##### National PBM Drug Monograph

####### Formoterol Fumarate Inhalation Solution (Perforomist™)

###### 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information is deemed to be no longer current.*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**

Formoterol, a long-acting beta-agonist (LABA), is now available in a
formulation for nebulizer use. It is approved for the long-term
maintenance treatment of bronchoconstriction in patients with COPD. The
dose of formoterol is 20mcg twice daily (morning and evening). It is not
presently approved for use in asthma or to manage acute deterioration of
COPD.

There is one 12-week double-blind, double-dummy, placebo-controlled
trial. Patients were randomized to receive formoterol 20mcg BID by
nebulizer, formoterol 12mcg BID by dry powder inhaler (DPI), or placebo.
The primary endpoint was the post-morning dose FEV1 AUC ~0-12h~ versus
placebo.

Compared to placebo, formoterol improved pulmonary function (FEV1
AUC~0-12h~ and peak and trough FEV1), quality of life based on St.
George's Hospital Respiratory Questionnaire (SGRQ), and need for rescue
albuterol. There was no significant difference in improvement in
pulmonary function and rescue albuterol use between formoterol by
nebulizer or DPI. Both formulations improved the SGRQ total score, but
only formoterol nebulizer was considered significant versus placebo. For
the SGRQ symptoms domain, both formulations were significantly better
than placebo.

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

**INTRODUCTION**

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

**PHARMACOKINETICS**

**Table 1: Pharmacokinetics of Formoterol^4^**

+----------------+-----------------------------------------------------+
| Mean Cmax      | Essentially undetectable (10mcg and 20mcg nebulized |
|                | and 12mcg dry powder)                               |
| (single-dose)  |                                                     |
|                | 72pg/mL (244mcg dose which is \~ 12 x the           |
|                | recommended clinical dose)                          |
+----------------+-----------------------------------------------------+
| Tmax           | \~ 12 minutes for the 244mcg single dose            |
| (single-dose)  |                                                     |
+----------------+-----------------------------------------------------+
| Mean half-life | \~ 7 hours (based on 244mcg dose)                   |
+----------------+-----------------------------------------------------+
| Protein        | Human plasma proteins: 61-64% over concentrations   |
| binding        | of 0.1-100ng/mL                                     |
|                |                                                     |
| (determined    | Human serum albumin: 31-38% over concentrations of  |
| *in vitro*)    | 5-500ng/mL                                          |
+----------------+-----------------------------------------------------+
| Metabolism     | -   Major pathways include direct glucuronidation   |
|                |     and O-demethylation followed by conjugation at  |
|                |     the phenolic 2'-hydroxyl group                  |
|                |                                                     |
|                | -   Minor pathways include sulfate conjugation and  |
|                |     deformylation followed by sulfate conjugation   |
+----------------+-----------------------------------------------------+
| CYP450 enzymes | O-demethylation is catalyzed by CYP2D6, CYP2C19,    |
|                | CYP2C9, and CYP2A6                                  |
+----------------+-----------------------------------------------------+
| Amount         | 109.7ng (10mcg dose)                                |
| excreted       |                                                     |
| unchanged in   | 349.6ng (20mcg dose)                                |
| urine          |                                                     |
| (single-dose)  | 3317.5ng (244mcg dose)                              |
+----------------+-----------------------------------------------------+

In the 12-week clinical trial, the median time to onset of
bronchodilation after the first dose (defined as FEV1 increase of 12%
and 200mL) was 13.1 minutes or 11.7 minutes if defined as a 15% increase
in FEV1. The median time to peak bronchodilator effect was 2 hours
post-dose.^1^

**FDA-APPROVED INDICATIONS**

Formoterol nebulizer solution is indicated for maintenance treatment of
bronchoconstriction in patients with COPD, including chronic bronchitis
and emphysema.

Formoterol solution is NOT indicated to treat the following:

-   Acute deterioration of COPD disease

-   Maintenance treatment of asthma

**DOSAGE**

The dose of formoterol is 20mcg every 12 hours via nebulizer. No
dilution of formoterol is necessary prior to administration. Doses
greater than 20 mcg BID are not recommended. The PARI LC PLUS nebulizer
with a PRONEB Ultra compressor was used in clinical trials. The safety
and efficacy of using non-compressor-based nebulizer devices to
administer formoterol has not been established. Formoterol should be
administered from a standard jet nebulizer connected to an air
compressor.

