##### National PBM Drug Monograph

####### Arformoterol tartrate (Brovana™)

###### VHA Pharmacy Benefits Management Service and Medical Advisory Panel

*The purpose of VACO PBM-SHG drug monographs is to provide a
comprehensive drug review for making formulary decisions.  These
documents will be updated when new data warrant additional formulary
discussion.  Documents will be placed in the Archive section when the
information is deemed to be no longer current.*

**EXECUTIVE SUMMARY**

Arformoterol is a long-acting beta-agonist (LABA) available in a
formulation for nebulizer use approved for the long-term maintenance
treatment of bronchoconstriction in patients with COPD. The dose of
arformoterol is 15mcg twice daily (morning and evening). It is not
presently approved for use in asthma or to manage acute deterioration of
COPD.

There are two 12-week double-blind, double-dummy, placebo-controlled
trials. Patients were randomized to one of 5 treatment groups:
arformoterol 15mcg or 25mcg BID, arformoterol 50mcg once daily,
salmeterol 42mcg BID, or placebo. The primary endpoint was the percent
change in trough FEV1 from baseline compared to placebo.

When compared to placebo, all active treatments resulted in
significantly improved pulmonary function as measured by percent change
in trough FEV1 from baseline and in the area under the percent change in
FEV1 curve from 0-12 hours (FEV1 AUC~0-12h~). The changes were similar
between arformoterol and salmeterol.

Compared to placebo, all active treatments showed improvement in dyspnea
(TDI score) and reduced need for supplemental short-acting agents.
Quality of life (SGRQ) improved with the active treatment groups;
however, the mean change in total score was not considered to be
clinically significant (change of [\>]{.underline} 4 units). For all
active treatments, the greatest improvement was seen in the symptom
domain of the SGRQ.

Arformoterol has a faster onset of activity (defined as [\>]{.underline}
10% increase in FEV1) than salmeterol.

Arformoterol was well tolerated. The rate of adverse events was similar
to salmeterol. Please note that patients with clinically significant
cardiac disorders or abnormal 12-lead EKG were excluded from the trial.

**INTRODUCTION**

Arformoterol is a long-acting beta-agonist available in a formulation
for nebulizer use. A second product, formoterol for nebulizer use, is
also available.

**PHARMACOLOGY**

Arformoterol is the (R, R)-enantiomer of formoterol. Racemic formoterol
contains both the (R, R) - and (S, S)-enantiomers. Based on binding
affinity and intrinsic activity studies, arformoterol was 2-fold more
potent than formoterol.

**PHARMACOKINETICS**

**Table 1: Pharmacokinetics of arformoterol**

+------------------+---------------------------------------------------+
| **Mean Cmax\***  | 4.3pg/mL                                          |
+------------------+---------------------------------------------------+
| **Median Tmax    | 0.5h                                              |
| \***             |                                                   |
+------------------+---------------------------------------------------+
| **Mean           | 34.5pg•hr/mL                                      |
| AUC~0-12h~\***   |                                                   |
+------------------+---------------------------------------------------+
| **Mean           | 26 hours                                          |
| half-life\***    |                                                   |
+------------------+---------------------------------------------------+
| **Protein        | 52-65%                                            |
| binding**        |                                                   |
+------------------+---------------------------------------------------+
| **Metabolism**   | Primary - glucuronidation via at least 5 UDT      |
|                  | isoenzymes                                        |
|                  |                                                   |
|                  | Secondary - O-demethylation via CYP2D6 (1°) and   |
|                  | CYP2C19 (2°)                                      |
+------------------+---------------------------------------------------+
| **Elimination¶** | urine 63%, feces 11% (within 48h)                 |
|                  |                                                   |
|                  | urine 67%, feces 22% (within 14 days)             |
+------------------+---------------------------------------------------+

\*Determined in patients with COPD receiving arformoterol 15mcg q12h x
14 days

¶ Based on single oral dose in healthy subjects

**FDA-APPROVED INDICATIONS**

Arformoterol nebulizer solution is indicated for the long-term
maintenance treatment of bronchoconstriction in patients with COPD.
Arformoterol is not indicated for maintenance treatment of asthma.

**DOSAGE**

The dose of arformoterol is 15mcg twice daily (morning and evening) via
nebulizer. No dilution of arformoterol is necessary prior to
administration. Doses greater than 15mcg BID are not recommended. The
PARI LC PLUS nebulizer and PARI DURA-NEB 3000 compressors were used in
clinical trials. The safety and efficacy of using other nebulizer
devices to administer arformoterol has not been established.
Arformoterol should be administered from a standard jet nebulizer at
adequate flow rates via face mask or mouthpiece.

