Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics
ATC code: R03AK14
This medicinal product is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), and mometasone furoate, an inhaled synthetic corticosteroid (ICS).
The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to increased cyclic-3', 5'-adenosine monophosphate (cyclic AMP) levels, which cause relaxation of bronchial smooth muscle.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the human heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors.
Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. In vitro, mometasone furoate inhibits the release of leukotrienes from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of leukotriene production and of the production of the Th2 cytokines IL-4 and IL-5 from human CD4+ T-cells.
The pharmacodynamic response profile of this medicinal product is characterised by rapid onset of action within 5 minutes after dosing and sustained effect over the 24-hour dosing interval, as evidenced by improvements in trough forced expiratory volume in the first second (FEV1) improvements versus comparators 24 hours after dosing.
No tachyphylaxis to the lung function benefits of this medicinal product was observed over time.
The effect of this medicinal product on the QTc interval has not been evaluated in a thorough QT (TQT) study. For mometasone furoate, no QTc-prolonging properties are known.
Two phase III randomised, double-blind studies (PALLADIUM and QUARTZ) of different durations evaluated the safety and efficacy of Atectura Breezhaler in adult and adolescent patients with persistent asthma.
The PALLADIUM study was a 52-week pivotal study evaluating Atectura Breezhaler 125 mcg/127.5 mcg once daily (N=439) and 125 mcg/260 mcg once daily (N=445) compared to mometasone furoate 400 mcg once daily (N=444) and 800 mcg per day (given as 400 mcg twice daily) (N=442), respectively. A third active control arm included subjects treated with salmeterol/fluticasone propionate 50 mcg/500 mcg twice daily (N=446). All subjects were required to have symptomatic asthma (ACQ-7 score ≥1.5) and were on asthma maintenance therapy using an inhaled synthetic corticosteroid (ICS) with or without LABA for at least 3 months prior to study entry. At screening, 31% of patients had history of exacerbation in the previous year. At study entry, the most common asthma medications reported were medium dose of ICS (20%), high dose of ICS (7%) or low dose of ICS in combination with a LABA (69%).
The primary objective of the study was to demonstrate superiority of either Atectura Breezhaler 125 mcg/127.5 mcg once daily over mometasone furoate 400 mcg once daily or Atectura Breezhaler 125 mcg/260 mcg once daily over mometasone furoate 400 mcg twice daily in terms of trough FEV1 at week 26.
At week 26, Atectura Breezhaler 125 mcg/127.5 mcg and 125 mcg/260 mcg once daily both demonstrated statistically significant improvements in trough FEV1 and Asthma Control Questionnaire (ACQ-7) score compared to mometasone furoate 400 mcg once or twice daily, respectively (see Table 2). Findings at week 52 were consistent with week 26.
Atectura Breezhaler 125 mcg/127.5 mcg and 125 mcg/260 mcg once daily both demonstrated a clinically meaningful reduction in the annual rate of moderate or severe exacerbations (secondary endpoint), compared to mometasone furoate 400 mcg once and twice daily (see Table 2).
Results for the most clinically relevant endpoints are described in Table 2.
Table 2. Results of primary and secondary endpoints in PALLADIUM study at weeks 26 and 52:
| Endpoint | Time point/ Duration | Atectura Breezhaler1 vs MF2 | Atectura Breezhaler1 vs SAL/FP3 | |
|---|---|---|---|---|
| Medium dose vs medium dose | High dose vs high dose | High dose vs high dose | ||
| Lung function | ||||
| Trough FEV14 | ||||
| Treatment difference P value (95% CI) | Week 26 (primary endpoint) | 211 ml <0.001 (167, 255) | 132 ml <0.001 (88, 176) | 36 ml 0.101 (-7, 80) |
| Week 52 | 209 ml <0.001 (163, 255) | 136 ml <0.001 (90, 183) | 48 ml 0.040 (2, 94) | |
| Mean morning peak expiratory flow (PEF)* | ||||