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**

Formoterol inhalation solution is available in 2 mL unit dose vials
containing 20mcg of formoterol. Each vial is overwrapped in a foil
pouch. Prior to dispensing to the patients, the vial in its foil pouch,
should be stored under refrigeration at 36° - 46°F. After dispensing to
the patient, the vial in it s foil pouch can be stored at 36° - 77°F for
up to 3 months. Once the foil pouch is opened, the contents should be
used immediately. Formoterol comes in a carton of 60 unit-dose vials.

**CLINICAL TRIALS**

There is 1 randomized, double-blind, double-dummy study comparing
formoterol 20mcg via nebulization, formoterol dry powder inhaler or
placebo twice daily over a 12-week period (study 201-065).^1,\ 2^ The
primary endpoint was post-morning dose FEV1 AUC ~0-12h~ versus placebo.
Completers and the last observation for dropouts were used in the
analysis.

The mean age of the study population was 62.8 ± 9.1 years. Mean FEV1
percent predicted was 44.5 ± 12.1%. There were 52% who currently smoked.
Bronchodilator reversibility (≥10% increase in FEV1 after albuterol
180mcg via MDI) was noted in 58% of patients. The percentage of patients
who used steroids was not provided.

Both active treatments produced a similar increase in FEV1 (AUC
~0-12h~), peak and trough FEV1 and were significantly better than
placebo. The improvement in FEV1 (AUC ~0-12h~) was maintained over the
12 week study.

Compared to placebo, both active treatments showed significant
improvement in the symptoms domain as measured by St. George's Hospital
Respiratory Questionnaire; however, the improvement in total score was
significant only for nebulized formoterol (a change of 4 units is
considered clinically significant). Both active treatments reduced the
need for PRN albuterol by approximately 1.2-1.4 puffs/day over that of
placebo. Please refer to the appendix for further details.

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

Study 201-059 is a 52-week randomized, open label extension trial of the
12-week study described above.^2^ Formoterol 20mcg BID via nebulizer
(n=463) was compared to formoterol 12mcg by DPI (n=106). Patients from
the 12-week trial were randomized as follows:

-   Those previously receiving nebs remained on nebs

-   Those previously receiving placebo were switched to nebs

-   Those previously receiving DPI, half continued on DPI and half were
    switched to nebs

The goals of this study were to evaluate long-term safety (discussed in
safety section) and effect on quality of life.

**Table 2: Change in SGRQ Total Score during the 52-week T**rial

  ----------------------- -------------------- --------------------------
                          **Formoterol NEB**   **Formoterol DPI**

  SGRQ change from week   -0.9                 -3.8
  12 to week 22                                

  SGRQ change from week   0.1                  improvement not maintained
  12 to week 64                                (data not shown)
  ----------------------- -------------------- --------------------------

**SAFETY**

Adverse events from the 12-week placebo controlled trial, where the rate
of AEs for either formoterol group were \>2% [and]{.underline} where the
rate exceeded that of placebo are shown in table 3.^3^

**Table 3**: Adverse Events from 12-week Study

  ----------------- ------------------ ------------------ ------------------
                    **Formoterol       **Formoterol dry   **Placebo
                    nebulizer solution powder (n=114)**   (n=114)**
                    (n=123)**                             

  Patients with any 51.2%              60.5%              57%
  AE                                                      

  Patients with any 14.6%              15.8%              17.5%
  drug-related AE                                         

  D/C treatment due 3.3%               3.5%               8.8%
  to AE                                                   

  Patients with SAE 0.8%               2.6%               4.4%

  Drug-related SAE  0                  0                  0

  Diarrhea          4.9%               1.8%               3.5%

  Nausea            4.9%               3.5%               2.6%

  Vomiting          2.4%               1.8%               1.8%

  Nasopharyngitis   3.3%               1.8%               1.8%

  Dry Mouth         3.3%               1.8%               1.8%

  Dizziness         2.4%               7.0%               0.9%

  Insomnia          2.4%               0                  0

  Upper respiratory 1.6%               2.6%               1.8%
  tract infection                                         

  Sinusitis         0                  3.5%               1.8%

  Dyspnea           0                  2.6%               0
  exacerbation                                            
  ----------------- ------------------ ------------------ ------------------

There were fewer exacerbations of COPD in the active treatment groups
(4.1%, 6.1%, and 7.9% for formoterol nebs, DPI and placebo
respectively). There was 1 patient in each active treatment group and 7
patients in the placebo group that discontinued the study due to COPD
exacerbation. Exacerbations considered as serious occurred in 2 patients
in the placebo group and in no patients receiving active treatment.

