Mechanism Of Action
Arformoterol, the (R,R)-enantiomer of formoterol, is a
selective long-acting beta2-adrenergic receptor agonist (beta2-agonist) that
has two-fold greater potency than racemic formoterol (which contains both the
(S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less
potent as a beta2-agonist than the (R,R)-enantiomer. While it is recognized
that beta2-receptors are the predominant adrenergic receptors in bronchial
smooth muscle and beta1-receptors are the predominant receptors in
the heart, data indicate that there are also beta2-receptors in the human heart
comprising 10% to 50% of the total beta-adrenergic receptors. The precise
function of these receptors has not been established, but they raise the
possibility that even highly selective beta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor agonist
drugs, including arformoterol, 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 AMP). Increased intracellular cyclic AMP levels cause
relaxation of bronchial smooth muscle and inhibition of release of mediators of
immediate hypersensitivity from cells, especially from mast cells.
In vitro tests show that arformoterol is an inhibitor of
the release of mast cell mediators, such as histamine and leukotrienes, from
the human lung. Arformoterol also inhibits histamine-induced plasma albumin
extravasation in anesthetized guinea pigs and inhibits allergen-induced
eosinophil influx in dogs with airway hyper-responsiveness. The relevance of
these in vitro and animal findings to humans is unknown.
Systemic Safety And Pharmacokinetic/Pharmacodynamic Relationships
The predominant adverse effects of inhaled beta2-agonists
occur as a result of excessive activation of systemic beta-adrenergic
receptors. The most common adverse effects may include skeletal muscle tremor
and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases
in plasma glucose.
Effects On Serum Potassium And Serum Glucose Levels
Changes in serum potassium and serum glucose were
evaluated in a dose-ranging study of twice daily (5 mcg, 15 mcg, or 25 mcg; 215
patients with COPD) and once daily (15 mcg, 25 mcg, or 50 mcg; 191 patients
with COPD) BROVANA Inhalation Solution in COPD patients. At 2 and 6 hours post
dose at week 0 (after the first dose), mean changes in serum potassium ranging
from 0 to -0.3 mEq/L were observed in the BROVANA Inhalation Solution groups
with similar changes observed after 2 weeks of treatment. Changes in mean serum
glucose levels, ranging from a decrease of 1.2 mg/dL to an increase of 32.8
mg/dL were observed for BROVANA Inhalation Solution dose groups at both 2 and 6
hours post dose, both after the first dose and 14 days of daily treatment.
The effect of BROVANA Inhalation Solution on QT interval
was evaluated in a dose-ranging study following multiple doses of BROVANA
Inhalation Solution 5 mcg, 15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or
50 mcg once daily for 2 weeks in patients with COPD. ECG assessments were performed
at baseline, time of peak plasma concentration and throughout the dosing
interval. Different methods of correcting for heart rate were employed,
including a subject-specific method and the Fridericia method.
Relative to placebo, the mean change in subject-specific
QTc averaged over the dosing interval ranged from -1.8 to 2.7 msec, indicating
little effect of BROVANA Inhalation Solution on cardiac repolarization after 2
weeks of treatment. The maximum mean change in subject-specific QTc for the BROVANA
Inhalation Solution 15 mcg twice daily dose was 17.3 msec, compared with 15.4
msec in the placebo group. No apparent correlation of QTc with arformoterol
plasma concentration was observed.
Electrocardiographic Monitoring In Patients With COPD
The effect of different doses of BROVANA Inhalation
Solution on cardiac rhythm was assessed using 24-hour Holter monitoring in two
12-week, double-blind, placebo-controlled studies of 1,456 patients with COPD
(873 received BROVANA Inhalation Solution at 15 or 25 mcg twice daily or 50 mcg
once daily doses; 293 received placebo; 290 received salmeterol). The 24-hour
Holter monitoring occurred once at baseline, and up to 3 times during the
12-week treatment period. The rates of new-onset cardiac arrhythmias not
present at baseline over the double-blind 12-week treatment period were similar
(approximately 33-34%) for patients who received BROVANA Inhalation Solution 15
mcg twice daily to those who received placebo. There was a dose-related
increase in new, treatment-emergent arrhythmias seen in patients who received
BROVANA Inhalation Solution 25 mcg twice daily and 50 mcg once daily, 37.6% and
40.1%, respectively. The frequencies of new treatment-emergent events of non-sustained
(3-10 beat run) and sustained ( > 10 beat run) ventricular tachycardia were
7.4% and 1.1% in BROVANA Inhalation Solution 15 mcg twice daily and 6.9% and
1.0% in placebo. In patients who received BROVANA Inhalation Solution 25 mcg
twice daily and 50 mcg once daily, the frequencies of non-sustained (6.2% and
8.2%, respectively) and sustained ventricular tachycardia (1.0% and 1.0%, respectively)
were similar. Five cases of ventricular tachycardia were reported as adverse
events (1 in BROVANA Inhalation Solution 15 mcg twice daily and 4 in placebo),
with two of these events leading to discontinuation of treatment (2 in
There were no baseline occurrences of atrial
fibrillation/flutter observed on 24-hour Holter monitoring in patients treated
with BROVANA Inhalation Solution 15 mcg twice daily or placebo. New,
treatmentemergent atrial fibrillation/flutter occurred in 0.4% of patients who
received BROVANA Inhalation Solution 15 mcg twice daily and 0.3% of patients
who received placebo. There was a dose-related increase in the frequency of
atrial fibrillation/flutter reported in the BROVANA Inhalation Solution 25 mcg
twice daily and 50 mcg once daily dose groups of 0.7% and 1.4%, respectively.
