ARCAPTA™
NEOHALER™
(indacaterol) Inhalation Powder
WARNING
ASTHMA-RELATED DEATH
Long-acting beta2-adrenergic agonists (LABA)
increase the risk of asthma-related death. Data from a large placebo-controlledUSstudy that compared the safety of another long-acting beta2-adrenergic agonist
(salmeterol) or placebo added to usual asthma therapy showed an increase in
asthma-related deaths in patients receiving salmeterol. This finding with
salmeterol is considered a class effect of LABA, including indacaterol, the
active ingredient in ARCAPTA NEOHALER. The safety and efficacy of ARCAPTA NEOHALER
in patients with asthma have not been established. ARCAPTA NEOHALER is not
indicated for the treatment of asthma. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
ARCAPTA™ NEOHALER™
(indacaterol) Inhalation Powder
WARNING
ASTHMA-RELATED
DEATH
Long-acting beta2-adrenergic
agonists (LABA) increase the risk of asthma-related death. Data from a large
placebo-controlledUSstudy that compared the safety of another long-acting beta2-adrenergic
agonist (salmeterol) or placebo added to usual asthma therapy showed an increase
in asthma-related deaths in patients receiving salmeterol. This finding with
salmeterol is considered a class effect of LABA, including indacaterol, the
active ingredient in ARCAPTA NEOHALER. The safety and efficacy of ARCAPTA
NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is
not indicated for the treatment of asthma. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
ARCAPTA NEOHALER consists of a dry powder formulation of
indacaterol maleate for oral inhalation only with the NEOHALER inhaler. The
inhalation powder is packaged in clear gelatin capsules.
Each clear, hard gelatin capsule contains a dry powder
blend of 75 mcg of indacaterol (equivalent to 97 mcg of indacaterol maleate)
with approximately 25 mg of lactose monohydrate (which contains trace levels of
milk protein) as the carrier.
The active component of ARCAPTA NEOHALER is indacaterol
maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic
agonist. Its chemical name is
(R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8hydroxy-1H-quinolin-2-one
maleate; its structural formula is
Indacaterol maleate has a molecular weight of 508.56, and
its empirical formula is C24H28N2O3 • C4H4O4. Indacaterol maleate is a white to very slightly grayish or very
slightly yellowish powder. Indacaterol maleate is freely soluble in
Nmethylpyrrolidone and dimethylformamide, slightly soluble in methanol,
ethanol, propylene glycol and polyethylene glycol 400, very slightly soluble in
water, isopropyl alcohol and practically insoluble in 0.9% sodium chloride in
water, ethyl acetate and n-octanol.
The NEOHALER inhaler is a plastic device used for inhaling
ARCAPTA. The amount of drug delivered to the lung will depend on patient
factors, such as inspiratory flow rate and inspiratory time. Under
standardized in vitro testing at a fixed flow rate of 60 L/min
for 2 seconds, the NEOHALER inhaler delivered 57 mcg for the 75 mcg dose
strength (equivalent to 73.9 mcg of indacaterol maleate) from the mouthpiece.
Peak inspiratory flow rates (PIFR) achievable through the NEOHALER inhaler were
evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95
L/min (range 52-133 L/min) for adult patients. Approximately ninety-five
percent of the population studied generated a PIFR through the device exceeding
60 L/min.
INDICATIONS
Maintenance
Treatment of COPD
ARCAPTA NEOHALER is
a long-acting beta2-agonist indicated for long-term,
once-daily maintenance bronchodilator treatment of airflow obstruction in
patients with chronic obstructive pulmonary disease(COPD), including chronic bronchitis and/or emphysema.
Important
Limitations of Use
ARCAPTA NEOHALER is
not indicated to treat acute deteriorations of chronic obstructive pulmonary
disease [see WARNINGS AND PRECAUTIONS].
ARCAPTA NEOHALER is
not indicated to treat asthma. The safety and
effectiveness of ARCAPTA NEOHALER in asthma have not been established.
DOSAGE
AND ADMINISTRATION
DO NOT SWALLOW
ARCAPTA CAPSULES
FOR USE WITH
NEOHALER DEVICE ONLY
FOR ORAL INHALATION
ONLY
ARCAPTA capsules
must not be swallowed as the intended effects on the lungs will not be obtained.
The contents of ARCAPTA capsules are only for oral inhalation and should only
be used with the NEOHALER device.
The recommended
dosage of ARCAPTA NEOHALER is the once-daily inhalation of the contents of one
75 mcg ARCAPTA capsule using the NEOHALER inhaler.
ARCAPTA NEOHALER
should be administered once daily every day at the same time of the day by the
orally inhaled route only. If a dose is missed, the next dose should be taken
as soon as it is remembered. Do not use ARCAPTA NEOHALER more than one time
every 24 hours.
ARCAPTA capsules
must always be stored in the blister, and only removed IMMEDIATELY BEFORE USE.
No dosage adjustment is required for geriatric patients, patients with mild and
moderate hepatic impairment, or renally impaired patients.
No data are
available for subjects with severe hepatic impairment [see CLINICAL PHARMACOLOGY].
Dosage Forms
And Strengths
Inhalation
powder:
75 mcg: hard
gelatin capsule with black product code “IDL 75” above a bar printed on one
side of the capsule and the logo printed on the other side.
75 mcg ARCAPTA
NEOHALER contains ARCAPTA (indacaterol inhalation powder) capsules packaged in
aluminum blister cards, one NEOHALER inhaler, and an FDA approved Medication
Guide.
Unit
Dose (blister pack), Box of 30 (5 blister cards with 6 capsules
each) NDC 0078-0619-15
The NEOHALER
inhaler consists of a white protective cap and a base with mouthpiece, capsule
chamber and two translucent red push buttons.
Storage and
Handling
Store in a dry
place at 25°C (77°F); excursions permitted to 15-30°C (59-86° F) [see USP
Controlled Room Temperature].
75 mcg: Protect
capsule from light and moisture.
