Bevespi Aerosphere - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Bevespi Aerosphere 7.2 micrograms/5 micrograms pressurised inhalation, suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single actuation (delivered dose, ex-actuator) contains glycopyrronium bromide 9 micrograms equivalent to 7.2 micrograms of glycopyrronium, and 5 micrograms of formoterol fumarate dihydrate.

This corresponds to a metered dose of glycopyrronium bromide 10.4 micrograms equivalent to

• 8.3 micrograms of glycopyrronium, and formoterol fumarate dihydrate 5.8 micrograms.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Pressurised inhalation, suspension (pressurised inhalation).

White suspension.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Bevespi Aerosphere is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD) (see section 5.1).

4.2 Posology and method of administration

Posology

The recommended dose is two inhalations twice daily (two inhalations in the morning and two inhalations in the evening).

Patients should be advised not to take more than 2 inhalations twice daily.

If a dose is missed, it should be taken as soon as possible and the next dose should be taken at the usual time. A double dose should not be taken to make up for a forgotten dose.

Special populations

Elderly

No dose adjustments are required in elderly patients (see section 5.2).

Renal impairment

Bevespi Aerosphere can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severe renal impairment or end-stage renal disease requiring dialysis it should be used only if the expected benefit outweighs the potential risk (see sections 4.4 and 5.2). Hepatic impairment

Bevespi Aerosphere can be used at the recommended dose in patients with mild to moderate hepatic impairment. There are no relevant data on the use of Bevespi Aerosphere 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 Bevespi Aerosphere in children and adolescents (under 18 years of age) for the indication of COPD.

Method of administration

For inhalation use.

Instructions for use

On actuation of Bevespi Aerosphere, a volume of the suspension is expelled from the pressurised container at high velocity. When the patient inhales through the mouthpiece at the same time as actuating the inhaler, the substance will follow the inspired air into the airways.

Note: Patients should be instructed on the correct inhalation technique. It is important to instruct the patient to:

• • Carefully read the instructions for use in the patient information leaflet, which is packed together with each inhaler.
• • Not use the inhaler if the drying agent, which is inside the foil pouch, has leaked out of its packet.
• • Prime the inhaler by shaking it and actuating into the air four times before first use or two times when the inhaler has not been used for more than seven days, has been exposed to low temperatures, or has been dropped.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Asthma

Bevespi Aerosphere should not be used to treat asthma.

Paradoxical bronchospasm

In clinical studies, paradoxical bronchospasm was not observed with Bevespi Aerosphere at its recommended dose. If paradoxical bronchospasm does occur, treatment with the medicinal product should be stopped and other treatments considered.

Not for acute use

Bevespi Aerosphere is not indicated for the treatment of acute episodes of bronchospasm, i.e. as a rescue therapy.

Cardiovascular effects

Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including glycopyrronium or formoterol. Patients with clinically significant uncontrolled cardiovascular disease were excluded from clinical studies. Bevespi Aerosphere should be used with caution in patients with severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.

Caution should also be exercised in patients with thyrotoxicosis or known or suspected prolongation of the QTc interval (see section 4.5).

Hypokalaemia

P2-adrenergic agonists may produce significant hypokalaemia, which may increase the susceptibility to cardiac arrhythmias. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see section 4.5).

Hyperglycaemia

Inhalation of high doses of P2-adrenergic agonists may produce increases in plasma glucose.

Anticholinergic activity

Due to its anticholinergic activity, Bevespi Aerosphere should be used with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma (see section 4.8).

Renal impairment

As glycopyrronium is predominantly renally excreted, patients with severe renal impairment (creatinine clearance of < 30 mL/min), including those with end-stage renal disease requiring dialysis, should only be treated with Bevespi Aerosphere if the expected benefit outweighs the potential risk (see section 5.2).

Hepatic impairment

In patients with severe hepatic impairment, Bevespi Aerosphere 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.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Clinical drug-drug interaction studies have not been conducted with Bevespi Aerosphere, however, the potential for metabolic interactions is considered to be low based on in-vitro studies (see section 5.2).

Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occur with medicinal products affecting renal excretion mechanisms. In-vitro glycopyrronium is a substrate for the renal transporters OCT2 and MATE1/2K. The effect of cimetidine, a probe inhibitor of OCT2 and MATE1, on inhaled glycopyrronium disposition showed a limited increase in its total systemic exposure (AUC0-t) by 22% and a slight decrease in renal clearance by 23% due to co-administration of cimetidine.

Pharmacodynamic interactions

Other antimuscarinics and sympatomimetics

Co-administration of Bevespi Aerosphere with other anticholinergic and/or long-acting P2-adrenergic agonist containing medicinal products has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist or beta2-adrenergic agonist adverse reactions (see section 4.4 and section 4.9).

Although no formal in-vivo drug interaction studies have been performed with Bevespi Aerosphere, studies indicate no clinical evidence of interactions when used concomitantly with other COPD medicinal products including short-acting P2-adrenergic bronchodilators, methylxanthines, and oral and inhaled steroids.

Drug-induced hypokalaemia

Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible initial hypokalaemic effect of P2-adrenergic agonists, therefore, caution is advised in their concomitant use (see section 4.4).

^¡-adrenergic blockers

P-adrenergic blockers (including eye drops) can weaken or inhibit the effect of P2-adrenergic agonists, such as formoterol. Concurrent use of either non-selective or selective P-adrenergic blockers should be avoided unless there are compelling reasons for their use. If P-adrenergic blockers are required (including eye drops), cardioselective P-adrenergic blockers are preferred, although they should also be administered with caution.

Other pharmacodynamic interactions

Bevespi Aerosphere should be administered with caution to patients being treated with medicinal products known to prolong the QTc interval (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of Bevespi Aerosphere in pregnant women.

Single-dose studies in humans found that very small amounts of glycopyrronium passed the placental barrier. In animal studies formoterol and glycopyrronium, individually, have caused adverse effects in reproduction studies at very high doses/systemic exposure levels (see section 5.3).

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

Breast-feeding

It is not known whether glycopyrronium or formoterol are excreted in human milk. Evidence of transfer of glycopyrronium and formoterol into maternal milk in rats has been reported.

Administration of Bevespi Aerosphere to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the infant (see section 5.3).

Fertility

Studies in rats have shown adverse effects on fertility only at dose levels higher than the maximum human exposure to formoterol (see section 5.3). Glycopyrronium did not cause any adverse effects on fertility in rats. It is unlikely that Bevespi Aerosphere administered at the recommended dose will affect fertility in humans.

4.7 Effects on ability to drive and use machines

Bevespi Aerosphere has no or negligible influence on the ability to drive and use machines. However dizziness and nausea are common side effects which should be taken into account when driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

The safety profile is characterised by anticholinergic and P2-adrenergic class effects related to the individual components of the combination. The most common adverse reactions reported in the clinical development program (comprised of 1,588 patients receiving Bevespi Aerosphere) were headache (1.9%), nausea (1.4%), muscle spasms (1.4%), and dizziness (1.3%).

Tabulated list of adverse reactions

The tabulated list of adverse reactions is based on the experience with Bevespi Aerosphere in clinical trials and experience with the individual components and related products.

The frequency of adverse reactions is defined using the following convention: 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).

Table 1Adverse reactions by frequency and system organ class (SOC)

System Organ Class	Preferred term	Frequency
Immune system disorders	Hypersensitivity reactions including rash and pruritus	Uncommon
Metabolism and nutrition disorders	Hyperglycaemia1	Uncommon
Psychiatric disorders	Anxiety	Common
	Agitation Restlessness Insomnia	Uncommon
Nervous system disorders	Headache1 Dizziness	Common
	Tremor1	Uncommon
Cardiac disorders	Tachycardia Palpitations Cardiac arrhythmias (atrial fibrillation, supraventricular tachycardia, and extrasystoles)	Uncommon
Gastrointestinal disorders	Dry mouth2, Nausea	Common
Musculoskeletal and connective tissue disorders	Muscle spasms1	Common
Renal and urinary disorders	Urinary tract infection	Common
	Urinary retention2	Uncommon
General disorders and	Chest pain	Common

administration site conditions

1 adverse reaction relates to formoterol

2 adverse reaction relates to glycopyrronium

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in.