| Treatment difference (95% CI) | Week 52 | 30.2 l/min (24.2, 36.3) | 28.7 l/min (22.7, 34.8) | 13.8 l/min (7.7, 19.8) |
| Mean evening peak expiratory flow (PEF)* | ||||
| Treatment difference (95% CI) | Week 52 | 29.1 l/min (23.3, 34.8) | 23.7 l/min (18.0, 29.5) | 9.1 l/min (3.3, 14.9) |
| Symptoms | ||||
| ACQ-7 | ||||
| Treatment difference P value (95% CI) | Week 26 (key secondary endpoint) | -0.248 <0.001 (-0.334, -0.162) | -0.171 <0.001 (-0.257, -0.086) | -0.054 0.214 (-0.140, 0.031) |
| Week 52 | -0.266 (-0.354, -0.177) | -0.141 (-0.229, -0.053) | 0.010 (-0.078, 0.098) | |
| ACQ responders (percentage of patients achieving minimal clinical important difference (MCID) from baseline with ACQ ≥0.5) | ||||
| Percentage | Week 26 | 76% vs 67% | 76% vs 72% | 76% vs 76% |
| Odds ratio (95% CI) | Week 26 | 1.73 (1.26, 2.37) | 1.31 (0.95, 1.81) | 1.06 (0.76, 1.46) |
| Percentage | Week 52 | 82% vs 69% | 78% vs 74% | 78% vs 77% |
| Odds ratio (95% CI) | Week 52 | 2.24 (1.58, 3.17) | 1.34 (0.96, 1.87) | 1.05 (0.75, 1.49) |
| Percentage of rescue medication free days* | ||||
| Treatment difference (95% CI) | Week 52 | 8.6 (4.7, 12.6) | 9.6 (5.7, 13.6) | 4.3 (0.3, 8.3) |
| Percentage of days with no symptoms* | ||||
| Treatment difference (95% CI) | Week 52 | 9.1 (4.6, 13.6) | 5.8 (1.3, 10.2) | 3.4 (-1.1, 7.9) |
| Annualised rate of asthma exacerbations** | ||||
| Moderate or severe exacerbations | ||||
| AR | Week 52 | 0.27 vs 0.56 | 0.25 vs 0.39 | 0.25 vs 0.27 |
| RR (95% CI) | Week 52 | 0.47 (0.35, 0.64) | 0.65 (0.48, 0.89) | 0.93 (0.67, 1.29) |
| Severe exacerbations | ||||
| AR | Week 52 | 0.13 vs 0.29 | 0.13 vs 0.18 | 0.13 vs 0.14 |
| RR (95% CI) | Week 52 | 0.46 (0.31, 0.67) | 0.71 (0.47, 1.08) | 0.89 (0.58, 1.37) |
* Mean value for the treatment duration
** RR <1.00 favours indacaterol/mometasone furoate.
1 Atectura Breezhaler medium dose: 125 mcg/127.5 mcg od; high dose: 125 mcg/260 mcg od.
2 MF: mometasone furoate medium dose: 400 mcg od; high dose: 400 mcg bid (content doses). Mometasone furoate 127.5 mcg od and 260 mcg od in Atectura Breezhaler are comparable to mometasone furoate 400 mcg od and 800 mcg per day (given as 400 mcg bid).
3 SAL/FP: salmeterol/fluticasone propionate high dose: 50 mcg/500 mcg bid (content dose).
4 Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours 45 min after the evening dose.
Primary endpoint (trough FEV1 at week 26) and key secondary endpoint (ACQ-7 score at week 26) were part of confirmatory testing strategy and thus controlled for multiplicity. All other endpoints were not part of confirmatory testing strategy.
RR = rate ratio, AR = annualised rate
od = once daily, bid = twice daily
Atectura Breezhaler 125 mcg/260 mcg once daily was also studied as an active comparator in another phase III study (IRIDIUM) in which all subjects had a history of asthma exacerbation requiring systemic corticosteroids in the past year. A pre-specified pooled analysis across the IRIDIUM and PALLADIUM studies was conducted to compare Atectura Breezhaler 125 mcg/260 mcg once daily to salmeterol/fluticasone 50 mcg/500 mcg twice daily for the endpoints of trough FEV1 and ACQ-7 at week 26 and annualised rate of exacerbations. The pooled analysis demonstrated that Atectura Breezhaler improved trough FEV1 by 43 ml (95% CI: 17, 69) and ACQ-7 score by -0.091 (95% CI: -0.153, -0.030) at week 26 and reduced the annualised rate of moderate or severe asthma exacerbations by 22% (RR: 0.78; 95% CI: 0.66, 0.93) and of severe exacerbations by 26% (RR: 0.74; 95% CI: 0.61, 0.91) versus salmeterol/fluticasone.
The QUARTZ study was a 12-week study evaluating Atectura Breezhaler 125 mcg/62.5 mcg once daily (N=398) compared to mometasone furoate 200 mcg once daily (N=404). All subjects were required to be symptomatic and on asthma maintenance therapy using a low-dose ICS (with or without LABA) for at least 1 month prior to study entry. At study entry, the most common asthma medications reported were low-dose ICS (43%) and LABA/low-dose ICS (56%). The primary endpoint of the study was to demonstrate superiority of Atectura Breezhaler 125 mcg/62.5 mcg once daily over mometasone furoate 200 mcg once daily in terms of trough FEV1 at week 12.