ARCAPTA capsules should be used with
the NEOHALER inhaler only. The NEOHALER inhaler should not be used with
any other capsules.Capsules should always be stored in
the blister and only removed from the blister immediately before use.Always use the new NEOHALER inhaler
provided with each new prescription. Keep out of the reach of children.
home drugs
a-z list side effects drug center arcapta neohaler (indacaterol
inhalation powder) drug
Drug Description
1. Understanding COPD
Slideshow Pictures
2. COPD (Chronic
Obstructive Pulmonary Disease) Quiz
3. Energy Foods for COPD Slideshow Pictures
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ARCAPTA™ NEOHALER™
(indacaterol) Inhalation Powder
WARNING
ASTHMA-RELATED
DEATH
Long-acting beta2-adrenergic
agonists (LABA) increase the risk of asthma-related death. Data from a large
placebo-controlledUSstudy that compared the safety of another long-acting beta2-adrenergic
agonist (salmeterol) or placebo added to usual asthma therapy showed an increase
in asthma-related deaths in patients receiving salmeterol. This finding with
salmeterol is considered a class effect of LABA, including indacaterol, the
active ingredient in ARCAPTA NEOHALER. The safety and efficacy of ARCAPTA
NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is
not indicated for the treatment of asthma. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
DESCRIPTION
ARCAPTA NEOHALER consists of a dry powder formulation of
indacaterol maleate for oral inhalation only with the NEOHALER inhaler. The
inhalation powder is packaged in clear gelatin capsules.
Each clear, hard gelatin capsule contains a dry powder
blend of 75 mcg of indacaterol (equivalent to 97 mcg of indacaterol maleate)
with approximately 25 mg of lactose monohydrate (which contains trace levels of
milk protein) as the carrier.
The active component of ARCAPTA NEOHALER is indacaterol
maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic
agonist. Its chemical name is
(R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8hydroxy-1H-quinolin-2-one
maleate; its structural formula is
Indacaterol maleate has a molecular weight of 508.56, and
its empirical formula is C24H28N2O3 • C4H4O4. Indacaterol maleate is a white to very slightly grayish or very
slightly yellowish powder. Indacaterol maleate is freely soluble in
Nmethylpyrrolidone and dimethylformamide, slightly soluble in methanol,
ethanol, propylene glycol and polyethylene glycol 400, very slightly soluble in
water, isopropyl alcohol and practically insoluble in 0.9% sodium chloride in
water, ethyl acetate and n-octanol.
The NEOHALER inhaler is a plastic device used for inhaling
ARCAPTA. The amount of drug delivered to the lung will depend on patient
factors, such as inspiratory flow rate and inspiratory time. Under
standardized in vitro testing at a fixed flow rate of 60 L/min
for 2 seconds, the NEOHALER inhaler delivered 57 mcg for the 75 mcg dose
strength (equivalent to 73.9 mcg of indacaterol maleate) from the mouthpiece.
Peak inspiratory flow rates (PIFR) achievable through the NEOHALER inhaler were
evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95
L/min (range 52-133 L/min) for adult patients. Approximately ninety-five
percent of the population studied generated a PIFR through the device exceeding
60 L/min.
For
Consumers
What are the possible side effects of indacaterol
(Arcapta Neohaler)?
Get emergency medical help if you have any of
these signs of an allergic reaction: hives; difficult breathing; swelling
of your face, lips, tongue, or throat.
Stop using indacaterol and call your doctor at once if you
have any of these serious side effects:
chest pain, tremors, fast heart rate, pounding heartbeats or
fluttering in your chest;new or worsening cough, fever, trouble breathing;swelling of your ankles or feet;bronchospasm (wheezing, chest tightness, trouble breathing);feeling suddenly short of...
Read All Potential Side Effects and See Pictures of
Arcapta Neohaler »
Indications & Dosage
1. Understanding COPD
Slideshow Pictures
2. COPD (Chronic
Obstructive Pulmonary Disease) Quiz
3. Energy Foods for COPD Slideshow Pictures
Maintenance Treatment of COPD
ARCAPTA NEOHALER is a long-acting beta2-agonist
indicated for long-term, once-daily maintenance bronchodilator treatment of
airflow obstruction in patients with chronic obstructive pulmonary disease(COPD),
including chronic bronchitis and/or emphysema.
Important Limitations of Use
ARCAPTA NEOHALER is not indicated to treat acute
deteriorations of chronic obstructive pulmonary disease [see WARNINGS
AND PRECAUTIONS].
ARCAPTA NEOHALER is not indicated to treat asthma. The safety and effectiveness of
ARCAPTA NEOHALER in asthma have not been established.
DOSAGE AND ADMINISTRATION
DO NOT SWALLOW ARCAPTA CAPSULES
FOR USE WITH NEOHALER DEVICE ONLY
FOR ORAL INHALATION ONLY
ARCAPTA capsules must not be swallowed as the intended
effects on the lungs will not be obtained. The contents
of ARCAPTA capsules are only for oral inhalation and should only be used with
the NEOHALER device.
The recommended dosage of ARCAPTA NEOHALER is the
once-daily inhalation of the contents of one 75 mcg ARCAPTA capsule using the
NEOHALER inhaler.
ARCAPTA NEOHALER should be administered once daily every
day at the same time of the day by the orally inhaled route only. If a dose is
missed, the next dose should be taken as soon as it is remembered. Do not use
ARCAPTA NEOHALER more than one time every 24 hours.
ARCAPTA capsules must always be stored in the blister, and
only removed IMMEDIATELY BEFORE USE. No dosage adjustment is required for
geriatric patients, patients with mild and moderate hepatic impairment, or
renally impaired patients.
No data are available for subjects with severe hepatic
impairment [see CLINICAL PHARMACOLOGY].
HOW SUPPLIED
Dosage Forms And Strengths
Inhalation powder:
75 mcg: hard gelatin capsule with black product code “IDL 75” above a bar printed on one side of
the capsule and the logo printed on the other side.
75 mcg ARCAPTA NEOHALER contains ARCAPTA (indacaterol
inhalation powder) capsules packaged in aluminum blister cards, one NEOHALER
inhaler, and an FDA approved Medication Guide.
Unit Dose (blister pack), Box of 30 (5
blister cards with 6 capsules each) NDC 0078-0619-15
The NEOHALER inhaler consists of a white protective cap and
a base with mouthpiece, capsule chamber and two translucent red push buttons.
Storage and Handling
Store in a dry place at 25°C (77°F); excursions permitted to 15-30°C (59-86° F) [see USP Controlled Room Temperature].
75 mcg: Protect capsule from light and moisture.
ARCAPTA capsules should be used with the NEOHALER inhaler only.
