Summary of
FDA Information:Approval Date: June 30, 1993
Freedom of
Information Summary
NADA 012-123
I. GENERAL INFORMATION:
NADA 012-123
Sponsor: Sanofi Animal Health, Inc.
7101 College Blvd., Suite 610
Overland Park, KS 66210
Generic Name: Erythromycin
Trade Name: GALLIMYCIN (erythromycin)INJECTION, 200 mg/mL
Marketing Status: Over The Counter
Effect of
Supplement: One supplemental application is a Category II change in dosage which
was
initiated in order to bring the drug product into
compliance with the National Academy of
Science/National Research Council- Drug. Efficacy Study Implementation (NAS/NRC/DESI) recommendations.The other supplemental application is a Category II change in tolerance for
drug residues from
zero to 0.1 ppm for
beef tissues.
II. INDICATIONS FOR USE
Indicated for
bovine respiratory disease (shipping fever complex and
bacterial pneumonia) associated with Pasteurella multocida susceptible to erythromycin.
III. DOSAGE:
A. DOSAGE FORM Sterile solution
B. ROUTE OF ADMINISTRATION Intramuscular injection only
C. RECOMMENDED DOSAGES: 4 mg/pound body weight (2 mL/100lbs) once daily up to 5 daysv
IV. EFFECTIVENESS:
NADA 012-123 was
originally approved as safe for
use as labeled on March 22, 1960.
The drug was
the subject of
National Academy of
Sciences/National Research Council/Drug Efficacy Study Implementation (NAS/NRC/DESI) reports which
were
published in the
FEDERAL REGISTER of
August 18, 1970: The Academy evaluated these products as probably effective in the
treatment of
certain diseases in cattle, sheep, swine, horses, dogs, cats, chickens, and
turkeys.
The Academy stated:
a. Each disease claim should be properly qualified "appropriate for
use (name of
disease) caused by pathogens sensitive to (name of
drug)", and
if the disease claim cannot be so qualified the claim must be dropped.
b. Claims made regarding "for prevention of
" or
"to prevent" should be replaced with "as an aid in the
control of
" or
"to aid in the
control of
."
c.
The dosage in large animals and
frequency of
administration in all species need to be documented - the dosage should be expressed on the basis of
milligrams of
erythromycin per pound of
body weight.
d.
The resistance statement and
statements claiming more effectiveness than other microbial agents need to be deleted.
e. Certain items in the
labeling need revision, including withdrawal times, cautions, misleading association of
sensitivity statement and
certain diseases and
the recommended use as an aid in curtailing weight losses due to handling and
transporting cattle.
f. Directions for
use should provide for
administering the preparation with sterile equipment.
g. Directions for
lay use are inadequate.
The Food and
Drug Administration concurs with the Academy's findings; interpreting the phrase "...cannot be so qualified ..." in paragraph (a.) to mean "...is not supported by adequate data..." FDA then proceeded to review all available data relating to the effectiveness of
products subject to NADA 012-123 to determine which
label claims were
supported by the requisite proof of
effectiveness.
That review resulted in a letter dated January 21, 1976, addressed to the firm , in which
the agency stated that it had concluded that data supported effectiveness for
the / treatment of
bovine respiratory disease only.
Thereafter, the
sponsor complied with the evaluation of
NAS/NRC and
the FDA's conclusions in the
following manner:
1.
The disease claim has been qualified as to the causative pathogen which
is susceptible to erythromycin. All other disease claims and
several animal species have been deleted from
the indications for
use.
2.
The labeled indications have been revised to read, "For the treatment of
bovine respiratory disease (shipping fever complex and
bacterial pneumonia)..." instead of
"Is indicated for
prompt and
effective treatment of
conditions resulting from
infections caused by organisms..."
3.
The dosage and
frequency of
administration in cattle has been documented. On January 21, 1976, the
Center for
VeterinaryMedicine determined the efficacy portion of
the application to be complete by virtue of
the fact that bioavailability and
comparability data submitted adequately demonstrated that sufficient drug levels were
maintained at a dosage of
4 mg per pound body weight administered daily for
up to 5 days.
4.
The labeling has been revised to delete the resistance statement and
statements claiming more effectiveness.
5.
