Atectura Jun2020.SINv1 App020721
Atectura Jun2020.SINv1 App020721
Atectura Jun2020.SINv1 App020721
Active substance(s)
Each capsule of Atectura Breezhaler 150/80 micrograms, contains 173 micrograms of indacaterol
acetate equivalent to 150 micrograms of indacaterol and 80 micrograms of mometasone furoate.
Each capsule of Atectura Breezhaler 150/160 micrograms, contains 173 micrograms of indacaterol
acetate equivalent to 150 micrograms of indacaterol and 160 micrograms of mometasone furoate.
Each capsule of Atectura Breezhaler 150/320 micrograms, contains 173 micrograms of indacaterol
acetate equivalent to 150 micrograms of indacaterol and 320 micrograms of mometasone furoate
The delivered dose of Atectura Breezhaler 150/80 micrograms (the dose that leaves the mouthpiece
of the inhaler) is equivalent to 125 micrograms indacaterol, and 62.5 micrograms mometasone furoate.
The delivered dose of Atectura Breezhaler 150/160 micrograms (the dose that leaves the mouthpiece
of the inhaler) is equivalent to 125 micrograms indacaterol, and 127.5 micrograms mometasone
furoate.
The delivered dose of Atectura Breezhaler 150/320 micrograms (the dose that leaves the mouthpiece
of the inhaler) is equivalent to 125 micrograms indacaterol, and 260 micrograms mometasone furoate.
2 Indications
Atectura Breezhaler is indicated as a once-daily maintenance treatment of asthma in adults and
adolescents 12 years of age and older where use of a combination of long-acting beta2-agonist and
inhaled corticosteroid is appropriate.
Special populations
Renal impairment
No dose adjustment is required in patients with renal impairment.
Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are
available for Atectura Breezhaler in subjects with severe hepatic impairment, therefore Atectura
Breezhaler should be used in these patients only if the expected benefit outweighs the potential risk
(see section 11 Clinical pharmacology).
4 Contraindications
Atectura Breezhaler is contraindicated in patients with hypersensitivity to any of the active substances
or excipients.
Table 6-1 Estimated cumulative incidence (%) of adverse drug reactions in study
PALLADIUM at 52 weeks
Adverse drug Atectura Breezhaler Mometasone furoate Frequency
reactions 150/160 150/320 400 400 category
micrograms micrograms micrograms micrograms [based on
once daily once daily once daily twice daily the higher
Medium dose High dose Medium dose High dose frequency
between
Rate (%) Rate (%) Rate (%) Rate (%)
the two
[number of [number of [number of [number of
arms]
events] events] events] events]
(95% CI) (95% CI) (95% CI) (95% CI)
N=437 N=443 N=443 N=440
Infections and infestations
0.48 [2] 0.25 [1] 1.25 [5] 0.71 [5] Uncommon
Candidiasis*1
(0.10, 1.63) (0.02, 1.34) (0.48, 2.75) (0.20, 1.94)
Immune system disorders
1.20 [6] 1.88 [8] 2.26 [10] 0 [0] Common
Hypersensitivity*2
(0.46, 2.64) (0.89, 3.53) (1.12, 4.10)
0.47 [2] 0 [0] 0.48 [2] 0.48 [2] Uncommon
Angioedema*3 (0.10, 1.58) (0.10, 1.62) (0.10, 1.62)
7 Interactions
Interactions linked to Atectura Breezhaler
No specific interaction studies were conducted with Atectura Breezhaler. Information on the potential
for interactions is based on the potential for each of the monotherapy components.
Clinically significant pharmacokinetic drug interactions mediated by Atectura Breezhaler at clinical
doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.
Concomitant administration of orally inhaled indacaterol and mometasone furoate under steady-state
conditions did not affect the pharmacokinetics of either active substances.
Animal data
The combination of indacaterol and mometasone furoate has not been studied in pregnant animals.
Indacaterol
Following subcutaneous administration in a rabbit study, adverse effects of indacaterol with respect
to pregnancy and embryonal/fetal development could only be demonstrated at doses more than 500-
fold than achieved following the daily inhalation of 150 micrograms 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.
Mometasone furoate
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
fetal growth (lower fetal 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 micrograms/kg prolonged gestation and difficult labor occurred with a reduction in
offspring survival and body weight.
8.2 Lactation
Risk summary
There is no information available on the presence of indacaterol or mometasone furoate in human
milk, on the effects on a breastfed child, or on the effects on milk production. Other inhaled
corticosteroids, similar to mometasone furoate, are transferred into human milk. Indacaterol
(including its metabolites) and mometasone furoate have been detected in the milk of lactating rats.