The NEOHALER inhaler should not be used with any other capsules.Capsules should always be stored in the blister and only
removed from the blister immediately before use.Always use the new NEOHALER inhaler provided with each new
prescription. Keep out of the reach of children.
Manufacturer
details: n.a. Revised: 09/2012
Side Effects & Drug Interactions
1. Understanding COPD
Slideshow Pictures
2. COPD (Chronic
Obstructive Pulmonary Disease) Quiz
3. Energy Foods for COPD Slideshow Pictures
Long-acting beta2-adrenergic agonists,
such as ARCAPTA NEOHALER, increase the risk of asthma-related death. ARCAPTA
NEOHALER is not indicated for the treatment of asthma [See BOXED WARNING and WARNING AND PRECAUTIONS].
Clinical Trials Experience in Chronic Obstructive
Pulmonary Disease
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The ARCAPTA NEOHALER safety database reflects exposure of
2516 patients to ARCAPTA NEOHALER at doses of 75 mcg or greater for at least 12
weeks in six confirmatory randomized, double-blind, placeboand active-controlled clinical trials.
In these trials, 449 patients were exposed to the recommended dose of 75 mcg
for up to 3 months, and 144, 583 and 425 COPD patients were exposed to a dose
of 150, 300 or 600 mcg for one year, respectively. Overall, patients had a mean
pre-bronchodilator forced expiratory volume in one second
(FEV1) percent predicted of 54%. The mean age of patients was 64 years,
with 47% of patients aged 65 years or older, and the majority (88%) was
Caucasian.
In these six clinical trials, 48% of patients treated with
any dose of ARCAPTA NEOHALER reported an adverse reaction compared with 43% of
patients treated with placebo. The proportion of patients who discontinued
treatment due to adverse reaction was 5% for ARCAPTA NEOHALER-treated patients
and 5% for placebo-treated patients. The most common adverse reactions that
lead to discontinuation of ARCAPTA NEOHALER were COPD and dyspnea.
The most common serious adverse reactions were COPD
exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar
rates across treatment groups.
Table 1 displays adverse drug reactions reported by at
least 2% of patients (and higher than placebo) during a 3 month exposure at the
recommended 75 mcg once daily dose. Adverse drug reactions are listed according
to MedDRA (version 13.0) system organ class and sorted in descending order of
frequency.
Table 1: Number and
frequency of adverse drug reactions greater than 2% (and higher than placebo)
in COPD patients exposed to ARCAPTA NEOHALER 75 mcg for up to 3 months in
multiple dose, controlled trials
|
|
Indacaterol 75 mcg once daily
n=449 n (%)
|
Placebo
n=445 n (%)
|
|
Respiratory, thoracic and mediastinal
disorders
|
|
Cough
|
29 (6.5)
|
20 (4.5)
|
|
Oropharyngeal pain
|
10 (2.2)
|
3 (0.7)
|
|
Infections and infestations
|
|
Nasopharyngitis
|
24 (5.3)
|
12 (2.7)
|
|
Nervous system disorders
|
|
Headache
|
23 (5.1)
|
11 (2.5)
|
|
Gastrointestinal disorders
|
|
- Nausea
|
11 (2.4)
|
4 (0.9)
|
In these trials the overall frequency of all cardiovascular
adverse reactions was 2.5% for ARCAPTA NEOHALER 75 mcg and 1.6% for placebo
during a 3 month exposure. There were no frequently occurring specific
cardiovascular adverse reactions for ARCAPTA NEOHALER 75 mcg (frequency at
least 1% and greater than placebo).
Additional adverse drug reactions reported in greater than
2% (and higher than on placebo) in patients dosed with 150, 300 or 600 mcg for
up to 12 months were as follows:
Musculoskeletal and connective tissue disorders: muscle
spasm, musculoskeletal painGeneral disorders and administration site conditions: edema
peripheralMetabolism and nutrition
disorder: diabetes mellitus, hyperglycemiaInfections and infestations: sinusitis, upper respiratory tract
infectionCough experienced post-inhalation
In the clinical trials, health care providers observed
during clinic visits that an average of 24% of patients experienced a cough on
at least 20% of visits following inhalation of the recommended 75 mcg dose of
ARCAPTA NEOHALER compared to 7% of patients receiving placebo. The cough
usually occurred within 15 seconds following inhalation and lasted for no more
than 15 seconds. Cough following inhalation in clinical trials was not associated
with bronchospasm, exacerbations, deteriorations of disease or loss of
efficacy.
Clinical Trials Experience in Asthma
In a 6-month randomized, active controlled asthma safety
trial, 805 adult patients with moderate to severe persistent asthma were treated
with ARCAPTA NEOHALER 300 mcg (n=268), ARCAPTA NEOHALER 600 mcg (n=268), and
salmeterol (n=269), all concomitant with inhaled corticosteroids, which were
not co-randomized. Of these patients, there were 2 respiratory-related deaths
in the ARCAPTA NEOHALER 300 mcg dose group. There were no deaths in the ARCAPTA
NEOHALER 600 mcg dose group or in the salmeterol active control group. Serious
adverse reactions related to asthma exacerbation were reported for 2 patients
in the indacaterol 300 mcg group, 3 patients in the indacaterol 600 mcg group,
and no patients in the salmeterol active control group.
In addition, a two-week dose-ranging trial was conducted in
511 adult patients with mild persistent asthma taking inhaled corticosteroids.
No deaths, intubations, or serious adverse reactions related to asthma
exacerbation were reported in this trial.
Postmarketing Experience
The following adverse reactions have been identified during
worldwide post-approval use of indacaterol, the active ingredient in ARCAPTA NEOHALER.
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure. These adverse reactions are:
tachycardia/heart rate increase/palpitations, pruritus/rash and dizziness.
Adrenergic Drugs
If additional adrenergic drugs are to be administered by
any route, they should be used with caution because the sympathetic effects of
ARCAPTA NEOHALER may be potentiated [see WARNINGS ANDPRECAUTIONS].
Xanthine Derivatives, Steroids, or Diuretics
Concomitant treatment with xanthine derivatives, steroids,
or diuretics may potentiate any hypokalemic effect of ARCAPTA NEOHALER
[see WARNINGS AND PRECAUTIONS].