Patients who have been taking regularly scheduled short-acting
beta-agonists should be instructed to discontinue these agents when
arformoterol is initiated. Short-acting agents should be used for as
needed symptomatic relief of acute symptoms.

**AVAILABILITY AND STORAGE**

Arformoterol inhalation solution is available in 2 mL unit dose vials
containing 15mcg of arformoterol (equivalent to 22mcg of arformoterol
tartrate). Each vial is overwrapped in a foil pouch. The vial, in its
foil pouch, should be stored under refrigeration at 36° - 46°F. Once the
foil pouch is opened, the contents should be used immediately. Unopened
foil pouches can be stored at room temperature (68° - 77°F) for up to 6
weeks (discard if not used within 6 weeks or if past the expiration,
whichever is sooner). Arformoterol comes in cartons of 30 and 60
unit-dose vials.

**CLINICAL TRIALS**

Single dose or short-term trials (\< 3-weeks duration) were not included
in this review.

*[12-week trials]{.underline}*

Two identical randomized, double-blind, double-dummy studies were
conducted comparing arformoterol (15mcg or 25mcg twice daily, or 50mcg
once daily) to placebo or salmeterol 42mcg bid over a 12-week
period.^1-3^ The primary endpoint was the percent change in trough FEV1
from baseline compared to placebo. One of these 2 studies has been
published.^2^

Criteria for entry into the trial included prior diagnosis of COPD;
smoking history of [\>]{.underline} 15 pack-years; [\>]{.underline} 35
years old; baseline FEV1 [\<]{.underline} 65% predicted and
[\>]{.underline} 0.70L; FEV1/FVC ratio [\<]{.underline} 70%; MRC Dyspnea
score [\>]{.underline} 2

Patients with the following were excluded from entry into the study:
history of life-threatening/ unstable respiratory status, including
upper or lower respiratory tract infection within 30 days prior to
screening; asthma or any chronic respiratory disorder other than COPD;
lung resection of more than 1 full lobe; requires continuous
supplemental O2; clinically significant cardiac disorders or abnormal
12-lead EKG

The mean age of the study population was 63 ± 9.1years (range 34-89
years) and 59.1% were male. Mean FEV1 percent predicted was 40.6 ±
12.8%. Inhaled or oral steroids were used in 27.6% of patients.
Approximately 46% of patients were current smokers (87% with history of
[\>]{.underline} 30 pack-year smoking). Bronchodilator reversibility
([\>]{.underline} 10% increase in FEV1 after albuterol 180mcg via MDI)
was noted in 80% of patients.

Refer to the appendix for detailed results of study. Compared to
placebo, all active treatments resulted in significantly improved
pulmonary function as measured by percent change in trough FEV1 from
baseline and percent change in FEV1 AUC~0-12h~. The changes were similar
between arformoterol and salmeterol. Tolerance or tachyphylaxis was seen
with arformoterol and salmeterol. At week 6, there was approximately a
33% and 28% decrease in bronchodilator effect as measured by FEV1 in the
arformoterol and salmeterol groups respectively. This decrease remained
stable over weeks 6-12.

Compared to placebo, all active treatments showed improvement in dyspnea
(TDI score) and reduced need for supplemental short-acting agents.
Quality of life (SGRQ) improved with the active treatment groups;
however, the mean change in total score was not considered clinically
significant (change of [\>]{.underline} 4 units). For all active
treatments, the greatest improvement was seen in the symptom domain of
the SGRQ.

*[Long-term trials]{.underline}*

Study 091-060 was an open-label 52-week trial comparing arformoterol
50mcg once daily (n=528) and salmeterol 42mcg BID (n=265).^3^ This trial
was designed as a safety study looking at a worst case scenario using a
high unapproved dose of arformoterol. Approximately 60% of the patients
were rolled over from the two 12-week trials described above. Efficacy
evaluation was considered exploratory.

> [Efficacy results shown for arformoterol and salmeterol
> respectively]{.underline}

-   Both groups had approx 6% improvement in pre-dose FEV1 from baseline

-   Similar decrease in ipratropium use: days/wk (-1.3 and -1.4);
    actuations/day (-1.3 and -1.2)

-   Similar decrease in albuterol use: days/wk (-1.1 and -0.9);
    actuations/day (-1.0 and -0.9)

-   Improvement in symptom-free days (0.25 and 0.1 days/wk)

-   Increase in symptom-free nights (0.5 and 0.1 nights/wk)

**SAFETY**

Safety was assessed in 1968 patients (\~ 59 patient exposure-years). The
number of patients exposed to arformoterol for up to 12 weeks were 342
and 345 for the 15 and 25mcg bid doses respectively. 383 patients
received arformoterol 50mcg once daily for at least 6 months and 308 for
1 year.^4^