Atectura Breezhaler 125 mcg/62.5 mcg once daily demonstrated a statistically significant improvement in baseline trough FEV1 at week 12 and Asthma Control Questionnaire (ACQ-7) score compared to mometasone furoate 200 mcg once daily.
Results for the most clinically relevant endpoints are described in Table 3.
Table 3. Results of primary and secondary endpoints in QUARTZ study at week 12:
| Endpoints | Atectura Breezhaler low dose* vs MF low dose** |
|---|---|
| Lung function | |
| Trough FEV1 (primary endpoint)*** | |
| Treatment difference P value (95% CI) | 182 ml <0.001 (148, 217) |
| Mean morning peak expiratory flow (PEF) | |
| Treatment difference (95% CI) | 27.2 l/min (22.1, 32.4) |
| Evening peak expiratory flow (PEF) | |
| Treatment difference (95% CI) | 26.1 l/min (21.0, 31.2) |
| Symptoms | |
| ACQ-7 (key secondary endpoint) | |
| Treatment difference P value (95% CI) | -0.218 <0.001 (-0.293, -0.143) |
| Percentage of patients achieving MCID from baseline with ACQ ≥0.5 | |
| Percentage Odds ratio (95% CI) | 75% vs 65% 1.69 (1.23, 2.33) |
| Percentage of rescue medication free days | |
| Treatment difference (95% CI) | 8.1 (4.3, 11.8) |
| Percentage of days with no symptoms | |
| Treatment difference (95% CI) | 2.7 (-1.0, 6.4) |
* Atectura Breezhaler low dose: 125/62.5 mcg od.
** MF: mometasone furoate low dose: 200 mcg od (content dose).
Mometasone furoate 62.5 mcg in Atectura Breezhaler od is comparable to mometasone furoate 200 mcg od (content dose).
*** Trough FEV1: the mean of the two FEV1 values measured at 23 hours 15 min and 23 hours 45 min after the evening dose.
od = once daily, bid = twice daily
In the PALLADIUM study, which included 106 adolescents (12-17 years old), the improvements in trough FEV1 at week 26 were 0.173 litres (95% CI: -0.021, 0.368) for Atectura Breezhaler 125 mcg/260 mcg once daily vs mometasone furoate 800 mcg (i.e. high doses) and 0.397 litres (95% CI: 0.195, 0.599) for Atectura Breezhaler 125 mcg/127.5 mcg once daily vs mometasone furoate 400 mcg once daily (i.e. medium doses).
In the QUARTZ study, which included 63 adolescents (12-17 years old), the Least Square means treatment difference for trough FEV1 at day 85 (week 12) was 0.251 litres (95% CI: 0.130, 0.371).
For the adolescent subgroups, improvements in lung function, symptoms and exacerbation reductions were consistent with the overall population.
The European Medicines Agency has deferred the obligation to submit the results of studies with indacaterol/mometasone furoate in one or more subsets of the paediatric population in asthma (see section 4.2 for information on paediatric use).
Following inhalation of Atectura Breezhaler, the median time to reach peak plasma concentrations of indacaterol and mometasone furoate was approximately 15 minutes and 1 hour, respectively.
Based on the in vitro performance data, the dose of each of the monotherapy components delivered to the lung is expected to be similar for the indacaterol/mometasone furoate combination and the monotherapy products. Steady-state plasma exposure to indacaterol and mometasone furoate after inhalation of the combination was similar to the systemic exposure after inhalation of indacaterol maleate or mometasone furoate as monotherapy products.
Following inhalation of the combination, the absolute bioavailability was estimated to be about 45% for indacaterol and less than 10% for mometasone furoate.
Indacaterol concentrations increased with repeated once-daily administration. Steady state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 60 and 480 mcg (delivered dose). Systemic exposure results from a composite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal absorption.
Mometasone furoate concentrations increased with repeated once-daily administration via the Breezhaler inhaler. Steady state was achieved after 12 days. The mean accumulation ratio of mometasone furoate, i.e. AUC over the 24-h dosing interval on day 14 compared to day 1, was in the range of 1.61 to 1.71 for once-daily inhaled doses between 62.5 and 260 mcg as part of the indacaterol/mometasone furoate combination.
Following oral administration of mometasone furoate, the absolute oral systemic bioavailability of mometasone furoate was estimated to be very low (<2%).