Two cases of atrial fibrillation/flutter were reported as adverse events (1 in
BROVANA Inhalation Solution 15 mcg twice daily and 1 in placebo).
Dose-related increases in mean maximum change in heart
rate in the 12 hours after dosing were also observed following 12 weeks of
dosing with BROVANA Inhalation Solution 15 mcg twice daily (8.8 bpm), 25 mcg
twice daily (9.9 bpm) and 50 mcg once daily (12 bpm) versus placebo (8.5 bpm).
Tolerance to the effects of inhaled beta-agonists can
occur with regularly-scheduled, chronic use.
In two placebo-controlled clinical trials in patients
with COPD involving approximately 725 patients in each, the overall efficacy of
BROVANA Inhalation Solution was maintained throughout the 12-weektrial
duration. However, tolerance to the bronchodilator effect of BROVANA Inhalation
Solution was observed after 6 weeks of dosing, as measured by a decrease in
trough FEV1. FEV1 improvement at the end of the 12-hour dosing interval decreased
by approximately one-third (22.1% mean improvement after the first dose
compared to 14.6% at week 12). Tolerance to the trough FEV1 bronchodilator
effect of BROVANA Inhalation Solution was not accompanied by other clinical
manifestations of tolerance in these trials.
The pharmacokinetics (PK) of arformoterol have been
investigated in healthy subjects, elderly subjects, renally and hepatically
impaired subjects, and COPD patients following the nebulization of the recommended
therapeutic dose and doses up to 96 mcg.
In COPD patients administered 15 mcg arformoterol every
12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma
concentration (Cmax) and systemic exposure (AUC0-12h) were 4.3 pg/mL and 34.5
pg•hr/mL, respectively. The median
steady-state peak (R,R)-formoterol plasma concentration time (tmax) was
observed approximately one-half hour after drug administration.
Systemic exposure to (R,R)-formoterol increased linearly
with dose in COPD patients following arformoterol doses of 5 mcg, 15 mcg, or 25
mcg twice daily for 2 weeks or 15 mcg, 25 mcg, or 50 mcg once daily for 2
In a crossover study in patients with COPD, when
arformoterol 15 mcg inhalation solution and 12 and 24
In a crossover study in patients with COPD, when
arformoterol 15 mcg inhalation solution and 12 and 24 mcg formoterol fumarate
inhalation powder (Foradil® Aerolizer®) was administered twice daily for 2 weeks,
the accumulation index was approximately 2.5 based on the plasma (R,R)-formoterol
concentrations in all three treatments. At steady- state, geometric means of
systemic exposure (AUC0-12h) to (R,R)-formoterol following 15 mcg of
arformoterol inhalation solution and 12 mcg of formoterol fumarate inhalation
powder were 39.33 pg•hr/mL and 33.93 pg•hr/mL, respectively (ratio 1.16; 90% CI
1.00, 1.35), while the geometric means of the Cmax were 4.30 pg/mL and 4.75
pg/mL, respectively (ratio 0.91; 90% CI 0.76, 1.09).
In a study in patients with asthma, treatment with
arformoterol 50 mcg with pre- and post-treatment with activated charcoal
resulted in a geometric mean decrease in (R,R)-formoterol AUC0-6h by 27% and C
by 23% as compared to treatment with arformoterol 50 mcg alone. This suggests
that a substantial portion of systemic drug exposure is due to pulmonary
The binding of arformoterol to human plasma proteins in
vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled
arformoterol. The concentrations of arformoterol used to assess the plasma
protein binding were higher than those achieved in plasma following inhalation
of multiple doses of 50 mcg arformoterol.