Results for the single published study and the pooled data did not
substantially differ; therefore, safety data from the two pooled 12-week
trials are presented below.^5^

Rates of adverse events and resultant discontinuations are shown in
table 2. There were 5 (0.6%) deaths in the arformoterol groups and none
in the salmeterol or placebo groups. None of the deaths were related to
treatment. ^5^

**Table 2: Pooled results from two 12-week trials**

  ------------- ----------- ----------- ----------- ----------- -------------
                **A15 bid** **A25 bid** **A50 QD**  **SAL bid** **Placebo**

  Any AE        70.1%       72.3%       77.5%       74.5%       74.7%

  d/c due to    6.6%        11.3%       8.2%        7.9%        9.2%
  any AE                                                        

  Serious AE    4.9%        6.2%        5.5%        3.8%        6.5%

  COPD AEs      7.3%        8.9%        9.9%        9.3%        8.2%

  d/c due to    1.4%        2.4%        2.4%        2.8%        3.1%
  COPD AE                                                       

  Serious COPD  1.0%        1.7%        2.0%        1.0%        2.0%
  AE                                                            
  ------------- ----------- ----------- ----------- ----------- -------------

**COPD adverse events=** COPD worsening or COPD exacerbation

Table 3 shows β-mediated and cardiac adverse events and COPD
exacerbations. COPD exacerbations were defined as respiratory adverse
events or symptoms leading to changes in baseline medication or
additional medical attention. Post hoc, the definition was expanded to
include adverse events of asthma, bronchitis, pneumonia, COPD, cough,
increased cough, dyspnea, increased sputum, apnea, or hypoxia.

**Table3: Pooled results from two 12-week trials**

  --------------- ----------- ----------- ----------- ----------- -------------
                  **A15 bid** **A25 bid** **A50 QD**  **SAL bid** **Placebo**

  Nervousness     0.7%        1.4%        3.4%        0.3%        0.7%

  Tremor          1.4%        2.4%        9.2%        0.7%        0.3%

  Insomnia        2.1%        4.1%        3.1%        1.4%        2.0%

  Cardiac         0.7%        0.7%        1.4%        0.7%        1.4%
  ischemia                                                        

  Arrhythmia      3.1%        5.5%        3.1%        5.5%        4.4%

  COPD            12.2%       13.5%       13%         14.2%       15.1%
  exacerbations                                                   
  (protocol                                                       
  defined)                                                        

  COPD            21.3%       21.8%       20.5%       23.2%       22.6%
  exacerbations                                                   
  (post-hoc                                                       
  defined)                                                        
  --------------- ----------- ----------- ----------- ----------- -------------

**Cardiac ischemic events=**angina pectoris, bundle branch block,
coronary artery disorder, myocardial infarct, myocardial ischemia, ST
depressed, ST elevated, T inverted.

**Arrhythmic events=** atrial or ventricular flutter, AV block, 2°AV
block, extrasystoles, ventricular or supraventricular extrasystoles,
heart block , syncope, ventricular or supraventricular tachycardia,
ventricular arrhythmia

The following adverse events occurred at a rate [\>]{.underline} 2% in
the arformoterol 15mcg bid group [and]{.underline} exceeded that of the
placebo group: pain (8% vs. 5%); chest pain (7% vs. 6%); back pain (6%
vs. 2%); diarrhea (6% vs. 4%); sinusitis (5% vs. 4%); leg cramps (4% vs.
2%); dyspnea (4% vs. 2%); rash (4% vs. 2%); flu syndrome (3% vs. 1%);
peripheral edema (3% vs. 2%); pulmonary/chest congestion (2% vs. 1%).^6^

*[Electrophysiology Studies]{.underline}*

EKGs assessing change in ventricular heart rate and QTc-interval were
evaluated 2 and 6 hours post-dose at weeks 0 and 12.^5^

-   The greatest mean increase in ventricular heart rate occurred in the
    arformoterol 50mcg once daily (2.97 ± 8.4 beats/minute; 6-hours
    post-dose at week 0) and salmeterol (3.13 ± 10.4 beats/minute;
    6-hours post-dose at week 12) groups.

-   The greatest mean increase in QTc-interval occurred in the
    arformoterol 50mcg once daily group (4.12 ± 15.5msec; 6-hours
    post-dose at week 0). In the salmeterol group, the greatest mean
    increase in QTc-interval was 3.59± 15.8msec (6-hours post-dose at
    week 0).

-   A [\>]{.underline} 60msec change on at least 1 post-dose EKG was
    seen in all groups as follows: arformoterol 15mcg bid (1.8%), 25mcg
    bid (0.7%), 50mcg QD (1.0%), salmeterol (1.4%), and placebo (1.0%).

