NADA 110-315

A target animal safety study was conducted under a similar protocol by Dr. Larry Corah, Kansas State University, Manhattan, KS at the following locations: Finegan Ranch, Bingham, NE; Gates Ranch, Coldwater, KS; KSU/Hays Experiment Station, Hays, KS; KSU/ASI, Manhattan, KS; Bar S Ranch, Paradise, KS; and Thielen Ranch, Dorrance, KS. The purpose of the study was to evaluate the effect of Implus-C implants administered to suckling heifer calves on their subsequent reproductive performance. At all six locations, suckling heifer calves were stratified by body weight and randomly assigned to one of three treatment groups. Heifers were either implanted with a single dose of Implus-C at 45-120 days of age (Early Implant Group), implanted with a single dose of Implus-C at 6-8 months of age (Late Implant Group), or were not implanted (Control Group). At approximately 15 months of age, the heifers were bred by AI during a 60-day breeding season. Heifers that became pregnant were allowed to calve the following spring.

The following table shows the mean values for each of the parameters recorded during the study:
Ed. note:  The following table has 4 columns.

                                                                                    
                                                       Dose Groups (mg/hd/day)
                                                -----------------------------------                                
                                                Control   
Items                                            Group      Early Group  Late Group
-----------------------------------------------------------------------------------
Initial No./Group                                 185          184          180          
Age at Onset of Puberty (days)                   382.8         383.7        383.4        
% Cycling at Breeding                             86.5          81.4         84.3         
Pelvic Area (cm)                                 167.9         181.7        175.2        
First Service Conception Rate (%)                 56.5         58.2          55.1         
Services/Conception - Pregnant Heifers             1.1          1.1           1.1          
Pregnancy Rate (%)                                83.2         83.6          84.3         
Calving Rate (%)                                  78.9         79.8          80.9         
Abortion Rate (%)                                  5.2          4.6           4.0          
Age of Heifer at Calving (days)                  725.9        725.2         724.0        
Calving Ease Score                                 1.3          1.3           1.3          
Heifer Initial Weight (lb)                       235.2        232.3         236.6        
Heifer Weaning Weight (lb)                       551.7        565.4         553.4        
Heifer Prebreeding Weight (lb)                   748.9        763.1         756.6        
Calf Birth Weight (lb)                            72.1         73.1          74.0         
Calf Weaning Weight (lb)                         478.2        489.7         476.7        
% Calves Weaned                                   94.5         95.9          93.0         
No differences were observed between any of the treatment groups for the parameters measured in the study. All treatment groups had comparable values for each parameter measured. The data demonstrates that any difference in calving rate between the treatment groups would be less than 10%. Accordingly, the data provides adequate evidence that IMPLUS-C had no adverse effect on subsequent reproduction when administered to heifer (suckling beef) calves after 45 days of age through 6-8 months of age.

VI. HUMAN FOOD SAFETY:

Adequate data were provided to demonstrate that IMPLUS-C had no adverse effect on subsequent reproduction when administered to heifer (suckling beef) calves after 45 days of age.

Under the Center's supplement approval policy (21 CFR 514.106(b)(2)), this is a Category II change providing for the deletion of the labeling limitation against the use of IMPLUS-C in heifer (suckling beef) calves intended for reproduction. The approval of this change is not expected to have any adverse effect on the safety or effectiveness of this new animal drug. Accordingly, this approval did not require a reevaluation of the safety and effectiveness data in the parent application.

Under section 512(c)(2)(F)(iii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the supplemental application contains substantial evidence of the effectiveness of the drug involved, any studies of animal safety, or, in the case of food producing animals, human food safety studies (other than bioequivalence or residue studies) required for the approval of the application and conducted or sponsored by the applicant. The three years of marketing exclusivity applies only to the change in the labeling (deletion of the present labeling limitation against the use of Implus-C in heifer (suckling beef) calves intended for reproduction) for which the supplemental application was approved.

Twelve (12) pages of labeling are attached as follows:

1. Foil Pouch Containing 20 Doses - Front Panel
2. Foil Pouch Containing 20 Doses - Back Panel
3. Carton Containing 5 Cartridge Belts of 20 Doses Each - Front Panel
4. Carton Containing 5 Cartridge Belts of 20 Doses Each - Back Panel
5. Carton Containing 5 Cartridge Belts of 20 Doses Each - Side Panel
6. Carton Containing 5 Cartridge Belts of 20 Doses Each - End Panel
7. 400 Dose Display Case - Front Panel
8. 400 Dose Display Case - Back Panel
9. 400 Dose Display Case - Top Panel
10. 400 Dose Display Case - Side Panel
11. Package Insert for 20 Dose Cartridge Belt - Front Panel
12. Package Insert for 20 Dose Cartridge Belt - Back Panel
Copies of applicable labels may be obtained by writing to the:

NADA	110-315
Sponsor:	Ivy Laboratories, Inc. 8857 Bond Street Overland Park, KS 66214
Generic Name:	progesterone and estradiol benzoate
Trade Name:	IMPLUS-C®
Marketing Status:	Over the Counter (OTC)
Effect of Supplement:	This supplement provides for the deletion of the present labeling limitation against the use of Implus-C in heifer (suckling beef) calves intended for reproduction.

A.	DOSAGE FORM	Implantation
B.	ROUTE OF ADMINISTRATION	Subcutaneous implantation on the posterior aspect of the middle one-third of the ear by means of an implant gun.
C.	RECOMMENDED DOSAGES:	One implant containing 100 mg progesterone and 10 mg estradiol benzoate