4.9 Overdose

An overdose of Bevespi Aerosphere may lead to exaggerated anticholinergic and/or P2-adrenergic signs and symptoms, the most frequent of which include blurred vision, dry mouth, nausea, muscle spasm, tremor, headache, palpitations and systolic hypertension.

If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases: adrenergics in combination with anticholinergics, ATC code: R03AL07.

Mechanism of action

Bevespi Aerosphere contains two bronchodilators: glycopyrronium a long-acting muscarinic antagonist (also referred to as an anticholinergic) and formoterol a long-acting P2-adrenergic agonist with a rapid onset of action.

Glycopyrronium has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. Formoterol causes direct relaxation of airway smooth muscle as a consequence of the increase in cyclic AMP through activation of adenylate cyclase. The combination of these substances with different mechanisms of action results in additive efficacy compared to use with either component alone.

As a consequence of the differential density of muscarinic receptors and P2-adrenoceptors in the central and peripheral airways of the lung, muscarinic antagonists are more effective in relaxing central airways, and P2-adrenergic agonists are more effective in relaxing peripheral airways; relaxation of both central and peripheral airways with combination treatment may contribute to its beneficial effects on lung function.

Pharmacodynamic effects

In three Phase III, 24-week studies (PINNACLE 1, PINNACLE 2 and PINNACLE 4) Bevespi Aerosphere provided improvements over placebo in lung function (as measured by morning pre-dose trough forced expiratory volume in 1 second [FEV1]), with a demonstrated onset of action at 5 minutes following administration of the first dose on Day 1 (improvement over placebo by 187 mL, 186 mL and 179 mL in PINNACLE 1, PINNACLE 2 and PINNACLE 4, respectively [p <0.001]). The mean bronchodilator effect derived from serial FEV1 measurements at Day 1 and Week 12 from

PINNACLE 1 are shown in Figure 1. In PINNACLE 2, the results were similar to those observed in

PINNACLE 1.

Figure 1 – Mean Change from Baseline in FEV 1 over Time on Day 1 and at Week 12

DAY 1

WEEK 12

Cardiac electrophysiology

A placebo- and active-controlled (moxifloxacin) thorough QT study in 69 healthy subjects did not demonstrate a clinically relevant effect on the QT interval, using a threshold of 10 ms. The largest mean (90% upper confidence bound) differences from placebo in baseline- and individually corrected QT was 3.1 (4.7) ms for Bevespi Aerosphere (14.4 /10 micrograms) and 7.6 (9.2) ms for glycopyrronium/for­moterol with eight times the recommended dose of glycopyrronium and four times the recommended dose of formoterol.

Clinical efficacy

The clinical development program for Bevespi Aerosphere included three 24-week, randomised, double-blind, placebo-controlled, parallel-group pivotal Phase III studies in 5,433 patients with moderate to very severe COPD (PINNACLE 1, PINNACLE 2 and PINNACLE 4).

Effects on lung function

In studies PINNACLE 1, PINNACLE 2 and PINNACLE 4, Bevespi Aerosphere showed improvements in trough FEV1 over 24 weeks relative to placebo, glycopyrronium and formoterol (p<0.0001) [see Table 2]. There was no attenuation of the bronchodilator effect over time. Bevespi Aerosphere also showed improvements in peak FEV1 within 2 hours post-dose over 24 weeks relative to placebo, glycopyrronium and formoterol (p<0.0001) [see Table 2].