Non-Potassium Sparing Diuretics
The ECG changes or hypokalemia that may result from the
administration of non-potassium sparing diuretics (such as loop or thiazide
diuretics) can be acutely worsened by beta-agonists, especially when the
recommended dose of the betaagonist is exceeded. Although the clinical
relevance of these effects is not known, caution is advised in the
coadministration of ARCAPTA NEOHALER with non-potassium-sparing diuretics.
Monoamine Oxidase Inhibitors, Tricyclic
Antidepressants, QTc Prolonging Drugs
Indacaterol, as with other beta2-agonists,
should be administered with extreme caution to patients being treated with
monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known
to prolong the QTc interval because the action of adrenergic agonists on
the cardiovascular system may be potentiated
by these agents. Drugs that are known to prolong the QTc interval may have an
increased risk of ventricular arrhythmias.
Beta-Blockers
Beta-adrenergic receptor antagonists (beta-blockers) and
ARCAPTA NEOHALER may interfere with the effect of each other when administered
concurrently. Beta-blockers not only block the therapeutic effects of
beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore,
patients with COPD should not normally be treated with beta-blockers. However,
under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable
alternatives to the use of beta-blockers in patients with COPD. In this
setting, cardioselective beta-blockers could be considered, although they
should be administered with caution.
Inhibitors of Cytochrome P450 3A4 and P-gp Efflux
Transporter
Drug interaction studies were carried out using potent and
specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin,
verapamil and ritonavir). The data suggest that systemic clearance is
influenced by modulation of both P-gp and CYP3A4 activities and that the
1.9-fold AUC0-24 increase caused by the strong dual inhibitor ketoconazole
reflects the impact of maximal combined inhibition. ARCAPTA NEOHALER was
evaluated in clinical trials for up to one year at doses up to 600 mcg. No dose
adjustment is warranted at the 75 mcg dose.
WARNINGS
Included as part of
the PRECAUTIONS section.
Asthma-Related
Death
[See BOXED WARNING]
Data from a large placebo-controlled
study in asthma patients showed that long-acting beta2-adrenergic agonists may increase the
risk of asthma-related death. Data are not available to determine whether
the rate of death in patients with COPD is increased by long-acting beta2-adrenergic agonists.A 28-week, placebo-controlled US
study comparing the safety of another long-acting beta2-adrenergic agonist (salmeterol) with
placebo, each added to usual asthma therapy, showed an increase in
asthma-related deaths in patients receiving salmeterol (13/13,176 in
patients treated with salmeterol vs. 3/13,179 in patients treated with
placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of
asthma-related death is considered a class effect of the long-acting beta2-adrenergic agonists, including
ARCAPTA NEOHALER. No study adequate to determine whether the rate of
asthma-related death is increased in patients treated with ARCAPTA
NEOHALER has been conducted. The safety and efficacy of ARCAPTA NEOHALER
in patients with asthma have not been established. ARCAPTA NEOHALER is not
indicated for the treatment of asthma. [see
CONTRAINDICATIONS].Serious asthma-related events,
including death, were reported in clinical studies with ARCAPTA NEOHALER.
The sizes of these studies were not adequate to precisely quantify the
differences in serious asthma exacerbation rates between treatment groups.
[see
ADVERSE REACTIONS].
Deterioration
of Disease and Acute Episodes
ARCAPTA NEOHALER
should not be initiated in patients with acutely deteriorating COPD, which may
be a life-threatening condition. ARCAPTA NEOHALER has not been studied in
patients with acutely deteriorating COPD. The use of ARCAPTA NEOHALER in this
setting is inappropriate.
ARCAPTA NEOHALER
should not be used for the relief of acute symptoms, i.e. as rescue therapy for
the treatment of acute episodes of bronchospasm. ARCAPTA NEOHALER has not been
studied in the relief of acute symptoms and extra doses should not be used for
that purpose. Acute symptoms should be treated with an inhaled short-acting
beta2-agonist.
When beginning
ARCAPTA NEOHALER, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis
(e.g., four times a day) should be instructed to discontinue the regular use of
these drugs and use them only for symptomatic relief of acute respiratory
symptoms. When prescribing ARCAPTA NEOHALER, the healthcare provider should
also prescribe an inhaled, short-acting beta2- agonist and instruct the
patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of
deteriorating disease for which prompt medical attention is indicated.
COPD may
deteriorate acutely over a period of hours or chronically over several days or
longer. If ARCAPTA NEOHALER no longer controls the symptoms of
bronchoconstriction, or the patient's inhaled, short-acting beta2-agonist becomes less
effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these
may be markers of deterioration of disease. In this setting, a re-evaluation of
the patient and the COPD treatment regimen should be undertaken at once.
Increasing the daily dosage of ARCAPTA NEOHALER beyond the recommended dose is
not appropriate in this situation.
Excessive Use
of ARCAPTA NEOHALER and Use with Other Long-Acting Beta2-Agonists
As with other
inhaled beta2-adrenergic drugs, ARCAPTA NEOHALER should not be used more
often, at higher doses than recommended, or in conjunction with other
medications containing long-acting beta2-agonists, as an overdose
may result. Clinically significant cardiovascular effects and fatalities have
been reported in association with excessive use of inhaled sympathomimetic
drugs.
Immediate
Hypersensitivity Reactions
Immediate
hypersensitivity reactions may occur after administration of ARCAPTA NEOHALER.
If signs suggesting allergic reactions (in particular, difficulties in
breathing or swallowing, swelling of tongue, lips and face, urticaria, skin
rash) occur, ARCAPTA NEOHALER should be discontinued immediately and
alternative therapy instituted.
Paradoxical
Bronchospasm
As with other
inhaled beta2-agonists, ARCAPTA NEOHALER may produce paradoxical bronchospasm
that may be life-threatening. If paradoxical bronchospasm occurs, ARCAPTA NEOHALER
should be discontinued immediately and alternative therapy instituted.
Cardiovascular
Effects
ARCAPTA NEOHALER,
like other beta2-agonists, can produce a clinically significant cardiovascular
effect in some patients as measured by increases in pulse rate, systolic or
diastolic blood pressure, or symptoms. If such effects occur, ARCAPTA NEOHALER
may need to be discontinued. In addition, beta-agonists have been reported to
produce ECG changes, such as flattening of the T wave, prolongation of the QTc
interval, and ST segment depression, although the clinical significance of
these findings is unknown. Therefore, ARCAPTA NEOHALER, like other
sympathomimetic amines, should be used with caution in patients with
cardiovascular disorders, especially coronary insufficiency, cardiac
arrhythmias, and hypertension.