The labeling has been revised to include appropriate withdrawal times and
cautions, and
to delete the other items mentioned above.
6.
The directions for
use have been revised to include the precautions to administer the preparation with sterile equipment.
7. Adequate directions for
lay use for
administering this drug by theintramuscular route are included.
V. ANIMAL SAFETY:
NADA 012-123 was
originally approved as safe on March 22, 1960. Safety of
this product is also substantiated by the absence of
any adverse effects reported in three new studies: a bioequivalency study
, and
the treatment periods of
a milk residue study
and a tissue residue study
.
During these three studies, 24 animals were
given two separate injections 14 days apart, five animals were
given three consecutive daily injections and
18 animals were
given five consecutive daily injections.
The injections were
given intramuscularly in the
leg or
neck at a dose of
4 mg/lb. body weight. Transient reactions such as injection site swelling were
observed over a few days following these injections, but no evidence of
hemorrhage, fibrosis, or
necrosis was
externally observable.
Gross histopathological examination was
made of
tissues at and
surrounding the injection site following intramuscular injections to 18 cattle of
6.5 ml to 8.8 mL/site of
GALLIMYCIN INJECTION.
These animals were
each given a single daily injection for
five days.
Three animals per time period were
then sacrificed at 6, 12, 18, 24, 36, and
48 hours post-last dose (injection #5). Injection site #3 was
excised for
examination. Gross inspection revealed that injection site lesions were
variable in size with approximate average dimensions of
1.25 cm diameter X 2.9 cm deep. Injection site lesions were
characterized by a central core of
muscle tissue, tan-gray to gray in color and
surrounding this central area of
discoloration was
a dark red zone of
more normalappearing muscle with obvious areas of
hemorrhage.
Histopathological examination revealed a central core of
acutely necrotic muscle fibers. Surrounding this central core was
a zone of
muscle fibers in various stages of
degeneration characterized by mineralization of
the sarcoplasm. Livers and
kidneys were
examined grossly and
histopathologically with no unusual or
unexpected observations reported.
Results of
these studies indicate that a cautionary label statement concerning the trimming of
cattle tissues during the dressing process is necessary based on the withdrawal period for
the product.
VI. HUMAN FOOD SAFETY:
A. Name and
Address of
Investigator:
Bio-Labs, Inc.
132 Las Cruces Ave.
Las Cruces, New Mexico 88001
Dr. John H. Kinzell
B. Tissue Residue Depletion Studies:
A single tissue residue depletion study
was conducted in cattle to determine the residues of
erythromycin following the administration of
GALLIMYCIN INJECTION.
The dosage regimen was
: intramuscular injection at 4 mg/lb. of
body weight for
five consecutive days. Residue determinations were
made at 6, 12, 18, 24, 36 and
48 hours post last-dose.
Three animals were
sacrificed at each time period and
tissues were
excised for
erythromycin assay.
Table 3. ERYTHROMYCIN RESIDUES IN TISSUES (PPM)
Hours Post
Injection Kidney Liver
6 1.90 (+ 0.39)* 6.13 (+ 4.36)
12 2.90 (+ 1.05) 3.88 (+ 3.14)
18 1.03 (+ 0.54) 4.31 (+ 2.68)
24 0.89 (+ 0.81) 0.82 (+ 0.69)
36 0.18 (+ 0.07) 0.12 (+ 0.02)
48 0.17 (+ 0.05) 0.13 (+ 0.08)
*standard deviation
Residues at the
injection site depleted slowly. However, using a conservative 30-hour half-life, residue at the
injection site will deplete to a consumption adjusted tolerance of
1.0 ppm within 6 days. Muscle remote from
the injection site was
less than 0.075 ppm at 48 hours.
A withdrawal period was
calculated by a statistical procedure based on the kidney depletion data from
this study
. Using the 99% statistical tolerance limit with 95% confidence procedure on the residue depletion data for
erythromycin in edible tissues, it was
determined that a 6-day withdrawal period for
cattle treated with up to 4 mg per pound body weight would be acceptable (less than 0.1 ppm erythromycin).
Temporary tissue irritation follows injection. To avoid excessive trim, cattle should not be slaughtered within 21 days of
last injection.
