Date of Approval: November 8, 1993
I. GENERAL INFORMATION:
Anthony Products Co.
5600 Peck Road
Arcadia, CA 91006
penicillin G benzathine and penicillin G procaine.
Combicillin ®; Combicillin-AG ®
OTC: Combicillin-AG ®; Rx: Combicillin ®
II. INDICATIONS FOR USE
The prescription product, Combicillin ® is indicated for use in beef cattle, in horses, and in dogs for bacterial infections due to the following microorganisms that are susceptible to the serum levels of penicillin common to this particular dosage form: Pneumonia (shipping fever complex) caused by Streptococcus spp., Corynebacterium pyogenes, Staphylococcus aureus; Upper respiratory infections such as rhinitis or pharyngitis caused by Corynebacterium pyogenes; Equine strangles caused by Streptococcus equi; Blackleg caused by Clostridium chauvoei.
The over-the-counter product, Combicillin-AG ® is indicated for use in beef cattle for bacterial infections due to the following microorganisms that are susceptible to the serum levels of penicillin common to this particular dosage form:
Bacterial pneumonia (shipping fever complex) caused by Streptococcus spp., Corynebacterium pyogenes, Staphylococcus aureus; Upper respiratory infections such as rhinitis or pharyngitis caused by Corynebacterium pyogenes; Blackleg caused by Clostridium chauvoei.
Combicillin ® and Combicillin-AG ® are supplied in 100 mL or 250 mL vials containing 150,000 units per mL of penicillin G benzathine and penicillin G procaine, each in aqueous suspension.
ROUTE OF ADMINISTRATION
Dogs: Administered as a single subcutaneous or intramuscular injection
Horses: Administered as a single intramuscular injection
Cattle: Administered as a single subcutaneous injection
Dogs: 1 mL per 10-25 lbs body weight or 6000 to 15,000 units of penicillin G procaine and penicillin G benzathine per lb of body weight
Horses: 2 mL per 150 lb body weight or 2000 units penicillin G procaine and 2000 units penicillin G benzathine per pound of body weight. This drug should not be used in horses intended for food.
Cattle: 2 mL per 150 lb body weight or 2000 units penicillin G procaine(beef) and 2000 units penicillin G benzathine per pound of body weight. Treatment should be limited to two (2) doses. Treatment should be repeated in 48 hours. Cattle should be withheld from slaughter for food use for 30 days following the last treatment.
The combination product, penicillin G benzathine and penicillin G procaine was the subject of a final rule and was published in the Federal Register of February 16, 1979 (44 FR 10059). The final rule amended the animal drug regulations (1) to indicate those portions which reflect the National Academy of Science-National Research Council, Drug Efficacy Study Group (NAS/NRC) evaluation of the product and (2) to specify the conditions of use for which approval of similar products need not include certain types of efficacy data, but may require submission of bioequivalence or similar data. Anthony's product has been shown to be bioequivalent to the pioneer product, Bristol's Flo-Cillin ® , (NADA 65-169) which was approved as effective (as well as safe) in 1979. The name and address of the investigator is:
Colorado Animal Research Enterprises, Inc.
6200 East County Road 56
Fort Collins, Colorado 80524
The bioequivalence study was designed as a 20-animal crossover trial in steers (beef cattle). The 20 test animals were randomized to two treatment groups after stratification for body weight. Single, equivalent doses (600,000 IU/150 lbs body weight) of either the Test or the Reference product were administered subcutaneously to individuals in 10-animal groups at each of two periods that were separated by a 28-day washout period. No adverse reactions were observed during the study. Blood samples were collected from each animal during each of the two periods prior to drug administration and 14 times post-dosing: at 20 min; 40 min; 60 min; 80 min; 100 min; 120 min; 4 hr; 6 hr; 12 hr; 18 hr; 24 hr; 48 hr; 72 hr; and 96 hr. Serum was analyzed for penicillin G concentration by a cylinder-plate microbiological method using Micrococcus luteus (ATCC 9341a), with a limit of detection less than or equal to 0.025 IU/mL. The method used is based on the method described in the publication: "Antibiotic Residues-in Milk, Dairy Products, and Animal Tissues: Methods, Reports and Protocols.", National Center for Antibiotic and Insulin Analysis, Food and Drug Administration, Dept. of Health and Human Services, Washington DC 20204. Bovine serum penicillin levels in response to both products during both periods of the trial were statistically analyzed. No statistically significant differences were noted between the two drugs. Values for serum levels over time, Ka, Tmax, Cmax, Ke, T1/2, Tp and AUC were very similar between the two products.
Therefore, it is concluded that Flocillin ® and Anthony's products, Combicillin ® and Combicillin-AG ® , are bioequivalent and will be similarly effective when used in cattle, horses, and dogs.
V. ANIMAL SAFETY:
The pioneer product, Bristol Laboratories' Flo-Cillin ® NADA 65-169, was approved as safe and effective for use as labeled on February 16, 1979 (44 Fed. Reg. 10059). The demonstration of bioequivalence to that product established that no additional target animal safety studies were required for Combicillin ® and Combicillin-AG ®.
VI. HUMAN SAFETY:
The bioequivalence study in cattle, described previously, demonstrates that the two Anthony Products, Combicillin ® and Combicillin-AG ® , are bioequivalent to the Bristol pioneer product. Residue depletion data gathered using equivalent, approved products have demonstrated that a preslaughter withdrawal period of 30 days in beef cattle is adequate to ensure that penicillin residues do not exceed 0.05 ppm in edible tissues of treated animals. Combicillin ® and Combicillin-AG ® will be assigned the same preslaughter withdrawal period on both labels.
This drug should not be used in horses intended for food. Use of this drug in beef cattle should be withheld for 30 days before slaughter for human consumption.
VII. AGENCY CONCLUSIONS:
The data submitted in support of this NADA satisfy the requirements of section 512 of the Act and demonstrate that Anthony Products, Combicillin ® or Combicillin-AG ® , when used under their labeled conditions of use are safe and effective in cattle, horses, and dogs.
The sponsor submitted bioequivalency data which demonstrated biological equivalence to the approved pioneer product. This bioequivalency blood level study was accepted in lieu of tissue depletion. Therefore, for human food safety considerations, when bioequivalence is demonstrated through blood level studies, the DESI "Me-Too" product is assigned the same withdrawal period as the reference product (30 days). The tolerance for penicillin is established at 0.05 parts per million (negligible residue) in the uncooked edible tissues of cattle (See 21 CFR 556.510).
The pioneer injectable penicillin G benzathine and penicillin G procaine product which is currently on the market for use in beef cattle only, is an over-the-counter drug. Adequate directions for use have been written for the layman, and the conditions for use are likely to be followed in practice.
Therefore, the Center for Veterinary Medicine has concluded that Combicillin-AG ® will also have over-the-counter marketing status. However, Combicillin ® which is indicated for use in horses, dogs, and beef cattle, is limited to prescription status because it carries nonfood species indications (dogs and horses) and must be administered under the supervision of a licensed veterinarian.
Under the Generic Animal Drug and Patent Term Restoration Act of 1988, this approval does not qualify for an exclusivity period under section 512 (c)(2)(F)(ii) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b(c)(2)(F)(ii)), this approval does not qualify for marketing exclusivity because no new clinical or field investigations other than bioequivalence or residue studies and no new human food safety studies other than bioequivalence or residue studies were essential to the approval and conducted or sponsored by the applicant.
VIII. LABELING (Attached)
- Combicillin-I00 mL
- Combicillin-250 mL
- Insert Combicillin-AG 100 mL
- Insert Combicillin-AG 250 mL
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.