The developmental and health benefits of breastfeeding should be considered along with the mother’s
clinical need for Atectura Breezhaler and any potential adverse effects on the breast-fed child from
Atectura Breezhaler or from the underlying maternal condition
10 Clinical pharmacology
Pharmacotherapeutic group, ATC
Pharmacotherapeutic group: Long-acting inhaled therapy (beta-agonists and glucocorticosteroids)
Pharmacodynamics (PD)
The primary pharmacodynamics of Atectura Breezhaler in obstructive airway disease reflects the
complementary mechanisms of action of the individual components of Atectura Breezhaler.
Clinical data confirmed the hypothesis that bronchodilation with indacaterol coupled with the anti-
inflammatory action of mometasone furoate results in improved lung function and asthma control.
The Atectura Breezhaler clinical program showed consistently superior lung function when Atectura
Breezhaler 150/80, 150/160, 150/320 micrograms once daily were compared to mometasone furoate
(MF) 200, 400 micrograms once daily and 400 micrograms twice daily, and placebo.
The pharmacodynamic response profile of Atectura Breezhaler is characterized by rapid onset of
action within 5 minutes after dosing (see section 12 Clinical studies) and sustained effect over the 24
h dosing interval as evidenced by improvements in trough forced expiratory volume in the first
second (FEV1) versus comparators, 24 hours after dosing.
No tachyphylaxis to the lung function benefits of Atectura Breezhaler were observed over time.
Pharmacokinetics (PK)
Absorption
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 Atectura Breezhaler and the monotherapy products. Steady-
state plasma exposure to indacaterol and mometasone furoate after Atectura Breezhaler inhalation
was similar to the systemic exposure after inhalation of indacaterol maleate or mometasone furoate
as monotherapy products.
Following inhalation of Atectura Breezhaler, the absolute bioavailability was estimated to be about
45% for indacaterol and less than 10% for mometasone furoate.
Indacaterol
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-
hour 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 75 and 600 micrograms. 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
Mometasone furoate concentrations increased with repeated once-daily administration via the
Breezhaler device. Steady state was achieved after 12 days. The mean accumulation ratio of
Distribution
Indacaterol
After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 to 2,557L
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.
Mometasone furoate
After intravenous bolus administration, the Vd is 332L. The in vitro protein binding for mometasone
furoate is high, 98 % to 99 % in concentration range of 5 to 500 ng/ml.
Biotransformation/metabolism
Indacaterol
After oral administration of radiolabelled indacaterol in a human absorption, distribution, metabolism,
excretion (ADME) 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 metabolized
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.
Mometasone furoate
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 metabolized by
CYP3A4.
Elimination
Indacaterol
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 L/h. When compared with the serum clearance of indacaterol of 18.8 to 23.3
L/h, 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 where indacaterol was given orally, the fecal route of excretion was
dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged
Linearity/non-linearity
Systemic exposure of mometasone furoate increased in a dose proportional manner following single
and multiple doses of Atectura Breezhaler 150/80 and 150/320 micrograms in healthy subjects. A
less than proportional increase in steady state systemic exposure was noted in patients with asthma
over the dose range of 150/80 to 150/320 micrograms. Dose proportionality assessments were not
performed for indacaterol as only one dose was used across all dose strengths of Atectura
Breezhaler.
Special populations
A population PK analysis in patients with asthma after inhalation of Atectura Breezhaler 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.
Race/Ethnicity
There were no major differences in total systemic exposure (AUC) for both compounds between
Japanese and Caucasian subjects. Insufficient pharmacokinetic data is available for other ethnicities
or races.
Renal impairment
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.
Hepatic impairment
The effect of indacaterol/mometasone furoate has not been evaluated in subjects with hepatic
impairment. However, studies have been conducted with the mono-components.
Indacaterol: Patients with mild or 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.
11 Clinical studies
Two phase III randomized, double-blind studies (PALLADIUM and QUARTZ) of different
durations evaluated the safety and efficacy of Atectura Breezhaler in adults and adolescent patients
with asthma.
Study PALLADIUM was a 52-week pivotal study evaluating Atectura Breezhaler 150/160
micrograms once daily (N=439) and 150/320 micrograms once-daily (N=445) via Breezhaler over
mometasone furoate (MF) 400 micrograms once daily (N=444) and 800 micrograms per day given
as 400 micrograms twice daily (N=442), respectively. A third active control arm included subjects
treated with salmeterol xinafoate /fluticasone propionate (SAL/FP) 50/500 micrograms twice daily
(N=446). All subjects were required to be asthma symptomatic and on asthma maintenance therapy
using an inhaled corticosteroid (ICS) with or without LABA for at least 3 months prior to study entry.
At screening, 30% of patients had a history of exacerbation in the previous year. At study entry, the
most common asthma medications reported were medium and high dose of ICS (27%) or LABA and
low dose of ICS (69%).
