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Veterinary Drugs

 
Product and
NADA/ANADA Number
Trade Name
Ingredients
Clenbuterol hydrochloride
140-973
VENTIPULMIN® SYRUP
clenbuterol hydrochloride

                                                                   
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Summary of 
FDA Information:

Approval Date: May 11, 1998 Freedom of
Information Summary NADA 140-973 I. GENERAL INFORMATION: NADA 140-973 Sponsor: Boehringer Ingelheim Vetmedica, Inc. 2621 North Belt Highway St. Joseph, Missouri 64506-2002 Generic Name: clenbuterol hydrochloride Trade Name: Ventipulmin® Syrup Marketing Status: Prescription Drug Product II. INDICATIONS FOR USE A. Ventipulmin® Syrup (clenbuterol hydrochloride) is indicated for
use in the
management of
horses affected with airway obstruction, such as occurs in chronic obstructive pulmonary disease (COPD). III. DOSAGE A. DOSAGE FORM Ventipulmin is a syrup containing 72.5 mcg of
clenbuterol hydrochloride per mL. B. ROUTE OF ADMINISTRATION for
oral administration only C. RECOMMENDED DOSAGES: 1. Administer orally twice a day (b.i.d.). Initial dose is 0.5 mL per 100 pounds body weight (0.8 micrograms per kilogram) twice daily. Dosage schedule: Initial dosage: 0.5 mL per 100 pounds (0.8micrograms per kilogram) for
3 days (6 treatments); If no improvement, administer 1 mL per 100 pounds (1.6 micrograms per kilogram) for
3 days (6 treatments); If no improvement, administer 1.5 mL per 100 pounds (2.4 micrograms per kilogram) for
3 days (6 treatments); If no improvement, administer 2.0 mL per 100 pounds (3.2 micrograms per kilogram) for
3 days (6 treatments); If no improvement, horse is non-responder to clenbuterol and
treatment should be discontinued. Recommended duration of
treatment at effective dose is 30 days. At the end of
the 30-day treatment period, drug should be withdrawn. If signs return, the
30-day treatment period may be repeated. If repeating treatment, the
step-wise dosage schedule should be repeated. D. SUPPLIED AS 100, 220 and
330 mL bottles IV. EFFECTIVENESS A. Dose justification: A dose titration study
was conducted. 1. Investigator: Deborah F. Erichsen, DVM, MS Boehringer Ingelheim Animal Health, Inc. St. Joseph, Missouri 64502 2. Purpose: To determine the dose-response relationship and
the upper limit of
a therapeutic dose range of
Ventipulmin Syrup alone in the
management of
COPD in horses. 3. Materials and
Methods a. Test Animals: Five (5) mature mares and
geldings with chronic obstructive pulmonary disease (COPD). COPD horses were
identified on the basis of
physical examination, response to moldy hay exposure and
medical history. COPD horses considered for
the trial demonstrated a marked maximum difference between peak inspiratory and
peak expiratory intrapleural pressure expressed in centimeters of
water (MDPP) response to intravenous atropine at a dosage of
8.8 mcg per kg. b. Study design: A four-period crossover design using five horses with chronic obstructive pulmonary disease (COPD) treated orally twice daily with Ventipulmin Syrup. Each horse served as its own control in accordance with Section 21 CFR 514.111(a)(5)(ii)(a)(2)(iii).
The measurements of
interest were
objectively collected and
therefore the need for
masking was
eliminated. c. Measurements: The MDPP was
monitored using the esophageal balloon technique. d. Treatment groups: Horses were
treated orally, twice daily, with 0.0, 47.6, 95.2 and
190.4 mcg per mL clenbuterol HCl in accordance with the trial design.
This provided for
the requirement of
administering the various dosage levels at a constant volume per 100 pounds of
body weight throughout the study
.
The marketed product contains 72.5 mcg of
clenbuterol HCl per mL. e. Test Duration: Each horse was
treated with each of
the four dosages (0.0, 1.6, 3.2 and
6.4 mcg per kg) over four treatment periods. Each treatment period consisted of
a 3-day pretreatment baseline observation and
6 days of
twice daily treatment at the
scheduled dosage, with a minimum 96-hour washout between periods, for
a complete crossover of
doses in each animal. 4. Results: Data obtained from
this study
indicated a significant linear dose response with progressive improvement in response as dose increased.
The data were
analyzed using an analysis of
variance design for
crossover studies.
The data support a linear dose response from
1.6 to 6.4 mcg/kg body weight of
Ventipulmin Syrup for
treatment of
COPD in horses (P = 0.0111). 5. Adverse Drug Responses: Clinical adverse drug responses effects, such as sweating, muscle tremor and
nervousness, occurred at all dose levels and
increased in intensity and
frequency of
occurrence as the dosage increased. Such side effects were
observed to be mild and
transient when
horses were
dosed under
the recommended regimen of
individual incremental dose titration to effect. 6. Conclusions: The adverse side effects limit the dosage to 3.2 mcg/kg body weight.
The information supports a dose of
3.2 mcg per kg body weight of
Ventipulmin Syrup for
treatment of
COPD in horses. B. Dose Confirmation/Clinical Efficacy 1. Investigators: Dr. Ralph E. Beadle School of
Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 Dr. Doyne Hamm RAH, Inc. Rt. 3, Box 203, Hunt Lane Fayetteville, AR 72701 2. Purpose of
Study: To confirm the efficacy of
Ventipulmin Syrup over an incremental dose range of
0.8 to 3.2 mcg per kg in the
treatment of
horses with COPD. In addition, the
study
was used to identify the correlation between a proposed numerical scoring system to be used in the
clinical field trial, and

