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CVM FOI…
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Approval
Date: June 30, 1993 Freedom
of Information Summary
Sanofi Animal Health, Inc.
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.
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.
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.
A. Name and Address of Investigator:
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.
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.
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:
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