*[Electrophysiology Studies]{.underline}*

Patients in the 12-week trial underwent 24-hour Holter monitoring at
baseline and after 8-12 weeks of treatment. Pre-dose and post-dose (2-3
hours post-dose) EKGs were also performed at baseline and after 4, 8,
and 12 weeks of treatment.^3,\ 4^

**Table 4: Holter Monitoring and EKG Results**

+----------------------------+-------------+-------------+-------------+
|                            | *           | *           | **Placebo** |
|                            | *Formoterol | *Formoterol |             |
|                            | nebulizer** | dry         |             |
|                            |             | powder**    |             |
+----------------------------+-------------+-------------+-------------+
| Mean increase in QTc       | [           | data not    | [           |
| interval from baseline     | \<]{.underl | shown       | \<]{.underl |
| over 12-weeks (Bazett's    | ine}4.8msec |             | ine}4.6msec |
| correction)                |             |             |             |
+----------------------------+-------------+-------------+-------------+
| \% of patients             | 82%/ 89.3%  | 81.3%/      | 83.8%/      |
| experiencing change in QTc |             | 84.8%       | 89.2%       |
|                            |             |             |             |
| \< 30 msec at any time     |             |             |             |
| (Bazett's correction/      |             |             |             |
| Fridericia's correction)   |             |             |             |
+----------------------------+-------------+-------------+-------------+
| \% of patients             | 18%/ 9%     | 17%/ 14.3%  | 14.4%/ 9.9% |
| experiencing change in QTc |             |             |             |
|                            |             |             |             |
| 30 - \< 60msec at any time |             |             |             |
| (Bazett's correction/      |             |             |             |
| Fridericia's correction)   |             |             |             |
+----------------------------+-------------+-------------+-------------+
| \% of patients             | 0/ 1.6%     | 1.8%/ 0.9%  | 1.8%/ 0.9%  |
| experiencing change in QTc |             |             |             |
| \> 60msec at any time      |             |             |             |
| (Bazett's correction/      |             |             |             |
| Fridericia's correction)   |             |             |             |
+----------------------------+-------------+-------------+-------------+
| Prolonged QT               | 1 (0.8%)    | data not    | 2 (1.8%)    |
|                            |             | shown       |             |
+----------------------------+-------------+-------------+-------------+
| Mean increase in heart     | 0.6 bpm     | data not    | 1.2 bpm     |
| rate                       |             | shown       |             |
+----------------------------+-------------+-------------+-------------+

No episodes of atrial fibrillation or ventricular tachycardia were
observed during 24-hour Holter monitoring.

When a single dose of 244mcg of formoterol was administered mean heart
rate at 6 hours increased by 6 ± 3 bpm (EKG-determined) and by 26bpm
(pulse rate determined). Maximum increase of mean QTc was 25msec
(Bazett's correction) and 8msec (Fridericia's correction). The QTc
returned to baseline within 12-24 hours post-dose.^4^

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

In a single-dose cross-over study of COPD patients (n=12), changes in
serum potassium and serum glucose were determined 1 hour after
formoterol was administered.^4^

**Table 5: Change in Glucose and Potassium after Single Dose Formoterol
by N**ebulizer

  ----------------------- --------------- --------------- ---------------
                          **Formoterol    **Formoterol    **Formoterol
                          10mcg**         20mcg**         244mcg**

  Increase in serum       26 ± 30         29 ± 28         38 ± 44
  glucose (mg/dL)                                         

  Decrease in serum       data not shown  data not shown  0.68 ± 0.4
  potassium (mEq/L)                                       
  ----------------------- --------------- --------------- ---------------

In healthy subjects who were given a single dose of formoterol 244mcg,
maximum reduction in plasma potassium from baseline ranged from 0.55 to
1.52mEq/L (median 1.01mEq/L).