-   A QTc interval of \> 500msec was seen in 0.7% and 0.3% of patients
    in the arformoterol 15mcg bid and 50mcg QD groups respectively. No
    patient in the arformoterol 25mcg bid, salmeterol, or placebo group
    had a \> 500msec change.

Patients underwent 24-hour Holter monitoring at weeks 0 and up to 3
times during the treatment period. Newly occurring arrhythmic events are
shown in table 4. Atrial tachycardia was the most commonly reported
event in all treatment groups, including placebo.^5^

**Table 4**: Arrhythmic events (not present at baseline) determined by
24-hour Holter monitoring

+-----------+-----------+-----------+-----------+-----------+-----------+
|           | **A15     | **A25     | **A50     | **SAL     | **        |
|           | bid**     | bid**     | QD**      | bid**     | Placebo** |
|           |           |           |           |           |           |
|           | **(n=277  | **(n=286  | **(n=289  | **(n=280  | **(n=285  |
|           | week 0)** | week 0)** | week 0)** | week 0)** | week 0)** |
|           |           |           |           |           |           |
|           | **(n=220  | **(n=214  | **(n=234  | **(n=236  | **(n=219  |
|           | week      | week      | week      | week      | week      |
|           | 12)**     | 12)**     | 12)**     | 12)**     | 12)**     |
+-----------+-----------+-----------+-----------+-----------+-----------+
| Atrial    | 17.7%/    | 15.4%/    | 17.3%/    | 18.2%/    | 14.7%/    |
| ta        | 18.6%     | 16.8%     | 16.2%     | 18.6%     | 15.5%     |
| chycardia |           |           |           |           |           |
|           |           |           |           |           |           |
| (week 0/  |           |           |           |           |           |
| week 12)  |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| Atrial    | 0/ 0.5%   | 0.3%/ 0   | 0.3%/     | 0/0       | 0/ 0.5%   |
| fi        |           |           | 0.9%      |           |           |
| b/flutter |           |           |           |           |           |
|           |           |           |           |           |           |
| (week 0/  |           |           |           |           |           |
| week 12)  |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| Non       | 2.9%/     | 3.8%/     | 3.1%/     | 2.9%/     | 3.5%/     |
| sustained | 3.2%      | 1.4%      | 2.1%      | 2.1%      | 2.7%      |
| VT        |           |           |           |           |           |
|           |           |           |           |           |           |
| (week 0/  |           |           |           |           |           |
| week 12)  |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| Sustained | 0.4%/ 0   | 1.0%/ 0   | 0.7%/     | 1.8%/     | 0.4%/     |
| VT        |           |           | 0.4%      | 0.4%      | 0.9%      |
|           |           |           |           |           |           |
| (week 0/  |           |           |           |           |           |
| week 12)  |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+

*[Change in serum potassium and glucose]{.underline}*

In the pooled results from the two 12-week trials, serum potassium was
obtained 2 and 6 hours after the first dose and at week 12. There was a
very small dose-dependent decrease in serum potassium for arformoterol.
The mean decrease in potassium ranged from 0.07-0.29mEq/L for all
arformoterol groups (greatest mean decrease occurred in the arformoterol
50mcg once daily group, 6-hours after the first dose). The mean decrease
in the salmeterol group ranged from 0.03-0.21mEq/L. No patient had a
serum potassium level of \< 3.0mEq/L.^5^

In a dose ranging study serum glucose was obtained 2 and 6 hours after
the first dose and after 2 weeks of treatment. Six doses were evaluated
(5mcg, 15mcg, 25mcg administered BID and 15mcg, 25mcg, 50mcg
administered once daily). Change in mean serum glucose levels ranged
from -1.2 to +32.8mg/dL for arformoterol.^6^

*[52-week trial]{.underline}*

The 52-week trial compared an unapproved dose of arformoterol (50mcg
once daily) to salmeterol 42mcg BID. The percentage of patients
reporting any adverse event was 90.5% and 88.3% for arformoterol and
salmeterol respectively. The majority of reactions were considered to be
mild to moderate in nature and determined not to be related to the study
drugs.^3^

The most frequently reported adverse events were respiratory-related,
which occurred at a similar rate for arformoterol and salmeterol.
Adverse events related to the nervous system (dizziness, insomnia,
nervousness, and tremor) occurred more frequently with arformoterol than
salmeterol (30.5% vs. 8.5%).

Protocol defined COPD exacerbations were slightly higher in the
arformoterol group than the salmeterol group (data not shown). In both
groups, the incidence of COPD exacerbations declined over the 12 month
study period.

**CONTRAINDICATIONS**

A history of hypersensitivity to arformoterol, formoterol, or other
components of the product

**WARNINGS/PRECAUTIONS**

Other studies with long-acting beta-agonists showed an increase in
asthma-related deaths. It is unknown if arformoterol has a similar risk
in this patient population.