Coexisting
Conditions
ARCAPTA NEOHALER,
like other sympathomimetic amines, should be used with caution in patients with
convulsive disorders or thyrotoxicosis, and in patients who are unusually
responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when
administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
Hypokalemia and
Hyperglycemia
Beta2-agonist medications may
produce significant hypokalemia in
some patients, possibly through intracellular shunting, which has the potential
to produce adverse cardiovascular effects [see CLINICAL PHARMACOLOGY]. The decrease in serum
potassium is usually transient, not requiring supplementation. Inhalation of
high doses of beta2-adrenergic agonists may produce
increases in plasma glucose.
Clinically notable
decreases in serum potassium or changes in blood glucose were infrequent during
clinical studies with long-term administration of ARCAPTA NEOHALER with the
rates similar to those for placebo controls. ARCAPTA NEOHALER has not been
investigated in patients whose diabetes mellitus is not well controlled.
Patient
Counseling Information
See FDA-approved
patient labeling (Medication Guide)
Asthma-Related
Death
Patients should be
informed that LABA, such as ARCAPTA NEOHALER, increase the risk of
asthma-related death. ARCAPTA NEOHALER is not indicated for the treatment of
asthma.
Instructions
for Administering ARCAPTA NEOHALER
It is important for
patients to understand how to correctly administer ARCAPTA capsules using the
NEOHALER device [see Instructions for Use at the end of the Medication Guide]. Patients should be
instructed that ARCAPTA capsules should only be administered via the NEOHALER
device and the NEOHALER device should not be used for administering other
medications. The contents of ARCAPTA capsules are for oral inhalation only
and must not be swallowed.
ARCAPTA capsules
should always be stored in sealed blisters. Only one ARCAPTA capsule should be
removed immediately before use, or its effectiveness may be reduced. Additional
ARCAPTA capsules that are exposed to air (i.e. not intended for immediate use)
should be discarded.
Not for Acute
Symptoms
ARCAPTA NEOHALER is
not meant to relieve acute symptoms or exacerbations of COPD and extra doses
should not be used for that purpose. Acute symptoms should be treated with an
inhaled, short-acting beta2-agonist such as albuterol. (The
healthcare provider should provide the patient with such medication and
instruct the patient in how it should be used.)
Patients should be
instructed to notify their physician immediately if they experience any of the
following:
Worsening of symptomsDecreasing effectiveness of inhaled,
short-acting beta2-agonistsNeed for more inhalations than usual
of inhaled, short-acting beta2-agonistsSignificant decrease in lung function
as outlined by the physician.
Patients should not
stop therapy with ARCAPTA NEOHALER without physician/provider guidance since
symptoms may recur after discontinuation.
Do Not Use
Additional Long-Acting Beta2-Agonists
Patients who have
been taking inhaled, short-acting beta2-agonists on a regular basis
should be instructed to discontinue the regular use of these products and use
them only for the symptomatic relief of acute symptoms.
When patients are
prescribed ARCAPTA NEOHALER, other inhaled medications containing long-acting
beta2-agonists should not be used. Patients should not use more than
the recommended once daily dose of ARCAPTA NEOHALER. Excessive use of
sympathomimetics may cause significant cardiovascular effects, and may be
fatal.
Risks
Associated With Beta-Agonist Therapy
Patients should be
informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart
rate, tremor, or nervousness.
Nonclinical
ToxicologyCarcinogenesis,
Mutagenesis, Impairment of Fertility
Long-term studies
were conducted in transgenic mice using oral administration and in rats using
inhalation administration to evaluate the carcinogenic potential of indacaterol
maleate. Indacaterol did not show a statistically significant increase in tumor
formation in mice or rats.
Lifetime treatment
of rats resulted in increased incidences of benign ovarian leiomyoma and focal
hyperplasia of ovarian smooth muscle in females at doses approximately
270-times the dose of 75 mcg once-daily for humans (on a mg/m² basis).
A 26-week oral
(gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show
any evidence of tumorigenicity at doses approximately 39,000-times the dose of
75 mcg once-daily for humans (on a mg/m2 basis).
Increases in
leiomyomas of the female rat genital tract have been similarly demonstrated
with other beta2-adrenergic agonist drugs. The relevance of these findings to
human use is unknown.
Indacaterol was not
mutagenic or clastogenic in Ames test, chromosome aberration test
in V79 Chinese hamster cells, and bone marrow micronucleus test in rats.
Indacaterol did not
impair fertility of rats in reproduction studies.
Use
In Specific PopulationsPregnancy
Teratogenic
Effects: Pregnancy Category C
There are no
adequate and well-controlled studies with ARCAPTA NEOHALER in pregnant women. ARCAPTA
NEOHALER should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Indacaterol was
not teratogenic following
subcutaneous administration to rats and rabbits at doses up to 1 mg/kg,
approximately 130 and 260 times, respectively, the 75 mcg dose on a mg/m²
basis.
Labor and
Delivery
There are no
adequate and well-controlled human studies that have investigated effects of
ARCAPTA NEOHALER on preterm labor or labor at term. Because of the potential
for beta-agonist interference with uterine contractility, use of ARCAPTA
NEOHALER during labor should be restricted to those patients in whom the
benefits clearly outweigh the risks.
Nursing Mothers
It is not known
that the active component of ARCAPTA NEOHALER, indacaterol, is excreted in
human milk. Because many drugs are excreted in human milk and because
indacaterol has been detected in the milk of lactating rats, caution should be
exercised when ARCAPTA NEOHALER is administered to nursing women.
Pediatric Use
ARCAPTA NEOHALER is
not indicated for use in children. The safety and effectiveness of ARCAPTA
NEOHALER in pediatric patients have not been established.
Geriatric Use
Based on available
data, no adjustment of ARCAPTA NEOHALER dosage in geriatric patients is
warranted. Of the total number of patients who received ARCAPTA NEOHALER at the
recommended dose of 75 mcg once daily in the clinical studies from the pooled
3-month database, 239 were < 65 years, 153 were 65–74 years and 57 were ≥ 75
years of age.
No overall
differences in effectiveness were observed, and in the 3-month pooled data, the
adverse drug reaction profile was similar in the older population compared to
the patient population overall. When treated at higher doses (300 mcg and 600
mcg) over the course of a year, the adverse drug reaction profiles for patients
> 65 years was similar to that of the general patient population.
