Approval Date: June 11, 1993
I. GENERAL INFORMATION:
Macleod Pharmaceuticals, Inc.
2600 Canton Court
Fort Collins, CO 80525
Dosage Form: Powder
How Supplied: 37.5 g packets
How Dispensed: Rx
Amount of Active Ingredients: Trimethoprim, 67 mg/g; Sulfadiazine, 333 mg/g
Route of Administration: Oral
Labeled Dosage: 3.75 g per 110 lbs body weight per day
Indications for Use: For control of bacterial infections of horses during treatment of acute strangles, respiratory tract infections, acute urogenital infections, wound infections and abscesses.
Pioneer Product: Tribrissen 400 Oral Paste (TMP/SDZ), Coopers Animal Health Inc., NADA 131 -918.
Date Stamped: June 11, 1993
II. TARGET ANIMAL SAFETY AND DRUG EFFECTIVENESS:
Under the provisions of the Federal Food, Drug, and Cosmetic Act, as amended by the Generic Animal Drug and Patent Term Restoration Act, (53 FR 50460, December 15, 1988, First GADPTRA Policy Letter) an Abbreviated New Animal Drug Application (ANADA) may be submitted for a generic version of an approved new animal drug (pioneer product). New target animal safety data, drug effectiveness data, and human food safety data (other than tissue residue data) are not required for approval of an ANADA. An ANADA relies on the target animal safety, drug effectiveness and human food safety data in the pioneer's new animal drug application. Ordinarily, the ANADA sponsor shows that the generic product is bioequivalent to the pioneer. If bioequivalence is demonstrated through a clinical end-point study in food animals, then a tissue residue study to establish the withdrawal time for the generic product is also required. For certain dosage forms, the agency will grant a waiver from conducting an in vivo bioequivalence study (55 FR 24645, June 18,1990; Fifth GADPTRA Policy Letter; Bioequivalence Guideline, April 1990)
Based on the formulation characteristics of the generic product, Dr. Mary Kiter, Colorado State University, College of Veterinary Medicine, and Dr. Dave Wheeler, Kerr Farms, Fort Collins, Colorado, generated the data of the in vivo bioequivalence study with Uniprim Powder (trimethoprim/ sulfadiazine) and Tribrissen Paste. The generic and pioneer products are powder and paste, respectively, with the same active ingredients.
A total of twenty-four horses were randomly assigned between two groups (12 horses/group). Using a two-period crossover experimental design, one group of horses in period one was administered the generic formulation, and the second group of horses was given the pioneer product. Following a washout period, the horse groups were given the opposite treatments. Both products were administered at dosage rates of 30 mg/kg of body weight in each of the two test periods.
During a 24-hour period, blood samples were collected from each horse predose and at 17 post-treatment intervals in each period (0.5,1,1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8,10,12,14,18, and 24 hours). The blood samples were centrifuged, and the serum was drawn off and frozen. The serum samples from "0" hour through 24 hours were subsequently assayed for trimethoprim and sulfadiazine using HPLC analysis.
The data of the serum assays are summarized in the tables below. The data were statistically analyzed with an analysis of variance procedure, following the Bioequivalence Guideline issued by the Center for Veterinary Medicine (FDA), April 12, 1990.
AUC = area under the curve
AUMC = area under the moment curve
Cmax = maximum concentration
Tmax = time to maximum concentration
MRT = mean residence time
The above parameters were analyzed using 90% confidence intervals. Two of the sulfadiazine parameters (Tmax and Cmax) did not have their confidence intervals, based on the difference between test and reference product means, within 20% of their reference means. The other three parameters have their confidence intervals, based on the difference between means, within 20% of their reference means.
Previously, bioequivalence of drug products were based on AUC, Cmax, and Tmax. However, due to the difficulty of accurately determining Tmax and Cmax, the bioequivalence of two products are currently determined by the parameters AUC, AUMC, and MRT (Bioequivalence Guideline, April 12, 1990).
Only one of the trimethoprim parameters (Tmax) did not have its confidence interval, based on the difference between test and reference product means, within 20% of its reference mean. The other four parameters have their confidence intervals within 20% of their reference means.
The results above are given with Lower = (L/mean of X sub R)*100% and Upper = (U/mean of X sub R)*100%. L= lower bound on the 90% confidence interval, and U = upper bound on the 90% confidence interval for the difference between the test and pioneer product means.
The results of this study are adequate to demonstrate bioequivalence between the test product and the reference product.
The palatability study was conducted by Dr. Dave Wheeler, Kerr Farms, Fort Collins, Colorado. Ten horses were divided into two groups of five horses each. Group A was fed 2.5 lbs of grain containing the normal dose of Uniprim Powder (37.5 g) once per day for five consecutive days. Group B horses were fed 2.5 lbs of unmedicated grain once daily for five consecutive days. The two groups were then crossed over and the study continued for another 5 days. At each feeding, the amount of grain consumed and the time taken to consume the grain were recorded. Essentially, all of the grain was consumed at each feeding by both groups. The average consumption time was 10 minutes for horses receiving the unmedicated grain and 12.5 minutes for horses given the medicated grain. No aversion to the medicated feed developed over the five day course of treatment. The horses consistently ate all of the medicated feed.
III. HUMAN FOOD SAFETY:
The drug is labeled: "Not for use in horses intended for food." Data on Human food safety were not required for approval of this Abbreviated New Animal Drug Application.
IV. AGENCY CONCLUSIONS:
This ANADA satisfies the requirements of section 512 of the Act and demonstrates that Uniprim Powder (trimethoprim/sulfadiazine), when used under its proposed conditions of use, is safe and effective for its labeled indications.
For the safe and effective use of Uniprim Powder, it is necessary to provide a diagnosis of acute strangles, respiratory tract infections, acute urogenital infections and to treat wound infections and abscesses. Accordingly, we have classified Uniprim Powder as a prescription item.
- Uniprim(TM) Powder product label
- Uniprim(TM) Powder package insert
- Tribrissen® 400 Oral Paste carton label
- Tribrissen® 400 Oral Paste product label
- Tribrissen® 400 Oral Paste package insert
Copies of these labels may be obtained by writing to the:
Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855