Data are not available to determine if the rate of death in patients
with COPD is increased with use of long-acting beta-agonists.

Arformoterol should not be used for rescue therapy or for patients with
acutely deteriorating COPD.

Arformoterol should not be used with other long-acting beta-agonists or
with regularly scheduled short-acting beta-agonists (e.g. 4 x daily
use). Short-acting beta-agonists on an as needed basis should be
available for relief of acute respiratory symptoms.

Drug compatibility and safety/efficacy of mixing arformoterol with other
nebulized drugs has not been established.

Use with caution in patients with cardiovascular disorders, especially
coronary insufficiency, cardiac arrhythmias, and hypertension; in
patients with convulsive disorders or thyrotoxicosis; and in patients
who are unusually responsive to sympathomimetic amines. Like other
beta~2~-agonists, arformoterol can produce a clinically significant
cardiovascular effect in some patients as measured by increases in pulse
rate, blood pressure, and/or symptoms.\
\
Administer with extreme caution to patients being treated with monoamine
oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong
the QTc interval because the action of adrenergic agonists on the
cardiovascular system may be potentiated by these agents.

As with other beta-agonists, arformoterol may cause hypokalemia and
transient hyperglycemia.

Plasma drug concentrations were 1.5-2 fold higher in patients with
hepatic impairment and was not associated with degree of impairment.
While dosage adjustment is not required, patients with hepatic
impairment should be closely monitored.

**LOOK-ALIKE/SOUND-ALIKE**

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names may be potential sources
of drug name confusion:

Brand name Brovana: Boniva

Generic name arformoterol: formoterol nebulizer solution, formoterol dry
powder inhaler, albuterol, salmeterol, levalbuterol

**DRUG INTERACTIONS**

Co-administration of paroxetine (potent CYP2D6 inhibitor) and
arformoterol for 7 days did not significantly alter the pharmacokinetic
parameters of either drug. Dosage adjustment of arformoterol is not
necessary when given concomitantly with CYP2D6 inhibitors.

As seen with other beta-agonists, the risk for hypokalemia may be
increased when arformoterol is co-administered with other drugs known to
decrease potassium (e.g. diuretics, xanthines, steroids).

Use with extreme caution in patients treated with other QT-interval
prolonging drugs. (See warnings/precautions)

**COST**

The VA cost for 30 doses of arformoterol 15mcg is \$92.11. Since this
drug is dosed BID, the monthly cost would be \$184.22. VA pricing was
not available for the 60-unit package.

**Table 5:** **Cost of beta-agonist solutions for nebulizer**

+---------------+----------+-------------+-------------+-------------+
|               | **Usual  | **          | *           | **C         |
|               | dose**   | Cost/dose** | *Cost/day** | ost/month** |
+---------------+----------+-------------+-------------+-------------+
| Arformoterol  | 15mcg    | \$3.07      | \$6.14      | \$184.22    |
| 15mcg/2mL     | bid      |             |             |             |
| unit dose     |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Formoterol    | 20mcg    | \$3.46      | \$6.93      | \$207.80    |
| 20mcg/2mL     | bid      |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Albuterol     | 2.5mg    | \$0.084     | 0.252 --    | \$7.56 --   |
| 0.083%        | tid-qid  |             | 0.336       | 10.08       |
| (2.5mg/3mL)   |          |             |             |             |
| unit dose     |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Albuterol     | 2.5mg    | \$0.052     | \$0.156 --  | \$4.68-     |
| 0.5% (5mg/mL) | tid-qid  |             | 0.21        | 6.24        |
| concentrate   |          |             |             |             |
| 20mL vial     |          |             |             |             |
| with dropper  |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Levalbuterol  | 0.63mg   | \$1.39      | \$4.17      | \$124.99    |
| 0.63mg/3mL    | tid      |             |             |             |
| unit dose     |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Levalbuterol  | 1.25mg   | \$0.96      | \$2.88      | \$86.47     |
| 1.25mg/3mL    | tid      |             |             |             |
| unit dose     |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Levalbuterol  | 1.25mg   | \$1.49      | \$4.47      | \$134.01    |
| concentrate   | tid      |             |             |             |
| 1.25mg/0.5mL  |          |             |             |             |
| unit dose     |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Albutero      | 1 vial   | \$0.79      | \$3.16      | \$94.90     |
| l/ipratropium | qid      |             |             |             |
| (3mg/0.5mg)   |          |             |             |             |
|               |          |             |             |             |
| 3mL unit dose |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+

**FUTURE STUDIES**

There are no long-term data with the marketed dose of arformoterol;
however, a large multi-center, randomized, placebo-controlled safety
trial to evaluate risk of fatal and life-threatening respiratory events
associated with long term use in patients with COPD is planned.