*[52-week safety data]{.underline}*

The incidence of adverse events was similar for formoterol given by
nebulizer or DPI. There were a total of 8 deaths reported during the
study which were considered as unrelated or unlikely related to study
drug.^2^

**Table 6:** Adverse Events

  --------------------------------- ---------------- --------------------
                                    **Formoterol     **Formoterol DPI**
                                    nebs**           

  Any AE                            76.9%            78.3%

  Severe AE                         18.1%            19.8%

  Discontinued study due to AE      5.8%             7.5%

  Exacerbation of COPD              17.3%            18.9%

  Upper respiratory tract infection 11.7%            12.3%

  Nasopharyngitis                   8.6%             6.6%

  Bronchitis                        7.3%             9.4%

  Headache                          5.2%             5.7%

  Urinary tract infection           5.0%             5.7%
  --------------------------------- ---------------- --------------------

**CONTRAINDICATIONS**

None

**WARNINGS/PRECAUTIONS**

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

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

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

Formoterol 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 formoterol with other
nebulized drugs has not been established.

Use with caution in patients with cardiovascular disorders (coronary
insufficiency, cardiac arrhythmias, hypertension), in patients with
convulsive disorders or thyrotoxicosis, and in patients who are
unusually responsive to sympathomimetic amines. Like other
beta~2~-agonists, formoterol 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, formoterol may cause hypokalemia and
transient hyperglycemia.

**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 Perforomist:** Porfirmer sodium, Prohist

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

**DRUG INTERACTIONS**

Formoterol did not inhibit CYP450 enzymes at therapeutically relevant
concentrations.

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 60 doses of formoterol solution is 207.80.

**Table 7:** **Cost of Beta-Agonist Solutions for Nebulizer**

+---------------+----------+-------------+-------------+-------------+
|               | **Usual  | **          | *           | **C         |
|               | dose**   | Cost/dose** | *Cost/day** | ost/month** |
+---------------+----------+-------------+-------------+-------------+
| Formoterol    | 20mcg    | \$3.46      | \$6.93      | \$207.80    |
| 20mcg/2mL     | bid      |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| Arformoterol  | 15mcg    | \$3.07      | \$6.14      | \$184.22    |
| 15mcg/2mL     | bid      |             |             |             |
| unit dose     |          |             |             |             |
| vial          |          |             |             |             |
+---------------+----------+-------------+-------------+-------------+
| 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   | \$1.40      | \$4.20      | \$126       |
| 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**

A large multicenter, 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 formoterol in the in-patient setting or for
acute exacerbation of COPD.

There are no studies using formoterol 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 formoterol via nebulizer was comparable to
formoterol via dry-powder inhaler. There are no data comparing
formoterol nebulizer solution to albuterol or levalbuterol nebulizer
solution; therefore, how formoterol compares with the agents it is
likely to replace is unknown.

Because formoterol cannot be mixed with other nebulizer solutions such
as ipratropium, switching from a short-acting beta-agonist to formoterol
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 formoterol solution.

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

**REFERENCES**

1.  Gross NJ, Lapidus R, Dunn LJ, et al. Nebulized formoterol is an
    effective bronchodilator and improves the quality of life for COPD
    patients. Poster presentation at the 2007 American Thoracic Society
    Annual Meeting.

2.  AMCP Dossier for Perforomist

3.  Nelson HS, ZuWallack R, Levine B, et al. Safety profile of
    formoterol fumarate delivered by nebulization to COPD patients.
    Poster presentation at the 2007 American Thoracic Society Annual
    Meeting.

