activity was observed for glycopyrronium bromide in a 26-week oral study in transgenic (rasH2) mice and a 2-year inhalational study in rats. The highest dose levels employed (150 mg/kg/day in mice and 447 microgram/kg/day in rats) yielded systemic exposure (plasma AUC) levels to glycopyrronium approximately 70-320 times higher in mice and 140 times higher in rats than in humans at the maximum recommended clinical dose of Trimbow.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethanol absolute, Hydrochloric acid, Norflurane (propellant).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

Store in a refrigerator (2-8°C) for a maximum of 18 months. Do Not Freeze.

After first use.

Store below 30°C (for a maximum of 2 months).

For pharmacists.

Single packs.

Enter the date of dispensing on the removable dispensing label and affix the label to the actuator.

Multipacks.

Advise the patient to enter the date of first use on the removable first use label and affix to the actuator.

6.5 Nature and Contents of Container

Pressurised container (coated aluminium), with a metering valve. The pressurised container is inserted in a polypropylene inhaler which incorporates a mouthpiece and a dose counter (60 actuations or 120 actuations per pressurised container) or dose indicator (180 actuations per pressurised container) and is provided with a polypropylene mouthpiece cap.

Trimbow 100/6/10 pack sizes.

Pack of 1 container with either 60, 120, or 180 actuations.
Multipack containing 240 actuations (2 containers of 120 actuations each).
Multipack containing 360 actuations (3 containers of 120 actuations each). Not all pack sizes may be marketed.

Trimbow 200/6/10 pack sizes.

Pack of 1 container with either 60 or 120 actuations.
Multipack containing 240 actuations (2 containers of 120 actuations each).
Multipack containing 360 actuations (3 containers of 120 actuations each).
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

Beclometasone dipropionate: 5534-09-8.
Formoterol fumarate dihydrate: 183814-30-4.
Glycopyrronium: 596-51-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription only medicine).