Hepatic
Impairment
Patients with mild
and moderate hepatic impairment showed no relevant changes in Cmax or AUC, nor
did protein binding differ between mild and moderate hepatically impaired
subjects and their healthy controls. Studies in subjects with severe hepatic
impairment were not performed.
Renal
Impairment
Due to the very low
contribution of the urinary pathway to total body elimination, a study in
renally impaired subjects was not performed.
OVERDOSE
Human
Experience
In COPD patients
single doses of 40 times the 75 mcg dose were associated with moderate
increases in pulse rate, systolic blood pressure and QTc interval.
The expected signs
and symptoms associated with overdosage of ARCAPTA NEOHALER are those of
excessive betaadrenergic stimulation and occurrence or exaggeration of any of
the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm,
arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle
cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and
insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and
even death may be associated with an overdose of ARCAPTA NEOHALER.
Treatment of
overdosage consists of discontinuation of ARCAPTA NEOHALER together with
institution of appropriate symptomatic and supportive therapy. The judicious
use of a cardioselective beta-receptor blocker may be considered, bearing in
mind that such medication can produce bronchospasm. There is insufficient
evidence to determine if dialysis is beneficial for
overdosage of ARCAPTA NEOHALER. Cardiac monitoring is recommended in cases of
overdosage.
All LABA are
contraindicated in patients with asthma without use of a
long-term asthma control medication. [see WARNINGS AND PRECAUTIONS]. ARCAPTA NEOHALER is not
indicated for the treatment of asthma.
ARCAPTA NEOHALER is
contraindicated in patients with a history of hypersensitivity to indacaterol
or to any of the ingredients. [see WARNINGS AND PRECAUTIONS].
CLINICAL
PHARMACOLOGY
Mechanism of
Action
Indacaterol is a
long-acting beta2-adrenergic agonist.
When inhaled,
indacaterol acts locally in the lung as a bronchodilator. Although beta2-receptors are the
predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors
are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the
human heart comprising 10%-50% of the total adrenergic receptors. The precise
function of these receptors is not known, but their presence raises the
possibility that even highly selective beta2adrenergic agonists may have
cardiac effects.
The pharmacological
effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least
in part attributable to stimulation of intracellular adenyl cyclase, the enzyme
that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',
5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels
cause relaxation of bronchial smooth muscle. In vitro studies have shown that
indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to
beta1-receptors and 20-fold greater agonist activity compared to
beta3-receptors. This selectivity profile is similar to formoterol. The
clinical significance of these findings is unknown.
Pharmacodynamics
Systemic Safety
The major adverse
effects of inhaled beta2-adrenergic agonists occur as a result
of excessive activation of systemic betaadrenergic receptors. The most common
adverse effects in adults include skeletal muscle tremor and cramps,
insomnia, tachycardia, decreases in serum
potassium and increases in plasma glucose.
Changes in serum
potassium and plasma glucose were evaluated in COPD patients in double-blind
Phase III studies. In pooled data, at the recommended 75 mcg dose, at 1 hour
post-dose at week 12, there was no change compared to placebo in serum
potassium, and change in mean plasma glucose was 0.07 mmol/L.
Electrophysiology
The effect of
ARCAPTA NEOHALER on the QT interval was evaluated in a double-blind, placebo-
and active (moxifloxacin)-controlled study following multiple doses of
indacaterol 150 mcg, 300 mcg or 600 mcg once-daily for 2 weeks in 404 healthy
volunteers. Fridericia's method for heart rate correction was employed to
derive the corrected QT interval (QTcF). Maximum mean prolongation of QTcF
intervals were < 5 ms, and the upper limit of the 90% confidence interval
was below 10 ms for all time-matched comparisons versus placebo. During these
studies, there were no clinically meaningful QT-interval prolongations. There
was no evidence of a clinically relevant concentration-delta QTc relationship
in the range of doses evaluated.
The effect of 150
mcg and 300 mcg once daily of ARCAPTA NEOHALER on heart rate and rhythm was
assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset
of 605 patients with COPD from a 26-week, double-blind, placebo-controlled
Phase III study. Holter monitoring occurred once at baseline and up to 3 times
during the 26week treatment period (at weeks 2, 12 and 26). A comparison of the
mean heart rate over 24 hours showed no increase from baseline. The hourly
heart rate analysis was similar compared to placebo. The pattern of diurnal
variation over 24 hours was maintained and was similar to placebo. No
difference from placebo was seen in the rates of atrial fibrillation,
time spent in atrial fibrillation and also the maximum ventricular rate of
atrial fibrillation. No clear patterns in the rates of single ectopic beats,
couplets or runs were seen across visits. Because the summary data on rates of
ventricular ectopic beats can be difficult to interpret, specific
pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of
ventricular ectopic beats was compared to change from baseline, setting certain
parameters for the change to describe the pro-arrhythmic response. The number
of patients with a documented pro-arrhythmic response was very similar compared
to placebo. Overall, there was no clinically relevant difference in the
development of arrhythmic events in patients receiving indacaterol treatment
over those patients who received placebo.
Tachyphylaxis/Tolerance
Tolerance to the
effects of inhaled beta-agonists can occur with regularly-scheduled, chronic
use. In two 12-week clinical efficacy trials in 323 and 318 adult patients with
COPD, ARCAPTA NEOHALER improvement in lung function (as measured by the forced expiratory volume in one second, FEV1) observed at Week 4 with
ARCAPTA NEOHALER was consistently maintained over the 12-week treatment period
in both trials.
Pharmacokinetics
Absorption
The median time to
reach peak serum concentrations of indacaterol was approximately 15 minutes
after single or repeated inhaled doses. Systemic exposure to indacaterol
increased with increasing dose (150 mcg to 600 mcg) in a dose proportional
manner, and was about dose-proportional in the dose range of 75 mcg to 150 mcg.
Absolute bioavailability of indacaterol after an inhaled dose was on average
43-45%. Systemic exposure results from a composite of pulmonary and intestinal
absorption.
Indacaterol serum
concentrations increased with repeated once-daily administration. Steady-state
was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol,
i.e. AUC over the 24-hour dosing interval on day 14 or day 15 compared to day
1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg
and 600 mcg.