the MDPP. 3. Materials and
methods a. Test Animals: Test animals were
clinically diagnosed to have COPD or
SPA-COPD [SPA,summer pasture associated]. Test animals were
identified as having COPD based on their response to daily exposure to moldy hay or
summer pasture exposure [SPA (summer pasture associated)-COPD]. Horses with pneumonia, strangles, influenza or
other respiratory or
systemic diseases were
not eligible for
study
. Each horse was
injected intravenously with 8.8mcgperkilogram atropine to demonstrate the ability of
the lungs to respond to bronchodilation. Intrapleural pressures were
monitored daily for
a minimum of
3 days to establish a baseline. Approximate MDPP was
required to be greater than 12 centimeters of
water on 3 consecutive baseline days before treatment was
initiated.
The severity of
COPD was
evaluated on a clinical basis at the
same time the pleural pressures curves were
being recorded for
each observation to determine the clinical overall heaves rating (OHR). b. Study Design: Sixteen horses were
used for
the study. Eight horses were
paired and
each of
these 4 pairs were
used twice.
The other 8 horses were
paired, and

used once.
This procedure is acceptable based on an assumption that a residual effect of
replicate treatment is unlikely based on a minimum 50-day-washout period between replications, and

a T1/2 of
10.4 h (± 2.25 SD) for
clenbuterol (Kallings P., J Vet Pharmacol 1991;14:243-249).
The treatments were
not known by the investigators until the study
was completed, i.e. the study
was masked to treatment. Horses were
assigned to pairs based on severity of
the COPD condition, i.e., horses with similar degree of
heaves were
paired together.
The assignment of
each horse within the pair to Ventipulmin Syrup or
placebo treatment was
determined from
a table of
randomized treatments. One horse in each pair received placebo syrup and
one received Ventipulmin syrup. Oral syrup containing 72.5 mcg/mL concentration of
clenbuterol HCl as intended for
marketing and
a placebo syrup were
used. c. Dosages: All test horses were
administered coded test product every 12 hours for
three days (6 treatments) beginning at the
low dose of
0.5 mL per 100pounds body weight (0.8 mcg per kg clenbuterol). Each horse was
titrated incrementally to its responsive dose up to a maximum of
2.0 mL per 100pounds body weight. Once the responsive dose was
found (MDPP < 60% of
mean baseline on the third day of
treatment), treatment at that dose was
continued for
7 more days for
a total of
10 treatments at the
responsive dose. d. Test Duration: Each test period consisted of
a 3-day baseline, a 3-day segmented dose titration of
test drug to effect with a 7-day, twice daily total treatment period (if a response dose was
obtained), and