There are no data using arformoterol in the in-patient setting or for
acute exacerbation of COPD. There are no planned studies at this time.

There are no studies using arformoterol for maintenance treatment of
asthma in adults. There will be a safety and efficacy study evaluating
acute exacerbation of asthma in children 12 years and younger and a
safety and tolerability study in children 12 years and younger with
asthma

**SUMMARY/RECOMMENDATIONS**

The efficacy and safety of arformoterol via nebulizer was comparable to
salmeterol via metered-dose inhaler. There are no data comparing
arformoterol to nebulized albuterol or levalbuterol; therefore, how
arformoterol compares with the agents it is likely to replace is
unknown.

Because arformoterol cannot be mixed with other nebulizer solutions such
as ipratropium, switching from a short-acting beta-agonist to
arformoterol is unlikely to improve convenience for most patients who
are using both agents.

Administration of drugs via nebulizer is sometimes used for patients who
are unable to coordinate their breath with actuation of the metered-dose
inhaler (MDI). Formoterol and salmeterol are available as dry-powder
inhalers and may be easier for patients to use than MDIs. If not
previously tried, a LABA via DPI should be considered first.

For patients who remain symptomatic on monotherapy with nebulized
short-acting beta-agonists, adding nebulized ipratropium (unless
contraindicated) or other bronchodilators via DPI should be considered
before switching to arformoterol solution.

Switching from a nebulized short-acting beta-agonist to arformoterol may
be helpful for patients who have frequent nighttime symptoms that
interfere with sleep.

**REFERENCES**

1.  Hanrahan JP, Sahn SA, Busse W, et al. Efficacy of nebulized
    arformoterol, a long-acting beta2-adrenergic bronchodilator, in
    patients with COPD: results from two pooled phase III trials. Poster
    presented at: Annual European Respiratory Society September 2-9^th^,
    2006; Munich Germany.

2.  Baumgartner FA, Nanania NA, Calhoun WJ, et al. Nebulized
    arformoterol in patients with COPD: a 12-week multicenter,
    randomized, double-blind, double-dummy placebo- and
    active-controlled trial.

Clin Ther 2007; 29: 261-278.

3.  AMCP Dossier for Brovana

4.  Brovana Inhalation Solution General Summary (provided by Sepracor)

5.  Hanrahan JP, Kerwin EM, Cheng H, et al. Nebulized arformoterol, a
    long-acting beta2-adrenergic bronchodilator, in COPD: Safety results
    from two pooled phase III trials. Poster presented at: Annual
    European Respiratory Society September 2-9^th^, 2006; Munich
    Germany.

6.  Product package insert for Brovana. October 2006

  -----------------------------------------------------------------------
  **Prepared October 2007 Contact Person: Deb Khachikian, Pharm D**