There were improvements in trough FEV1 irrespective of age, sex, degree of airflow limitation, baseline symptoms, smoking status, or inhaled corticosteroid use.

Symptomatic outcomes

Breathlessness:

In PINNACLE 1 and PINNACLE 2, Bevespi Aerosphere provided improvements in breathlessness as demonstrated by Self-administered Computerised Transitional Dyspnoea Index (SAC TDI) focal score over 24 weeks compared to placebo and glycopyrronium (see Table 2). Improvements compared to formoterol were observed in PINNACLE 2 (see Table 2). In PINNACLE 4, Bevespi Aerosphere provided improvements in breathlessness as demonstrated by TDI focal score over 24 weeks compared to placebo and glycopyrronium (see Table 2).

Health-related quality of life:

In PINNACLE 1, PINNACLE 2 and PINNACLE 4, Bevespi Aerosphere provided an improvement in disease-specific health-related quality of life, as indicated by a reduction in the St George’s Respi­ratory Questionnaire (SGRQ) total score over 24 weeks compared to placebo and glycopyrronium [see Table 2]. There were improvements compared to formoterol in PINNACLE 1 and PINNACLE 2.

Table 2 Lung function, symptomatic and health related quality of life outcomes over 24 weeks

Treatment comparisons with Bevespi Aersophere	Treatment difference (95% confidence intervals, p-value)
	Trough FEV1 (ml)a	Peak FEV1 (ml)	SAC-TDI / TDI Focal Score b	SGRQ total score	Daily rescue Ventolin (inhalations/day)c
PINNACLE 1
Bevespi Aerosphere (N=526) vs placebo (N=219)	158 (132, 183) p<0.0001	288 (259, 317) p<0.0001#	0.47 (0.21, 0.72) p=0.0003	–2.39 (-4.07, –0.71) p=0.0053#	–1.08 (-1.43, –0.73) p<0.0001#
Bevespi Aerosphere (N=526) vs Glycopyrronium (N=451)	60 (39, 80) p<0.0001	123 (100, 146) p<0.0001#	0.27 (0.07, 0.47) p=0.0086#	–1.90 (-3.24, 0.57) p=0.0052#	–0.26 (-0.53, 0.01) p=0.0619
Bevespi Aerosphere (N=526)	64 (44, 84)	81 (59, 104)	0.16 (-0.03, 0.36)	–0.75 (-2.08, 0.57)	–0.01 (-0.27, 0.26)

vs formoterol fumarate (N=449)	p<0.0001	p<0.0001#	p=0.1060	p=0.2640	p=0.9683
PINNACLE 2
Bevespi Aerosphere (N=510) vs placebo (N=223)	129 (103,155) p<0.0001	278 (249, 308) p<0.0001	0.33 (0.11,0.56) p=0.0041	–1.66 (-3.34, 0.02) p=0.0534	–1.04 (-1.37, –0.72) p<0.0001
Bevespi Aerosphere (N=510) vs Glycopyrronium (N=439)	55 (34, 76) p<0.0001	129 (106,153) p<0.0001	0.21 (0.03, 0.40) p=0.0199	–1.28 (-2.62, 0.06) p=0.0605	–0.57 (-0.83, –0.31) p<0.0001
Bevespi Aerosphere (N=510) vs formoterol fumarate (N=437)	57 (36, 78) p<0.0001	76 (52, 99) p<0.0001	0.28 (0.10, 0.46) p=0.0028	–1.22 (-2.56, 0.13) p=0.0760	–0.29 (-0.55, –0.03) p=0.0274#
PINNACLE 4
Bevespi Aerosphere (N=551) vs placebo (N=235)	155 (129, 180) p<0.0001	293 (265, 321) p<0.0001	0.80 (0.47, 1.13) p<0.0001	–3.50 (-5.18, –1.82) p<0.0001	–0.98 (-1.47, –0.49) p<0.0001
Bevespi Aerosphere (N=551) vs glycopyrronium (N=474)	55 (35, 76) p<0.0001	141 (119, 163) p<0.0001	0.33 (0.07, 0.59) p=0.0125	–1.62 (-2.94, –0.30) p=0.0165	–0.77 (-1.16, –0.38) p<0.0001
Bevespi Aerosphere (N=551) vs formoterol fumarate (N=480)	72 (52, 92) p<0.0001	97 (75, 119) p<0.0001	0.15 (-0.11, 0.41) p=0.2530	–0.27 (-1.59, 1.05) p=0.6908	–0.41 (-0.80, –0.03) p=0.0345#