4.  Product package insert for Perforomist. April 2007

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

**Appendix: Clinical Trial**

+------+--------+----------+------------+-----------------------------+
| *    | **Incl | **       | **D        | **Results**                 |
| *Stu | usion/ | Dosing** | emographic |                             |
| dy** | exc    |          | s/baseline |                             |
|      | lusion |          | data**     |                             |
|      | crit   |          |            |                             |
|      | eria** |          |            |                             |
+------+--------+----------+------------+-----------------------------+
| S    | Dia    | 4-14 day | **Mean     |   -                         |
| tudy | gnosis | placebo  | age:**     | ---------- -------------- - |
| 201  | of     | run-in   | 62.8 ± 9.1 | ------------- ------------- |
| -065 | COPD   |          | years      |                             |
|      |        | Fo       |            |              **Formoterol   |
| R,   | S      | rmoterol | **%        |  **Formoterol   **Placebo** |
| DB,  | moking | 20mcg    | male:**    |               NEB           |
| DD,  | h      | BID via  | 56%        | **          DPI**           |
| PC   | istory | Neb      |            |                             |
| and  | of     |          | **Mean     |   Completed   106 (86%)     |
| a    | [\>]   | Fo       | FEV1       |     98 (86%)       84 (74%) |
| ctiv | {.unde | rmoterol | (pr        |   trial                     |
| e-co | rline} | 12mcg    | e-bronchod |                             |
| ntro | 10     | BID via  | ilator):** |                             |
| lled | pack   | DPI      | 1.34±      |   d/c due to  3.3%          |
|      | -years |          | 0.45L      |         3.5%           8.8% |
| 12-w |        | Placebo  |            |   AE                        |
| eeks | 40-86  |          | **Mean     |                             |
|      | years  | PRN      | FEV1       |                             |
| n    | old    | a        | (pos       |   Endpoint    1.51± 0.52§   |
| =351 |        | lbuterol | t-bronchod |   1.49 ± 0.46§   1.33± 0.57 |
|      | FE     | allowed  | ilator):** |   FEV1 AUC                  |
| Nebs | V1/FVC | for      | 1.5± 0.45L |                             |
| (n=  | ratio  | rescue   |            |   ~0-12hr~                  |
| 123) | [\<]   |          | **Mean     |                             |
|      | {.unde | con      | FEV1 %     |   (L)                       |
| DPI  | rline} | comitant | pred:**    |                             |
| (n=  | 0.7    | ICS      | 44.5% ±    |                             |
| 114) |        | allowed  | 12.1       |   Peak FEV1   1.69§/ 1.65§  |
|      | **[Ex  |          |            |   1.63§/ 1.62§   1.52/ 1.47 |
| Pla  | clusio | pr       | **F        |   (day 1/                   |
| cebo | ns:]{. | ohibited | EV1/FVC:** |                             |
| (n=  | underl | meds:    | 0.53 ±     |   week 12)                  |
| 114) | ine}** | other    | 0.10       |                             |
|      | a      | beta-a   |            |                             |
| ITT  | sthma, | gonists, | **Current  |   Tough FEV1  1.46§/ 1.41§  |
|      | other  | a        | smoker:**  |   1.39§/ 1.41§   1.34/ 1/32 |
|      | signi  | nticholi | 52%        |   (day 1/                   |
|      | ficant | nergics, |            |                             |
|      | d      | xa       | **Steroid  |   week 12)                  |
|      | isease | nthines, | user:**    |                             |
|      | other  | c        | not shown  |                             |
|      | than   | romolyn, |            |   SGRQ total  -4.9§         |
|      | COPD,  | ne       | 58% of     |         -4.0†          -1.0 |
|      | un     | dcromil, | patients   |   score                     |
|      | stable | non-     | had        |                             |
|      | h      | specific | bron       |                             |
|      | epatic | beta-    | chodilator |   Daily       \-            |
|      | or     | blockers | rev        | 1.23 ,      no sig          |
|      | renal  |          | ersibility |   rescue      -1.           |
|      | d      |          | ([\>]{.    | 48, -1.25   difference      |
|      | isease |          | underline} |   albuterol   \*            |
|      |        |          | 10%        |             between NEB     |
|      |        |          | increase   |   (LS mean                  |
|      |        |          | in FEV1    |             and DPI (data   |
|      |        |          | after      |   diff vs.                  |
|      |        |          | albuterol  |             not shown)      |
|      |        |          | 180mcg via |   placebo)                  |
|      |        |          | MDI)       |                             |
|      |        |          |            |   -                         |
|      |        |          |            | ---------- -------------- - |
|      |        |          |            | ------------- ------------- |
|      |        |          |            |                             |
|      |        |          |            | §Significant vs. placebo    |
|      |        |          |            |                             |
|      |        |          |            | † Significant difference    |
|      |        |          |            | vs. placebo only for        |
|      |        |          |            | symptoms subscore           |
|      |        |          |            |                             |
|      |        |          |            | \*data for day 1-week 4,    |
|      |        |          |            | weeks 4-8, and weeks 8-12   |
|      |        |          |            | respectively ; all          |
|      |        |          |            | significant versus placebo  |
+------+--------+----------+------------+-----------------------------+