a minimum 50-day-washout period. e. Pertinent Parameters Measured: The primary parameter measured in the
dose confirmation study
was success or
failure of
Ventipulmin treatment compared to placebo control as determined by measured MDPP. Response was
calculated as percent of
baseline MDPP [Percent baseline MDPP = (treatment MDPP/baseline MDPP) x 100]. Individual test animals were
classified as either responders or
non-responders. Responders were
those horses that maintained a percent of
baseline MDPP less than or
equal to 60% for
treatment Days 4 through 10 at any of
the four incremental dosages (0.5, 1.0, 1.5, or
2.0 mL per 100 pounds body weight). Non-responders were
those animals that did not maintain a percent of
baseline MDPP less than or
equal to 60% for
the same treatment period.
The severity of
COPD was
also evaluated on a clinical basis to show the correlation between measured MDPP and
observed respiratory effort.
The overall heaves rating (OHR) score was
a weighted numerical index of
the subjective evaluation of
the difficulty in breathing as observed by the veterinary clinician.
There were
five clinical parameters that were
scored and
then summed at the
end of
each clinical observation to obtain the OHR score.
The parameters scored were
expiratory effort, nostril flare, audible wheezing, nasal discharge, and

coughing. Expiratory effort was
more heavily weighted numerically in the
total OHR score in comparison to the other clinical parameters, because expiratory effort most closely reflects the MDPP measurement. 4. Results: Forty-two percent (42%) of
the 12 COPD horses treated with Ventipulmin Syrup were
responders, with an average percent baseline MDPP of
32%, i.e., an average improvement in MDPP of
68% from
baseline. None of
the 12 placebo treated horses were
responders.
A one-sided sign test was
used to compare responders and
nonresponders for
Ventipulmin Syrup and
placebo based on the MDPP measurement.
The difference between the Ventipulmin and
placebo treatment groups was
statistically significant (p = 0.03125). See Table1below. Table 1. Summary of
response of
horses by treatment in a study
evaluating the effects of
Ventipulmin Syrup in the
treatment of
chronic obstructive pulmonary disease. Treatment Number of
horses treated Number of
responders (%) Number of
Non-responders (%) Placebo 12 0 (0%) 12 (100%) Ventipulmin 12 5 (42%) 7 (58%) In this blinded test, the
relationship between the OHR and
MDPP measurement for
all horses and
for
each horse was
calculated.
The same analysis was
done for
the expiratory effort to MDPP relationship.
The analysis of
pretreatment MDPP showed that the
horses were
adequately assigned to the treatment groups.
The study
confirmed that the
dosing regimen described in the
protocol provided a significant response to Ventipulmin treatment. Ventipulmin-treated horses had a 42% (5 out of
12) success rate while placebo-treated horses had a 0% success rate (P=0.03125, one-sided sign test).
The relationship between the ORH and
MDPP measurement and
expiratory effort and
MDPP measurement for
all horses was
examined. For the correlation study
, four horses were
eliminated completely and
one horse had some observations eliminated because of
a compromise of
subjective and
objective measurements. Each horse had multiple measures so the observations were
not independent and
thus only the simple correlation is presented.
A good linear relationship between ORH and
MDPP was
demonstrated with a simple correlation of
0.832.
The expiratory effort/MDPP data provided a simple correlation of
0.791.
Thus there was
a strong correlation between the OHR/MDPP and
the expiratory effort/MDPP data.
There was
only 1 horse where there was
no agreement between the OHR and
MDPP with regard to the decision of
a horse being declared a treatment responder versus a nonresponder to treatment.