Distribution
After intravenous
infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L
indicating an extensive distribution. The in vitro human serum
and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
Metabolism
After oral
administration of radiolabeled indacaterol in the 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 Oglucuronides of indacaterol and
hydroxylated indacaterol were further prominent metabolites. A diastereomer of
the hydroxylated derivative, a 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 Oglucuronide. 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
indicated that indacaterol is a low affinity substrate for the efflux pump
P-gp.
In vitro investigations
indicated that indacaterol has negligible potential to cause metabolic
interactions with medications (by inhibition or induction of cytochrome P450
enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in
clinical practice. In vitro investigation furthermore indicated that, in vivo,
indacaterol is unlikely to significantly inhibit transporter proteins such as
P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the
human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that
indacaterol has negligible potential to induce P-gp or MRP2.
Elimination
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 1.2 L/h. When compared with the
serum clearance of indacaterol of 18.8 L/h 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 parent drug (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 with once daily
doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent
with the observed time-to-steady state of approximately 12-15 days.
Special
Populations
A population
pharmacokinetic analysis was performed for indacaterol utilizing data from 3
controlled clinical trials that included 1,844 patients with COPD aged 40 to 88
years who received treatment with ARCAPTA NEOHALER.
The population
analysis showed that no dose adjustment is warranted based on the effect of
age, gender and weight on systemic exposure in COPD patients after inhalation
of ARCAPTA NEOHALER. The population pharmacokinetic analysis did not suggest
any difference between ethnic subgroups in this population.
Hepatic
Impairment
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
hepatically impaired subjects and their healthy controls. Studies in subjects
with severe hepatic impairment were not performed.
Renal
Impairment
Due to the very low
contribution of the urinary pathway to total body elimination, a study in
renally impaired subjects was not performed.
Drug-drug
Interaction
Drug interaction
studies were carried out using potent and specific inhibitors of CYP3A4 and
P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir).
Verapamil: Co-administration of
indacaterol 300 mcg (single dose) with verapamil (80 mg t.i.d for 4 days)
showed 2-fold increase in indacaterol AUC0-24, and 1.5-fold increase in
indacaterol Cmax.
Erythromycin: Co-administration of
indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg
q.i.d for 7 days) showed a 1.4-fold increase in indacaterol AUC0-24, and
1.2-fold increase in indacaterol Cmax
Ketoconazole: Co-administration of
indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg
b.i.d for 7 days) caused a 1.9-fold increase in indacaterol AUC0-24, and
1.3-fold increase in indacaterol Cmax
Ritonavir: Co-administration of
indacaterol 300 mcg (single dose) with ritonavir (300 mg b.i.d for 7.5 days)
resulted in a 1.7-fold increase in indacaterol AUC0-24 whereas indacaterol Cmax
was unaffected. [See DRUG INTERACTIONS].
Pharmacogenomics
The
pharmacokinetics of indacaterol were prospectively investigated in subjects
with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to
as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and Cmax of indacaterol
were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant
effect of UGT1A1 genotype of indacaterol exposure.
The ARCAPTA
NEOHALER COPD clinical development program included three dose-ranging trials
and six confirmatory trials (Trial 3, a 26-week seamless adaptive design trial
that included an initial 2 week dose ranging phase; Trials 4, 5, and 6, 12-week
trials; Trial 7, a 26-week trial; and Trial 8, a 52 week trial).
Dose-ranging
trials
Dose selection for
ARCAPTA NEOHALER for COPD was based on three dose-ranging trials (Trial 1, a
2-week dose- ranging trial in an asthma population; Trial 2, a 2-week
dose-ranging trial in a COPD population; and Trial 3, a 26-week adaptive
seamless design trial that included an initial 2-week dose ranging phase).
Although ARCAPTA NEOHALER is not indicated for asthma, dose selection was
primarily based upon the results from the dose-ranging trial in asthma patients
(Trial 1) as an asthma population is the most responsive to beta-agonist
bronchodilation and is most likely to demonstrate a dose response. Dose-ranging
in COPD patients (Trials 2 and 3) provided supportive information.
Dose-ranging in
asthma
ARCAPTA
NEOHALER is not indicated for asthma.
Trial 1 was a
2-week, randomized, double-blinded, placebo-controlled design that enrolled 511
patients with persistent asthma 18 years of age and older. All enrolled
patients were required to be taking inhaled corticosteroids, had a forced
expiratory volume in one second (FEV1) of ≥ 50% and ≤ 90%
predicted, and FEV1 reversibility after albuterol of
at least 12% and at least 200 mL. Trial 1 included ARCAPTA NEOHALER doses of
18.75, 37.5, 75, and 150 mcg once daily, a salmeterol active control group, and
placebo. The trial showed that the effect on FEV1 in patients treated
with ARCAPTA NEOHALER 18.75 and 37.5 mcg doses was lower compared to patients
treated with other ARCAPTA NEOHALER doses, particularly after the first dose.
The effect did not clearly differ between the 75 and 150 mcg doses.
Results of the
ARCAPTA NEOHALER and placebo treatment arms are as follows. After the first
dose (Day 1), the peak (4 hour) FEV1 was 2.58L in the
placebo group, with a treatment difference of 0.04L (95% CI -0.01, 0.09) in the
18.75 mcg ARCAPTA NEOHALER group, 0.04L (-0.01, 0.09) in the 37.5 mcg group,
0.12L (0.07, 0.17) in the 75 mcg group, and 0.15L (0.10, 0.20) in the 150 mcg
group. The Day 2 trough FEV1 was 2.45L in the placebo group,
with a treatment difference of 0.02L (95% CI -0.05, 0.08), 0.08L (0.01, 0.15),
0.09L (0.03, 0.16) and 0.16L (0.09, 0.22) in the ARCAPTA NEOHALER groups,
respectively. At Day 14, the peak (4 hour) FEV1 was 2.55L in the
placebo group, with a treatment difference of 0.12L (95% CI 0.05, 0.20) in the
18.75 mcg ARCAPTA NEOHALER group, 0.14L (0.06, 0.21) in the 37.5 mcg group,
0.23L (0.15, 0.30) in the 75 mcg group, and 0.20L (0.13, 0.27) in the 150 mcg
group. The Day 15 FEV1 (primary endpoint) was 2.42L in
the placebo group, with a treatment difference of 0.09L (95% CI 0.00, 0.17),
0.11L (0.02, 0.19), 0.17L (0.08, 0.26), and 0.12L (0.04, 0.21) in the ARCAPTA
NEOHALER groups, respectively.