  -----------------------------------------------------------------------

**Appendix: Efficacy Results**

+---------------+------------------------------------------------------+
| **Study**     | **Results**                                          |
+---------------+------------------------------------------------------+
| Hanrahan^1^   | +-------------+------+------+------+------+------+   |
|               | |             | *    | *    | *    | *    | **   |   |
| Pooled        | |             | *A15 | *A25 | *A50 | *SAL | PL** |   |
| results from  | |             | b    | b    | qd** | b    |      |   |
| Baumgartner   | |             | id** | id** |      | id** |      |   |
| and study     | +-------------+------+------+------+------+------+   |
| 091-051       | | \%          | 92%  | 9    | 9    | 8    | 5    |   |
|               | | responders  |      | 4.2% | 4.1% | 5.9% | 5.2% |   |
| n=1456        | | (1^st^      | 8    |      |      |      |      |   |
|               | | dose/week   | 2.5% | 7    | 8    | 5    | 4    |   |
| Arformoterol  | | 12)\*       |      | 8.4% | 6.6% | 6.1% | 3.9% |   |
| 15mcg BID     | +-------------+------+------+------+------+------+   |
| (n=288)       | | Median time | 2.   | 1.   | 2.   | 14.  | 179. |   |
|               | | to resp     | 9min | 9min | 2min | 3min | 2min |   |
| Arformoterol  | | (1^st^      |      |      |      |      |      |   |
| 25mcg BID     | | dose/ week  | 10.  | 12.  | 3.   | 142. | 353. |   |
| (n=292)       | | 12)\*       | 1min | 8min | 1min | 4min | 4min |   |
|               | +-------------+------+------+------+------+------+   |
| Arformoterol  | | Trough FEV1 | 22.  | 25.  | 20.  | 21.  | 6    |   |
| 50mcg QD      | | (%Δ from    | 13%† | 94%† | 13%† | 46%† | .88% |   |
| (n=293)       | | baseline)   |      |      |      |      |      |   |
|               | |             | 14.  | 17.  | 15.  | 15.  | 4    |   |
| Salmeterol    | | post-1^st^  | 63%† | 78%† | 33%† | 47%† | .71% |   |
| 42mcg MDI bid | | dose/week   |      |      |      |      |      |   |
| (n=290)       | | 12          |      |      |      |      |      |   |
|               | +-------------+------+------+------+------+------+   |
| Placebo       | | FEV1        | 22.  | 25.  | 27.  | 19.  | 3    |   |
| (n=293)       | | AUC~0-12h~  | 56%† | 59%† | 87%† | 33%† | .50% |   |
|               | | (%Δ from    |      |      |      |      |      |   |
|               | | pre-dose)   | 8.   | 7.   | 15.  | 4    | 2    |   |
|               | |             | 39%† | 53%† | 18%† | .25% | .51% |   |
|               | | post-1^st^  |      |      |      |      |      |   |
|               | | dose/week   |      |      |      |      |      |   |
|               | | 12          |      |      |      |      |      |   |
|               | +-------------+------+------+------+------+------+   |
|               |                                                      |
|               | \*Defined as [\>]{.underline} 10% increase in FEV1   |
|               |                                                      |
|               | †Significant vs. placebo                             |
+---------------+------------------------------------------------------+
| Baumgartner   | <table>                                              |
| 2007^2^       | <colgroup>                                           |
|               | <col style="width: 30%" />                           |
| R, DB, DD, PC | <col style="width: 14%" />                           |
|               | <col style="width: 0%" />                            |
| ITT analysis  | <col style="width: 13%" />                           |
|               | <col style="width: 1%" />                            |
| n=724         | <col style="width: 12%" />                           |
|               | <col style="width: 2%" />                            |
| Arformoterol  | <col style="width: 11%" />                           |
| 15mcg BID     | <col style="width: 3%" />                            |
| (n=141)       | <col style="width: 8%" />                            |
|               | </colgroup>                                          |
| Arformoterol  | <tbody>                                              |
| 25mcg BID     | <tr class="odd">                                     |
| (n=143)       | <td></td>                                            |
|               | <td><strong>A15 bid</strong></td>                    |
| Arformoterol  | <td colspan="2"><strong>A25 bid</strong></td>        |
| 50mcg QD      | <td colspan="2"><strong>A50 QD</strong></td>         |
| (n=146)       | <td colspan="2"><strong>SAL bid</strong></td>        |
|               | <td colspan="2"><strong>PL</strong></td>             |
| Salmeterol    | </tr>                                                |
| 42mcg MDI bid | <tr class="even">                                    |
| (n=144)       | <td>FEV1</td>                                        |
|               | <td colspan="9">See above for pooled results by      |
| Placebo       | Hanrahan</td>                                        |
| (n=143)       | </tr>                                                |
|               | <tr class="odd">                                     |
| PRN albuterol | <td>Mean change in TDI score</td>                    |
| allowed for   | <td colspan="2">2.0†</td>                            |
| rescue        | <td colspan="2">2.2†</td>                            |
|               | <td colspan="2">2.1†</td>                            |
| Ipratropium   | <td colspan="2">1.4</td>                             |
| was provided  | <td>1.1</td>                                         |
| for           | </tr>                                                |
| supplemental  | <tr class="even">                                    |
| medication on | <td>% pts. with <u>&gt;</u>1 unit improvement in     |
| a PRN basis   | TDI score at week 12</td>                            |
|               | <td colspan="5">57-62%</td>                          |
| Stable doses  | <td colspan="3">51%</td>                             |
| of steroids,  | <td>37%</td>                                         |
| xanthines,    | </tr>                                                |
| and           | <tr class="odd">                                     |
| leukotriene   | <td><p>Mean change in SGRQ total score</p>           |
| inhibitors    | <p>(diff vs. placebo) [95%CI] at week 6</p></td>     |
| were allowed  | <td colspan="2">-1.62 [-3.85, 0.61]</td>             |
| (they were    | <td colspan="2">-2.44 [-4.62, -0.26] †</td>          |
| withheld for  | <td colspan="2">-1.41 [-3.64, 0.83]</td>             |
| at least 24h  | <td colspan="2">-3.18 [-5.44, -0.92] †</td>          |
| prior to each | <td></td>                                            |
| clinic visit) | </tr>                                                |
|               | <tr class="even">                                    |
|               | <td>Δ in # days/ week of rescue albuterol use        |
|               | weeks 0-12 (diff vs. placebo)</td>                   |
|               | <td colspan="2">-0.42 [-0.85, 0]</td>                |
|               | <td colspan="2">-0.91 [-1.36, -0.46]†</td>           |
|               | <td colspan="2">-0.52 [-0.96, -0.07]†</td>           |