N number in Intent to Treat population

a primary endpoint in all studies

b PINNACLE 1 and PINNACLE 2 used SAC-TDI. PINNACLE 4 used TDI. SAC-TDI was a primary endpoint in PINNACLE 1 and PINNACLE 2 only

c From the Rescue Ventolin User Population in PINNACLE 4

# A hierarchical statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.

COPD exacerbations:

The individual studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations and patients were withdrawn from the studies if a severe exacerbation or more than 2 moderate exacerbations occurred.

Paediatric population

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

5.2 Pharmacokinetic properties

Following inhalation of the glycopyrronium and formoterol combination, the pharmacokinetics of each component was similar to those observed when each active substance was administered separately. For pharmacokinetic purposes each component can therefore be considered separately.

Effect of a spacer

The use of Bevespi Aerosphere with the Aerochamber Plus Flow-Vu spacer in COPD patients increased the total systemic exposure to glycopyrronium (as measured by AUC0–12) by 16% while formoterol exposure was unchanged.

Absorption

Following inhaled administration of Bevespi Aerosphere in subjects with COPD, glycopyrronium Cmax occurred at approximately 5 minutes, and formoterol Cmax occurred within 20 to 60 minutes. Steady state is achieved within 2–3 days of repeated dosing of Bevespi Aerosphere, and the extent of exposure is approximately 2.3 times and 1.5 times higher than after the first dose, for glycopyrronium and formoterol, respectively.

A lung deposition study with Bevespi Aerosphere conducted in healthy volunteers demonstrated that on average 38% of the nominal dose is deposited into the lung. Both central and peripheral deposition were observed.

Distribution

Glycopyrronium

The estimated glycopyrronium Vc/F (volume of the central compartment), and Vp1/F (volume of the peripheral compartment) are 741 L, and 2990 L, respectively, via population pharmacokinetic analysis. Over the concentration range of 2–500 nmol/L, plasma protein binding of glycopyrronium ranged from 43% to 54%.

Formoterol

The estimated formoterol Vc/F (volume of the central compartment), and Vp1/F (volume of the peripheral compartment) are 1030 L, and 647 L, respectively, via population pharmacokinetic analysis. Over the concentration range of 10–500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%.

Biotransformation

Glycopyrronium

Based on literature, and an in-vitro human hepatocyte study, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

In-vitro studies indicate the glycopyrronium does not inhibit any subtype of cytochrome P450 and that there is no induction of CYP1A2, 2B6, or 3A4.

Formoterol

The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation.

In-vitro studies indicate that formoterol does not inhibit the CYP450 enzymes at therapeutically relevant concentrations.

Elimination

After IV administration of a 0.2 mg dose of radiolabelled glycopyrronium, 85% of the dose was recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile. The terminal elimination half-life of glycopyrronium following oral inhalation derived via population pharmacokinetics analysis was 15 hours.

The excretion of formoterol was studied in six healthy subjects following simultaneous administration of radiolabelled formoterol via the oral and IV routes. In that study, 62% of the radiolabelled formoterol was excreted in the urine while 24% was eliminated in the faeces. The terminal elimination half-life of formoterol following oral inhalation derived via population pharmacokinetics analysis was 13 hours.

Linearity/non-linearity

Linear pharmacokinetics were observed for glycopyrronium (dose range: 14.4 to 115.2 mcg) and formoterol (dose range: 2.4 to 19.2 mcg) after oral inhalation.