The primary objective of the study was to demonstrate superiority of either Atectura Breezhaler
150/160 micrograms once daily to MF 400 micrograms once daily or Atectura Breezhaler 150/320
micrograms once daily to MF 400 micrograms twice daily in terms of trough FEV1 at week 26.
Mometasone furoate (MF) 160 (medium dose) and 320 (high dose) micrograms in Atectura
Breezhaler once daily are comparable to MF 400 micrograms once daily (medium dose) and 800
micrograms (given as 400 micrograms twice daily, high dose) using multi-dose dry powder inhaler,
respectively.
Atectura Breezhaler 150/160 and 150/320 micrograms once daily both demonstrated statistically
significant improvements in trough FEV1 at week 26 and Asthma Control Questionnaire (ACQ-7)
score compared to MF 400 micrograms once or twice daily, respectively (see Table 12-1). A greater
percentage of subjects were ACQ responders (defined as achieving minimal clinical important
difference (MCID) from baseline with ACQ ≥ 0.5) for both doses of Atectura Breezhaler compared
to MF 400 micrograms once or twice daily, respectively (see Table 12-1). Findings at week 52 were
consistent with week 26.
Atectura Breezhaler 150/160 and 150/320 micrograms once daily both demonstrated a clinically
meaningful reduction in the annual rate of moderate or severe exacerbations, 53% and 35%
respectively, compared to MF 400 micrograms once and twice daily (see Table 12-3).
For information on other endpoints see Table 12-1 and 12-3.
Lung function and symptoms
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 Week 26 1.73 1.31 1.06
P value <0.001 0.094 0.746
(95% CI) (1.26, 2.37) (0.95, 1.81) (0.76, 1.46)
Percentage Week 52 82% vs 69% 78% vs 74% 78% vs 77%
Odds Ratio Week 52 2.24 1.34 1.05
P value <0.001 0.088 0.771
(95% CI) (1.58, 3.17) (0.96, 1.87) (0.75, 1.49)
Mean number of daily puffs of rescue medication
Treatment Week 1-26*** -0.19 -0.31 -0.09
difference 0.017 <0.001 0.290
Table 11-2 Onset of action on Day 1 based on treatment difference in FEV1 by time points
in study PALLADIUM
Treatment difference Day 1
Atectura Breezhaler (medium dose) vs MF* (medium dose)
5 min 152 mL**
15 min 174 mL**
30 min 185 mL**
Atectura Breezhaler 150/160 and 150/320 micrograms once daily were also studied as active
comparators in another Phase III study (IRIDIUM) in an asthma development program for
indacaterol/glycopyrronium/mometasone furoate in adult patients with asthma. To enroll in this study,
all subjects were required to be symptomatic on asthma maintenance therapy with a medium or high
dose ICS and LABA combination therapy for at least 3 months prior to study entry. All subjects had
Table 11-4 Results of primary and secondary endpoints in study QUARTZ at week 12
Endpoints Atectura Breezhaler low dose (150/80 od)
vs
MF* low dose (200 od)
P value
(95% CI)
Lung Function
Trough FEV1** 182 mL
<0.001
(148, 217)
Mean Morning PEF 27.2 L/min
<0.001
(22.1, 32.4)
Evening PEF 26.1 L/min
<0.001
(21.0, 31.2)
Symptoms
ACQ-7 (key secondary endpoint) -0.218
<0.001
(-0.293, -0.143)
Percentage of patients achieving MCID from baseline with 75% vs 65%
ACQ ≥ 0.5 1.69
0.001
(1.23, 2.33)
Mean number of daily puffs of rescue medication -0.26
Indacaterol
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 were 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.
Mometasone furoate
All observed effects are typical of the glucocorticoid class of compounds and are related to
exaggerated pharmacologic 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.
1 2 3 Check
Step 3d :
Rinse mouth
Rinse your mouth with
water after each dose
and spit it out.
Your Atectura Breezhaler Inhaler pack contains: Frequently Asked Cleaning the inhaler
One Atectura Breezhaler inhaler Questions Wipe the mouthpiece
One or more blister cards each containing either inside and outside with a
10 Atectura Breezhaler capsules to be used in the Why didn’t the inhaler clean, dry, lint-free cloth to
inhaler make a noise when I remove any powder
Capsule Mouthpiece
inhaled? residue. Keep the inhaler
Cap
chamber dry. Never wash your
Screen
inhaler with water.
Side
buttons Blister
Base
Manufacturer
See folding box.
Presentation
Atectura Breezhaler 150/80, 150/160, 150/320 micrograms:
Single pack 10 capsules (1x10’s) or 30 capsules (3x10’s), together with one inhaler.
Not all pack sizes may be available locally.