There was
100% agreement between the expiratory effort and
MDPP responder/nonresponder decisions. 5. Conclusions: Ventipulmin Syrup produced an improvement in heaves condition in 42% of
the COPD horses as determined by measured MDPP and
clinical evaluation while none of
the placebo horses improved. 6. Adverse Drug Responses: Adverse drug responses were
mild and
of short duration. Based on 145 observation days, there were
23 observations of
mild sweating or
dampness (15.9%); 17 observations of
wet patches from
sweating (11.7%); 26 observations of
mild muscle tremor (18%); and
4 observations of
anxiety (2.8%). C. Clinical Field Study 1. Investigators: The following thirty-five (35) investigators, in nine geographical locations, were
involved in this study
: Investigators Mailing address Investigators Mailing address Dr. Beverly Anderhol Dr. Ralph E. Beadle Dr. Dennis D. French Dr. Michael J. Betley Dr. Gary J. Dillon Dr. Sharon Doolittle Dr. Sarah Horin Dr. Ernest J. Finocchio Dr. Ann E. Dwyer Dr. Paul Foy Dr. Richard J. Paumer Dr. Ellen J. Imhof Dr. Kevin P. Syvrud Dr. Geoffrey W. Tucker Dr. John W. Schlipf Dr. Lesley J. Smith R.D. 1, Box 369 Centre Hall, PA 16828 School of
Veterinary Medicine Louisiana State University Baton Rouge, LA 70803 4332 Forest Glen Drive Hoffman Estates, IL 60195 Cascade Equine Clinic 29450 S.E. Lariat Lane Boring, OR 97009 New England Horse Care Centre 2205 Providence Pike N. Smithfield, RI 02895 Genesee Valley Equine Clinic 1089 Bowerman Road Scottsville, NY 14546 Animal Clinic 105 West O Street Ogallala, NE 6953 Aurora Veterinary Clinic 46 South Aurora Road Aurora, OH 44202 Summit Research 8732 Mountain View Road Polson, MT 59860 330 W. Dryden Road Freeville, NY 13068 5551 Delano Road Melamora, MI 48455 Washington State University Dept. of
Vet. Clin. Sciences McCoy Hall, Stadium Way Pullman, WA 99164 Dr. John Jagar Dr. Lance F. Karcher Dr. Steven M. Lascher Dr. Richard F. Lesser Dr. Pamela A. Wilkins Dr. Scott McAllister Dr. William J. McGinty Dr. Johnnie F. Copeland Dr. Joseph G. Merriam Dr. Ellen Ruth Singer Dr. Sarah L. Cochran Dr. Daniel R. O’Leary Dr. Charles D. Vail Dr. Helen O. Noble Dr. Robert M. Orcutt Dr. Bryan G. Parrott Dr. Mary M. Patterson Dr. Steven E. Rhodes Dr. Frances G. Woodworth RD 3, Box 65 Millbrook, NY 12545 12 Hidden Lane Westbury Long Island, NY 11590 Adirondack Veterinary Clinic 418 Geyser Road Balston Spa, NY 12020 The Equine Clinic of
Oakencroft RR 2, Box 235 Ravena, NY 12143 RR 1, Box 369 Centre Hall, PA 16828 Sarasota Equine Associates 1514 Shadow Ridge Road Sarasota, FL 34240 Massachusetts Equine Clinic 75 Locust Street Uxbridge, MA 01569 Littleton Large Animal Clinic 8025 South Santa Fe Drive Littleton, CO 80120 Combined Veterinary Services 447 Boston Road New Meadows Professional Bldg. Topsfield, MA 01983 Blood Red Farm Box 411, Conklingtown Road Goshen, NY 10924 5063 Watson Road Elba, NY 14058 2. Purpose of
Study: The purpose of
this study
was to confirm the clinical safety and
efficacy of
an incremental dose range of
Ventipulmin Syrup in horses with chronic obstructive pulmonary disease (COPD). 3. Materials and
Methods a. Test Animals: Two-hundred and
forty-one (241) horses, two years of
age and
older, of
either sex and
any breed (except pony breeds, i.e. Shetland, Welsh, Connemara, etc.), with a history of
COPD were
enrolled into
the study
. Horses in an active breeding program (i.e., brood mares or
breeding stallions) were
not used in the
study
. b. Study Design: Horses were
individually titrated to their effective dose. Response was
determined by the clinical evaluation of
the heaves condition based on an overall heaves rating (OHR). c. Diagnosis and
study
criteria: Determination of
COPD was
based on evaluation of
five clinical parameters which
included expiratory effort, nostril flare, audible wheezing, nasal discharge, and