|               | <td colspan="2">-0.50 [-0.93, -0.07]†</td>           |
|               | <td></td>                                            |
|               | </tr>                                                |
|               | <tr class="odd">                                     |
|               | <td>Δ in # puffs/ day of rescue albuterol use        |
|               | weeks 0-12 (diff vs. placebo)</td>                   |
|               | <td colspan="2">-0.68 [-1.07, -0.29]†</td>           |
|               | <td colspan="2">-0.95 [-1.44, -0.46]†</td>           |
|               | <td colspan="2">-0.75 [-1.15, -0.34]†</td>           |
|               | <td colspan="2">-0.5 [-0.99, -0.21]†</td>            |
|               | <td></td>                                            |
|               | </tr>                                                |
|               | <tr class="even">                                    |
|               | <td><p>Δ in # days/ week of supplemental             |
|               | ipratropium use weeks 0-12</p>                       |
|               | <p>(diff vs. placebo)</p></td>                       |
|               | <td colspan="2">-0.52 [-0.97, -0.07]†</td>           |
|               | <td colspan="2">-0.60 [-1.05, -0.15]†</td>           |
|               | <td colspan="2">-0.61 [-1.07, -0.16]†</td>           |
|               | <td colspan="2">-0.58 [-1.03, -0.12]†</td>           |
|               | <td></td>                                            |
|               | </tr>                                                |
|               | <tr class="odd">                                     |
|               | <td><p>Δ in # puffs/ day of supplemental             |
|               | ipratropium use weeks 0-12</p>                       |
|               | <p>(diff vs. placebo)</p></td>                       |
|               | <td colspan="2">-0.57 [-0.98, -0.17]†</td>           |
|               | <td colspan="2">-0.53 [-0.98, -0.08]†</td>           |
|               | <td colspan="2">-0.62 [-1.0, -0.24]†</td>            |
|               | <td colspan="2">-0.62 [-1.0, -0.23]†</td>            |
|               | <td></td>                                            |
|               | </tr>                                                |
|               | </tbody>                                             |
|               | </table>                                             |
|               |                                                      |
|               | †Significant vs. placebo                             |
+---------------+------------------------------------------------------+
| Study         |   ---------------                                    |
| 091-051^3^    | ---- -------------- ------- ------- ------- -------- |
|               |                                                      |
| Same study    |        **A15 bid**    **A25   **A50   **SAL   **PL** |
| design as in  |                                                      |
| Baumgartner   |                             bid**   QD**    bid**    |
| et al.        |                                                      |
|               |   FEV1                                               |
| n=739         |              See above for                           |
|               |                                                      |
| Arformoterol  |              pooled results                          |
| 15mcg BID     |                                                      |
| (n=147)       |              by Hanrahan                             |
|               |                                                      |
| Arformoterol  |   Mean chang                                         |
| 25mcg BID     | e in TDI  1.6-2.1                        2.2     not |
| (n=149)       |   score                                              |
|               |                                                shown |
| Arformoterol  |                                                      |
| 50mcg QD      |   \% pts. wi                                         |
| (n=146)       | th        48-60%                         59%     44% |
|               |   [\>]{.u                                            |
| Salmeterol    | nderline}1                                           |
| 42mcg MDI bid |   unit im                                            |
| (n=146)       | provement in                                         |
|               |   TDI sco                                            |
| Placebo       | re at week                                           |
| (n=150)       |   12                                                 |
|               |                                                      |
|               |                                                      |
|               |   Mean change                                        |
|               |  in SGRQ -2.6 to -3.5                           -0.2 |
|               |   total s                                            |
|               | core at week (all active                             |
|               |   6                                                  |
|               |              treatments)                             |
|               |                                                      |
|               |   Supplem                                            |
|               | ental        Use declined                            |
|               |   ipratro                                            |
|               | pium or      for all active                          |
|               |   albuter                                            |
|               | ol use       treatments                              |
|               |                                                      |
|               |              compared to                             |
|               |                                                      |
|               |              placebo. The                            |
|               |                                                      |
|               |              greatest                                |
|               |                                                      |
|               |              decrease was                            |
|               |                                                      |
|               |              seen with                               |
|               |                                                      |
|               |              arformoterol                            |
|               |                                                      |
|               |              15mcg and                               |
|               |                                                      |
|               |              salmeterol                              |
|               |   ---------------                                    |
|               | ---- -------------- ------- ------- ------- -------- |
|               |                                                      |
|               | p values or confidence intervals were not provided   |
|               | in the AMCP dossier                                  |
+---------------+------------------------------------------------------+