After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 to 2,557 litres, indicating an extensive distribution. The in vitro human serum and plasma protein binding were 94.1 to 95.3% and 95.1 to 96.2%, respectively.
After intravenous bolus administration, the Vd is 332 litres. The in vitro protein binding for mometasone furoate is high, 98% to 99% in concentration range of 5 to 500 ng/ml.
After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, an N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolised indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6 and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low-affinity substrate for the efflux pump P-gp.
In vitro the UGT1A1 isoform is a major contributor to the metabolic clearance of indacaterol. However, as shown in a clinical study in populations with different UGT1A1 genotypes, systemic exposure to indacaterol is not significantly affected by the UGT1A1 genotype.
The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes mometasone furoate is metabolised by CYP3A4.
In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 litres/hour. Compared with the serum clearance of indacaterol of 18.8 to 23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study in which indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40 to 52 hours which is consistent with the observed time to steady state of approximately 12 to 14 days.
After intravenous bolus administration, mometasone furoate has a terminal elimination T½ of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the faeces (74%) and to a lesser extent in the urine (8%).
Concomitant administration of orally inhaled indacaterol and mometasone furoate under steady-state conditions did not affect the pharmacokinetics of either active substance.
Systemic exposure of mometasone furoate increased in a dose proportional manner following single and multiple doses of Atectura Breezhaler 125 mcg/62.5 mcg and 125 mcg/260 mcg in healthy subjects. A less than proportional increase in steady-state systemic exposure was noted in patients with asthma over the dose range of 125 mcg/62.5 mcg to 125 mcg/260 mcg. Dose proportionality assessments were not performed for indacaterol as only one dose was used across all dose strengths.
Atectura Breezhaler may be used in adolescent patients (12 years of age and older) at the same posology as in adults.
A population pharmacokinetic analysis in patients with asthma after inhalation of indacaterol/mometasone furoate indicated no significant effect of age, gender, body weight, smoking status, baseline estimated glomerular filtration rate (eGFR) and FEV1 at baseline on the systemic exposure to indacaterol and mometasone furoate.
Due to the very low contribution of the urinary pathway to total body elimination of indacaterol and mometasone furoate, the effects of renal impairment on their systemic exposure have not been investigated (see section 4.2).
The effect of indacaterol/mometasone furoate has not been evaluated in subjects with hepatic impairment. However, studies have been conducted with the monotherapy components (see section 4.2).
Indacaterol: Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. No data are available for subjects with severe hepatic impairment.
Mometasone furoate: A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/ml). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels (assay lower limit of quantification was 50 pcg/ml) were few.
There were no major differences in total systemic exposure (AUC) for both compounds between Japanese and Caucasian subjects. Insufficient pharmacokinetic data are available for other ethnicities or races.
The non-clinical assessments of each monotherapy and of the combination product are presented below.
The findings during the 13-week inhalation toxicity studies were predominantly attributable to the mometasone furoate component and were typical pharmacological effects of glucocorticoids. Increased heart rates associated with indacaterol were apparent in dogs after administration of indacaterol/mometasone furoate or indacaterol alone.
Effects on the cardiovascular system attributable to the beta2-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritation of the nasal cavity and larynx was seen in rodents.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential.
Carcinogenicity was assessed in a two-year rat study and a six-month transgenic mouse study. Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistent with similar findings reported for other beta2-adrenergic agonists. No evidence of carcinogenicity was seen in mice.
All these findings occurred at exposures sufficiently in excess of those anticipated in humans.
Following subcutaneous administration in a rabbit study, adverse effects of indacaterol with respect to pregnancy and embryonal/foetal development could only be demonstrated at doses more than 500-fold those achieved following daily inhalation of 150 mcg in humans (based on AUC0-24h).
Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease in the number of pregnant F1 offspring was observed in the peri- and post-natal developmental rat study at an exposure 14-fold higher than in humans treated with indacaterol. Indacaterol was not embryotoxic or teratogenic in rats or rabbits.
All observed effects are typical of the glucocorticoid class of compounds and are related to exaggerated pharmacological effects of glucocorticoids. Mometasone furoate showed no genotoxic activity in a standard battery of in vitro and in vivo tests.
In carcinogenicity studies in mice and rats, inhaled mometasone furoate demonstrated no statistically significant increase in the incidence of tumours.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice. In studies of reproductive function, subcutaneous mometasone furoate at 15 mcg/kg prolonged gestation and difficult labour occurred, with a reduction in offspring survival and body weight.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