coughing.
The primary clinical parameter, expiratory effort, was
maximally weighted in the
scoring system by making the OHR category identical to the expiratory effort category.
The OHR categories for
the scoring system were
defined as follows: 0 = not heavey 1 = slightly heavey 2 = moderately heavey 3 = markedly heavey 4 = severely heavey The only deviations from
the OHR category being the same as the expiratory effort category were
as follows: 1) The OHR might be increased 1 category above the expiratory effort score if the nostril flaring score and
the wheezing score were
both at least 2 categories higher than the expiratory effort score, or
2) the OHR might be decreased 1 category below the expiratory effort score if the nostril flaring score and
the wheezing score were
both at least 2 categories lower than the expiratory effort score. Each horse was
required to have a minimum of
two equal baseline OHR scores of
"slightly heavey" or
greater and
demonstrate a marked clinical improvement in response to intravenous atropine to be accepted into
the study
.
The intravenous atropine test was
given to determine reversibility of
bronchospasm. Horses were
not allowed concomitant bronchodilator therapy within ten days of
the atropine test nor during the course of
the study
. Horses with respiratory diseases, other than COPD, and

horses with other systemic diseases were
not eligible for
the study. d. Assignment to treatment group: Horses were
assigned to one of
two treatment schedules by a random distribution schedule provided to each investigator. Horses on Schedule A were
treated for
a 10 day period at the
effective dose. Treatment was
then withdrawn and
the COPD condition monitored over an 8-day washout period. Schedule B horses were
treated for
a total of
30 days at the
effective dose with no washout monitoring at the
end of
the treatment period. e. Type of
Control Group: Each animal served as its own control.
The study
design in accordance with Section 21 CFR 514.111(a)(5)(ii)(a)(2)(iii) allowed for
assessment of
the drug effects independent of
other variables. f. Dosage: The oral syrup, as intended for
marketing, was
administered orally at doses of
0.8 mcg per kg, 1.6 mcg per kg, 2.4 mcg per kg, and

3.2 mcg per kg, for
10 or
30 days at the
effective dose level for
each horse. Schedule A treatment was
a 10-day duration with a washout period of
8 days. Schedule B treatment was
a 30-day duration with no washout period (see table 2). 4. Results: A total of
241horses were
eligible and
enrolled in the
study
. Two horses died of
non-drug related causes before reaching a responsive dose. Fifty-seven (57) horses responded when
treated with 0.8 mcg per kg, 55 responded when
titrated with 1.6 mcg per kg, 40 responded when
titrated with 2.4 mcg/kg, and

28 responded when
treated with 3.2 mcg/kg, while 59 horses did not respond to treatment (see table 2).
The average response of
horses on Schedule A was
improvement in the
COPD condition while on test drug, with a worsening of
the condition after drug withdrawal. Horses on Schedule B demonstrated an overall improvement in the
COPD condition while on test drug. See Table 2 below for
improvement in COPD condition based on OHR evaluation: Table 2.
The average Baseline Overall Heaves Rating (BOHR) and
Overall Heaves Rating (OHR) by treatment with Ventipulmin. Schedule A is 10 days of
treatment with a washout period of
8 days. Schedule B is 30days of
treatment with no washout. OHR Dose (mcg/kg) Schedule No. of
horses BOHR Day 3 Day 10 Washout Day 11 to 18 Day 20 Day 30 0.8 A 34 2.00 0.79 0.68 1.41 0.8 B 23 1.87 0.70 0.48 0.48 0.61 1.6 A 29 2.03 0.83 0.55 1.68 1.6 B 26 2.08 0.85 0.69 0.88 0.72 2.4 A 20 2.05 0.80 0.75 1.63 2.4 B 20 2.20 1.15 1.05 1.37 0.88 3.2 A 15 2.60 1.47 1.47 2.53 3.2 B 13 2.62 1.38 1.31 1.31 1.62 Non-responder 59 2.39 2.40 3.00 Horses which
showed an improved overall heaves rating over the baseline after one of
the dosing levels above were
termed Responders. If a horse did not show an improvement over the baseline after receiving 3.2 mcg/kg for
3 days, or
maintain the improvement from
day 3 through day 10 at 3.2 mcg/kg, it was
considered a Nonresponder. One hundred eighty (180) horses out of
a total of
239 were
Responders. Improvement in the
COPD condition of
horses treated with Ventipulmin Syrup was
demonstrated by the OHR scoring system which
has been shown to correlate well with the objective MDPP measurement for
the determination of
severity of
heaves and
response to treatment.
The average improvement from
baseline OHR of
responders over all doses was
1.31 categories on day 10. 6. Conclusions: Ventipulmin Syrup was
shown to be safe and
effective for
management of
COPD in horses when
used according to the recommended regimen of
incremental dose titration to effect. 7. Adverse Reactions: Clinical side effects, such as sweating, muscle tremor and
attitude change, were
of low intensity, occurred at all dose levels and
were
transient under
the conditions of
recommended use. V. ANIMAL SAFETY A. Target Animal Safety 1. Investigator: Philip Geeding, DVM Boehringer Ingelheim Animal Health, Inc. Research Farm Cosby, MO 64436 2. Purpose: The purpose of
the study
was to evaluate the safety of
VentipulminSyrup at the
recommended dosage levels of
0.8, 1.6, 2.4, and