Dose-ranging in
COPD
Trial 2 was a
2-week, randomized, double-blinded, placebo-controlled design that enrolled 552
patients with a clinical diagnosis of COPD, who were 40 years or older, had a
smoking history of at least 10 pack years, had a postbronchodilator FEV1 less than 80% and at
least 30% of the predicated normal value and a post-bronchodilator ratio of FEV1 over forced vital
capacity (FEV1/FVC) of less than 70%. Trial 2 included ARCAPTA NEOHALER doses
of 18.75, 37.5, 75 and 150 mcg once daily, a salmeterol active control group,
and placebo. Results of the ARCAPTA NEOHALER and placebo arms are shown in
Figure 1. The trial showed that the effect on FEV1 in patients treated
with ARCAPTA NEOHALER 18.75 mcg dose was lower compared to patients treated
with other ARCAPTA NEOHALER doses. Although a dose-response relationship was
observed at Day 1, the effect did not clearly differ among the 37.5, 75 and 150
mcg doses by Day 15.
Figure 1: LS Mean FEV1 time profile curve
over 24 hours after ARCAPTA NEOHALER Day 1 and Week 2 in Trial 2 (COPD dose
ranging)
The 2-week dose
ranging phase of Trial 3 included ARCAPTA NEOHALER doses of 75, 150, 300, and
600 mcg once daily, placebo, and two active comparators. Although a dose-response
relationship was observed at week 2, the effect did not clearly differ among
the ARCAPTA NEOHALER doses.
Confirmatory
Trials
The ARCAPTA
NEOHALER COPD development program included six confirmatory trials that were
randomized, double-blinded placebo and active-controlled in design (Trial 3, a
26-week seamless adaptive design trial that included an initial 2 week
dose-ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week
trial; and Trial 8, a 52 week trial). After the initial 2-week dose-ranging
portion of the design, Trial 3 was conducted with ARCAPTA NEOHALER doses of 150
mcg and 300 mcg once daily, placebo, and an active comparator. Trials 4 and 5
were conducted with ARCAPTA NEOHALER dose of 75 mcg once daily, and placebo.
Trial 6 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily and
placebo. Trial 7 was conducted with ARCAPTA NEOHALER dose of 150 mcg once
daily, an active comparator, and placebo. Trial 8 was conducted with ARCAPTA
NEOHALER doses of 300 mcg and 600 mcg once daily, an active comparator, and
placebo.
As Trials 3, 6, 7,
and 8 were conducted with doses of ARCAPTA NEOHALER higher than 75 mcg, the
results of Trials 4 and 5, which included ARCAPTA NEOHALER 75 mcg are the focus
of this section.
These six trials
enrolled 5474 patients with a clinical diagnosis of COPD, who were 40 years or
older, had a smoking history of at least 10 pack years, had a
post-bronchodilator FEV1 less than 80% and at least 30% of
the predicted normal value and a post-bronchodilator ratio of FEV1 over FVC of less than
70%.
Assessment of
efficacy in these six COPD trials was based on FEV1. The primary efficacy
endpoint was 24-hour post-dose trough FEV1 (defined as the
average of two FEV1 measurements taken after 23 hours
10 minutes and 23 hours and 45 minutes after the previous dose) after 12 weeks
of treatment in all 6 trials. Other efficacy variables included other FEV1 and FVC time points,
rescue medication use, symptoms, and health-related quality of life measured
using theSt. George'sRespiratory Questionnaire (SGRQ).
In all six
confirmatory COPD trials, all doses of ARCAPTA NEOHALER tested (75 mcg, 150
mcg, 300 mcg, and 600 mcg) showed significantly greater 24-hour post-dose
trough FEV1 compared to placebo at 12 weeks. Results of Trials 4 and
5, which compared ARCAPTA NEOHALER at the dose of 75 mcg once daily to placebo
are shown in Table 2.
Table 2: LS Mean for trough FEV1 at 12 weeks
|
Treatment
|
Trough FEV1 at
Week 12 (liters)
|
Treatment Difference LS Mean
(95% CI)
|
|
Trial 4 (N=323)
|
|
Indacaterol 75 mcg
|
1.38
|
0.12 (0.08, 0.15)
|
|
Placebo
|
1.26
|
|
|
Trial 5 (N=318)
|
|
Indacaterol 75 mcg
|
1.49
|
0.14 (0.10, 0.18)
|
|
Placebo
|
1.35
|
|
In addition, serial
FEV1 measurements in patients treated with ARCAPTA NEOHALER
demonstrated a bronchodilatory treatment effect after the first dose compared
to placebo at 5 minutes post dose of 0.09 L (Trial 4) and 0.10 L (Trial 5). The
mean peak improvement relative to baseline within the first 4 hours after the
first dose (Day 1) was 0.19 L (Trial 4) and 0.22 L (Trial 5) and was 0.24 L
(Trial 4) and 0.27 L (Trial 5) after 12 weeks. Improvement in lung function
observed at week 4 was consistently maintained over the 12-week treatment
period in both trials. In Trial 5, 24-hour spirometry was assessed in a subset
of 239 patients. See Figure 2.
Figure 2 : LS Mean FEV1 time profile curve
over 24 hours at Week 12 in Trial 5
In both COPD
clinical trials including the 75 mcg dose (Trials 4 and 5), patients treated
with ARCAPTA NEOHALER used less daily rescue albuterol during the trial
compared to patients treated with placebo.
Health-related
quality of life was measured using theSt.
George'sRespiratory Questionnaire (SGRQ) in all six
confirmatory COPD clinical trials. SGRQ is a disease-specific patient reported
instrument which measures symptoms, activities, and its impact on daily life.
At week 12, pooled data from these trials demonstrated an improvement over
placebo in SGRQ total score of -3.8 with a 95% CI of (-5.3, -2.3) for the
ARCAPTA NEOHALER 75 mcg dose, -4.6 with a 95% CI of (-5.5, -3.6) for 150 mcg,
and -3.8 with a 95% CI of (-4.9, -2.8) for 300 mcg. The confidence intervals
for this change are widely overlapping with no dose ordering. Results from
individual studies were variable, but are generally consistent with the pooled
data results.