Special patient populations

Elderly patients

Based on available data, no adjustment of the dosage of Bevespi Aerosphere in geriatric patients is necessary.

Renal impairment

Studies evaluating the effect of renal impairment on the pharmacokinetics of glycopyrronium and formoterol have not been conducted. The effect of renal impairment on the exposure to glycopyrronium and formoterol for up to 12 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 30–196 mL/min, representing a range of moderate to no renal impairment. The systemic exposure (AUC0–12) in subjects with COPD with moderate-severe renal impairment (eGFR of 30–45 mL/min) is approximately 30% higher for glycopyrronium compared to subjects with COPD with normal renal function (eGFR of >90 mL/min). Subjects with COPD with both low body weight and moderate-severe impaired renal function may have an approximate doubling of systemic exposure to glycopyrronium. Renal function was found not to affect exposure to formoterol.

Hepatic impairment

No pharmacokinetic studies have been performed with Bevespi Aerosphere in patients with hepatic impairment. However, because formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment. Glycopyrronium is primarily cleared from the systemic circulation by renal excretion and hepatic impairment would therefore not be expected to lead to unsafe systemic exposure.

Other special populations

A population pharmacokinetic analysis of glycopyrronium was performed based on data collected in a total of 311 subjects with COPD. The pharmacokinetics of glycopyrronium was best described by a two-compartment disposition model with first-order absorption and linear elimination. The typical clearance (CL/F) of glycopyrronium was 124 L/h.

A population pharmacokinetic analysis of formoterol was performed based on data collected in a total of 437 subjects with COPD. The pharmacokinetics of formoterol was best described by a two-compartment disposition model with a first-order rate constant of absorption and linear elimination. The typical clearance (CL/F) of formoterol was 99 L/h.

Dose adjustments are not necessary based on the effect of age, sex and weight on the pharmacokinetic parameters of glycopyrronium and formoterol.

There were no major differences in total systemic exposure (AUC) for both compounds between healthy Japanese and Western subjects. Insufficient pharmacokinetic data are available to compare exposure for other ethnicities or races.

5.3 Preclinical safety data

Non-clinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

The toxicity observed in studies with the combination of glycopyrronium and formoterol in dogs were associated with the pharmacological actions of formoterol, including effects mainly on the cardiovascular system, consisting of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These are known pharmacological manifestations seen after administration of high doses of p-adrenoceptor agonists. No significant effects attributable to glycopyrronium were seen.

Animal reproduction studies with formoterol have shown a slightly reduced fertility in male rats at high systemic exposure and implantation losses, as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results have little relevance to man. A slight increase in the incidence of uterine leiomyomas has been observed in rats and mice treated with formoterol; an effect which is considered to be a class-effect in rodents after long-term exposure to high doses of P2-adrenoreceptor agonists.

Animal reproduction studies with glycopyrronium have shown reduced rat and rabbit fetal weights, and low body weight gain of rat offspring before weaning was observed at considerably higher systemic exposures than those reached during clinical use. No evidence of carcinogenicity was seen in 2-year studies in rats and mice.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Norflurane

1,2-distearoyl-sn-glycero-3-phosphocholine Calcium chloride

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

To be used within 3 months of opening the pouch.

6.4 Special precautions for storage

Do not store above 30oC.

Do not expose to temperatures higher than 50°C.

Do not pierce the pressurised container.

6.5 Nature and contents of container

The inhaler is a pressurised metered dose inhaler, comprising an aluminium pressurised container with an attached dose indicator, supplied with a white plastic actuator body and mouthpiece with an orange dust cap. Each inhaler is individually packaged in a foil laminate pouch containing a desiccant sachet and packed into a carton.

Carton containing 1 inhaler with 120 actuations.

Multipack containing 3 inhalers each with 120 actuations.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. The pressurised container should not be broken, punctured or burnt, even when apparently empty.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Sodertalje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1339/001

EU/1/18/1339/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 December 2018