Regulatory Method for
Tissue Residues:
The regulatory analytical method for
detection of
residues of
erythromycin is a microbiological test using Micrococcus luteus suspension.
This method has been approved by the Food and
Drug Administration and
was
fully validated by the research laboratory.
The method is capable of
measuring residues of
erythromycin at the
tolerance level of
0.1 part per million for
edible tissues.
The supplemental application providing for
the revision of
the tolerance from
"zero" to 0.1 ppm reflects the change in FDA policy regarding the concept of
residue tolerance. No new toxicity data were
used to revise the tolerance because 0.1 part per million is equivalent to the tolerance level that would have been established when
the drug was
originally approved (March 22, 1960). Furthermore, this tolerance is consistent with data supporting the published tolerance of
0.1 ppm in uncooked edible tissues of
swine.
Under the-zero tolerance concept, no detectable residues of
a new animal drug were
permissible in edible tissues of
treated food animals when
tissues were
assayed using available analytical methods. However, as analytical technologies advanced, methodologies became increasingly sensitive and
capable of
measuring progressively smaller amounts of
drug residues in tissues.
Thus, residues which
were
not detectable using older, less sensitive methods (i.e., zero residues) began to be found using the more advanced analytical methods.
Therefore, FDA adopted the concept of
maximum negligible, or
permissible, residues which
reflect the lower level of
quantitative sensitivity of
the official regulatory analytical method. For erythromycin, this level is 0.1 part per million.
The validated regulatory analytical method for
detection of
erythromycin residues is filed in the
Food Additives Analytical Manual on display in FDA's Freedom of
Information Public Room (Room 12A-30), 5600 Fishers Lane, Rockville, MD 20857.
VII. AGENCY CONCLUSIONS:
The DESI finalization supplemental NADA satisfies the requirement of
section 512 of
the Act and
dem'onstrates that GALLIMYCIN INJECTION, 200 mg/mL, when
used in accordance with its proposed conditions of
use, is safe and
effective for
the labeled indications.
The approval provides for
use of
GALLIMYCIN INJECTION, 200 mg/mL for
the treatment of
bovine respiratory disease (shipping fever complex and
bacterial pneumonia) associated with Pasteurella multocida susceptible to erythromycin.
The "probably effective" finding of
the NAS/NRC/DESI regarding Erythromycin which
was
published in the
FEDERAL REGISTER of
Auguest 18, 1970 was
subsequently reviewed by FDA, resulting in a January 21, 1976 letter to Sanofi. NADA 012-123 was
upgraded to "effective" status with respect to the claim noted in the
previous paragraph.
The firm submitted revised labeling to conform to the letter and
, therefore, this supplemental NADA complies with the NAS/NRC/DESI evaluation and
FDA's conclusions.
GALLIMYCIN INJECTION, 200mg/mL for
use in food-producing animals is currently on the market as an over-the-counter product. When
the NADA was
reviewed under
NAS/NRC/DESI program, it was
an over the-counter product and
this marketing status remains unchanged.
Therefore, the
Center for
Veterinary Medicine has concluded that this product should retain over-the-counter marketing status.
Additionally, the
supplemental application providing for
revision of
the tolerance from
"zero" to 0.1 ppm for
cattle is acceptable and
is approved.
Under the Center's supplemental approval policy (21 CFR 514.106(b) (2) these are Category II changes.
The approval of
these changes are not expected to have any adverse effect on the safety of
this new animal drug and
, therefore, did not require a re-evaluation of
the human food or
target animal safety data in the
parent application.
Under the Generic Animal Drug and
Patent Term Restoration Act of
1988, these approvals do not qualify for
an exclusivity period under
section 512(c)(2)(F)(iii) of
the Federal, Food, Drug, and
Cosmetic Act (21 U.S.C.360b(c) (2) (F) (iii)) because the supplemental applications do not contain reports of
new clinical or
field investigations (other than bioequivalence or
residue studies) and
in the case of
food producing animals, human food safety studies (other than bioequivalence or
residue studies) essential to the approvals and
conducted or
sponsored by the applicant.
VIII. LABELING (Attached)
Copies of
applicable labels may be obtained by writing to the:
Food and
Drug Administration
Freedom of
Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857
Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.
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