3.2mcg per kg of
clenbuterol HCl for
a period of
90 days. It was
previously documented that doses above 3.2mcgperkg clenbuterol HCl resulted in unacceptable side effects. 3. Materials and
methods a. Test animals: Thirty (30) normal mares and
geldings of
various saddle-horse breeds, from
3- to 15-years of
age, were
randomly assigned to 5 treatment groups, at 6 horses per group. Horses were
deemed acceptable on the basis of
three pretrial physical examinations, and

CBC and
serum chemistry analyses of
blood samples that indicated the values were
within normal limits. b. Group assignment: Assignment of
horses to the 5 treatment groups was
performed using a random distribution table. c. Treatments and
groups: Ventipulmin Syrup was
administered twice daily at oral dose rates of
0.0 mcg per kg (0.0 mL per 100 lbs body weight), 0.8mcgper kg (0.5mL per 100lbs body weight), 1.6 mcg per kg (1.0 mL per 100 lbs body weight), 2.4mcg per kg (1.5mL per 100lbs body weight), 3.2 mcg per kg (2.0mLper100 lbs body weight) of
clenbuterol HCl for
90 days, followed by a 14-day washout period. d. Pertinent parameters measured: The determination of
the long term effects of
administration of
Ventipulmin Syrup was
based on physical examination, clinical evaluation, and

assessment of
CBC and
serum chemistry.
The results from
the analysis of
blood samples collected at pre-treatment Days 21, 7, and

0 were
used as baseline values for
comparison to subsequent treatment values. Horses were
weighed at Day 0 to calculate initial dosage, then approximately every 30 days until the end of
the study
to monitor the body condition and
to calculate the test product dosage. Gross pathology and
histopathology examinations were
done on all animals between 1 and
7 days beyond study
completion.
The horses were
randomly clustered for
consecutive days of
necropsy, since not all animals could be necropsied on the same day. Each cluster contained individuals from
all treatment groups. 4. Results: Doses of
0.8 to 3.2 mcg per kg of
clenbuterol HCl for
90 days were
not associated with clinically relevant changes except for
intermittent elevation of
serum creatine kinase (CK). No other hematological or
clinical parameters demonstrated an effect due to drug. Gross pathology and
histopathology evaluations revealed no drug associated lesions. 5. Conclusion: Ventipulmin Syrup at the
label-recommended dosages was
shown to be safe for
use in horses. VI. HUMAN SAFETY A. Data on human safety, pertaining to consumption of
drug residues in food, were
not required for
approval of this NADA. Clenbuterol is prohibited from
extralabel use in food producing animals (21 CFR 530.41(b)). B.
The product labeling carries the following statements: 1. "For use in horses not intended for
food." 2. "Federal (U.S.A.) law prohibits the extralabel use of
this drug in food animals." 3. HUMAN WARNINGS: This product is not for
human use or
for use in animals intended for
food. Keep out of
the reach of
children. In case of
accidental ingestion, contact a physician immediately. Ingestion of
Ventipulmin Syrup may cause undesirable reactions. Clenbuterol, like
other beta adrenergic agonists, can produce significant cardiovascular effects in some people as evidenced by elevated pulse rates, blood pressure changes and
/or ECG changes. VII. AGENCY CONCLUSIONS: The data in support of
this NADA comply with the requirements of
section 512 of
the Federal Food Drug and
Cosmetic Act and
section 514 of
the implementing regulations.
The data indicate that Ventipulmin® Syrup (clenbuterol hydrochloride), when
used under
labeled conditions, is safe and
effective.
The drug is restricted to use by or
on the order of
a licensed veterinarian because professional expertise is judged to be critical for
the diagnosis of
chronic obstructive pulmonary disease (COPD) in horses and
for
the safe use of
the product. Federal law prohibits the extralabel use of
this drug in food animals. Under section 512(c)(2)(F)(i) of
the FFDCA, this approval qualifies for
FIVE years of
marketing exclusivity beginning on the date of
approval since no active ingredient of
the drug (including any ester or
salt of
the active ingredient) has been approved in any other application. VIII. LABELING (Attached) Labeling attached for
100, 220, and

330 mL container sizes: 1. Bottle label 2. Package insert 3. Box label 4. Carton label Copies of
applicable labels may be obtained by writing to the: Freedom of
Information Office Center for
Veterinary Medicine, FDA 7500 Standish Place Rockville, MD 20855

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