In vitro profiling studies in hepatocytes and liver
microsomes have shown that arformoterol is primarily metabolized by direct
conjugation (glucuronidation) and secondarily by O-demethylation. At least five
human uridine diphosphoglucuronosyltransferase (UGT) isozymes catalyze
arformoterol glucuronidation in vitro. Two cytochrome P450 isozymes (CYP2D6 and
secondarily CYP2C19) catalyze the O-demethylation of arformoterol.
Arformoterol was almost entirely metabolized following
oral administration of 35 mcg of radiolabeled arformoterol in eight healthy
subjects. Direct conjugation of arformoterol with glucuronic acid was the major
metabolic pathway. Most of the drug-related material in plasma and urine was in
the form of glucuronide or sulfate conjugates of arformoterol. O-Desmethylation
and conjugates of the Odesmethyl metabolite were relatively minor metabolites
accounting for less than 17% of the dose recovered in urine and feces.
After administration of a single oral dose of
radiolabeled arformoterol to eight healthy male subjects, 63% of the total
radioactive dose was recovered in urine and 11% in feces within 48 hours. A
total of 89% of the total radioactive dose was recovered within 14 days, with
67% in urine and 22% in feces. Approximately 1% of the dose was recovered as
unchanged arformoterol in urine over 14 days. Renal clearance was 8.9 L/hr for
unchanged arformoterol in these subjects.
In COPD patients given 15 mcg inhaled arformoterol twice
a day for 14 days, the mean terminal half-life of arformoterol was 26 hours.
A population PK analysis indicated that there was no
effect of gender upon the pharmacokinetics of arformoterol.
The influence of race on arformoterol pharmacokinetics
was assessed using a population PK analysis and data from healthy subjects.
There was no clinically significant impact of race upon the pharmacokinetic
profile of arformoterol.
The pharmacokinetic profile of arformoterol in 24 elderly
subjects (aged 65 years or older) was compared to a younger cohort of 24
subjects (18-45 years) that were matched for body weight and gender. No
significant differences in systemic exposure (AUC and Cmax) were observed when
the two groups were compared.
The pharmacokinetics of arformoterol have not been
studied in pediatric subjects.
The pharmacokinetic profile of arformoterol was assessed
in 24 subjects with mild, moderate, and severe hepatic impairment. The systemic
exposure (C and AUC) to arformoterol increased 1.3 to 2.4-fold in subjects with
hepatic impairment compared to 16 demographically matched healthy control subjects.
No clear relationship between drug exposure and the severity of hepatic
impairment was observed. BROVANA Inhalation Solution should be used cautiously
in patients with hepatic impairment.
The impact of renal disease upon the pharmacokinetics of
arformoterol was studied in 24 subjects with mild, moderate, or severe renal
impairment. Systemic exposure (AUC and Cmax) to arformoterol was similar in
renally impaired patients compared with demographically matched healthy control
When paroxetine, a potent inhibitor of CYP2D6, was
co-administered with BROVANA Inhalation Solution at steady-state, exposure to
either drug was not altered. Dosage adjustments of BROVANA Inhalation Solution
are not necessary when the drug is given concomitantly with potent CYP2D6 inhibitors.
Arformoterol did not inhibit CYP1A2, CYP2A6, CYP2C9/10,
CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 enzymes at > 1,000-fold
higher concentrations than the expected peak plasma concentrations following a
Arformoterol is eliminated through the action of multiple
drug metabolizing enzymes. Direct glucuronidation of arformoterol is mediated
by several UGT enzymes and is the primary elimination route. O-Desmethylation
is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise
healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was
no impact on systemic exposure to arformoterol compared to subjects with normal
CYP2D6 and/or UGT1A1 enzyme activities.
Animal Toxicology And/Or Pharmacology
In animal studies investigating its cardiovascular
effects, arformoterol induced dose-dependent increases in heart rate and
decreases in blood pressure consistent with its pharmacology as a
betaadrenergic agonist. In dogs, at systemic exposures higher than anticipated
clinically, arformoterol also induced exaggerated pharmacologic effects of a
beta-adrenergic agonist on cardiac function as measured by electrocardiogram
(sinus tachycardia, atrial premature beats, ventricular escape beats, PVCs).
Studies in laboratory animals (minipigs, rodents, and
dogs) have demonstrated the occurrence of arrhythmias and sudden death (with
histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines
are administered concurrently. The clinical significance of these findings is
Reproductive Toxicology Studies
Arformoterol has been shown to be teratogenic in rats
based upon findings of omphalocele (umbilical hernia), a malformation, at oral
doses of 1 mg/kg and above (AUC exposure approximately 370 times adult exposure
at the maximum recommended daily inhalation dose). Increased pup loss at birth
and during lactation and decreased pup weights were observed in rats at oral
doses of 5 mg/kg and above (AUC exposure approximately 1100 times adult
exposure at the maximum recommended daily inhalation dose). Delays in
development were evident with an oral dose of 10 mg/kg (AUC exposure approximately
2400 times adult exposure at the maximum recommended daily inhalation dose).
Arformoterol has been shown to be teratogenic in rabbits
based upon findings of malpositioned right kidney, a malformation, at oral
doses of 20 mg/kg and above (AUC exposure approximately 8400 times adult
exposure at the maximum recommended daily inhalation dose). Malformations
including brachydactyly, bulbous aorta, and liver cysts were observed at doses
of 40 mg/kg and above (approximately 22,000 times the maximum recommended daily
inhalation dose in adults on a mg/m² basis). Malformations including adactyly,
lobular dysgenesis of the lung, and interventricular septal defect were
observed at 80 mg/kg (approximately 43,000 times the maximum recommended daily inhalation
dose in adults on a mg/m² basis). Embryolethality was observed at 80 mg/kg/day (approximately
43,000 times the maximum recommended daily inhalation dose in adults on a mg/m²
basis). Decreased pup body weights were observed at doses of 40 mg/kg/day and
above (approximately 22,000 times the maximum recommended daily inhalation dose
in adults on a mg/m² basis). There were no teratogenic findings in rabbits with
oral dose of 10 mg/kg and lower (AUC exposure approximately 4900 times adult
exposure at the maximum recommended daily inhalation dose).
Adult COPD Trials
BROVANA (arformoterol tartrate) Inhalation Solution was
studied in two identical, 12-week, doubleblind, placebo- and active-controlled,
randomized, multi-center, parallel group trials conducted in the United States
(Clinical Trial A and Clinical Trial B). A total of 1,456 adult patients (age
range: 34 to 89 years; mean age: 63 years; gender: 860 males and 596 females)
with COPD who had a mean FEV1 of 1.3 L (42% of predicted) were enrolled in the
two clinical trials. The racial/ethnic distribution in these two trials
included 1383 Caucasians, 49 Blacks, 10 Asians, and 10 Hispanics, and 4
patients classified as Other. The diagnosis of COPD was based on a prior
clinical diagnosis of COPD, a smoking history (greater than 15 pack-years), age
(at least 35 years), spirometry results (baseline FEV1 ≤ 65% of predicted
value and > 0.70 L, and a FEV1 /forced vital capacity (FVC) ratio
≤ 70%). About 80% of patients in these studies had bronchodilator
reversibility, defined as a 10% or greater increase in FEV after inhalation of
2 actuations (180 mcg racemic albuterol from a metered dose inhaler). Both
trials compared BROVANA Inhalation Solution 15 mcg twice daily (288 patients),
25 mcg twice daily (292 patients), 50 mcg once daily (293 patients) with
placebo (293 subjects). Both trials included salmeterol inhalation aerosol, 42
mcg twice daily as an active comparator (290 patients).
In both 12-week trials, BROVANA Inhalation Solution 15
mcg twice daily resulted in a statistically significant change of approximately
11% in mean FEV1 (as measured by percent change from study baseline FEV1 at the
end of the dosing interval over the 12 weeks of treatment, the primary efficacy
endpoint) compared to placebo. Compared to BROVANA Inhalation Solution 15 mcg
twice daily, BROVANA Inhalation Solution 25 mcg twice daily and 50 mcg once
daily did not provide sufficient additional benefit on a variety of endpoints,
including FEV1, to support the use of higher doses. Plots of the mean change in
FEV1 values obtained over the 12 hours after dosing for the BROVANA Inhalation Solution
15 mcg twice daily dose group and for the placebo group are provided in Figures
1 and 2 for Clinical Trial A, below. The plots include mean FEV1 change
observed after the first dose and after 12 weeks of treatment. The results from
Clinical Trial B were similar.
Figure 1: Mean Change in FEV Over Time for Clinical
Trial A at Week 0 (Day 1)
Figure 2 : Mean Change in FEV Over Time for Clinical
Trial A at Week 12
BROVANA Inhalation Solution 15 mcg twice daily
significantly improved bronchodilation compared to placebo over the 12 hours
after dosing (FEV1 AUC0-12h). This improvement was maintained over the 12-week
Following the first dose of BROVANA Inhalation Solution
15 mcg, the median time to onset of bronchodilation, defined by an FEV1
increase of 15%, occurred at 6.7 min. When defined as an increase in FEV1 of
12% and 200 mL, the time to onset of bronchodilation was 20 min after dosing.
Peak bronchodilator effect was generally seen within 1-3 hours of dosing.
In both clinical trials, compared to placebo, patients
treated with BROVANA Inhalation Solution demonstrated improvements in peak
expiratory flow rates, supplemental ipratropium and rescue albuterol use.