Animal & Veterinary

NADA 141-079 Ivomec® Eprinex™ Pour-On - original approval (continued 2)

3. Dose Confirmation Against Cattle Grubs

a. Type of Study: Dose confirmation in cattle with infestations of Hypoderma lineatum and Hypoderma bovis. There were four studies (ASR 13976, ASR 14154, ASR 14359 and ASR 14360).

b. Investigators:

ASR 14154
Dr. D. D. Colwell
Agriculture Canada
Lethbridge, Alberta
Canada

ASR 14360
Dr. J. E. Lloyd
University of Wyoming
Laramie, WY
USA

ASR 14359
Dr. J. E. Holste
Merck Research Laboratories
Fulton, MO
USA

ASR 13976
Dr. N.P.M. Pinkall
Merck Research Laboratories
Highfield Farm
Hertford SG 138QJ, UK

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against first larval stage (L1) and second/third larval stage (L2/L3) H. lineatum and H. bovis.

ii. Animals: One hundred and twelve calves. Thirty or 36 crossbred calves aged 7 to 9 months and weighing 126 to 274 kg were used in studies ASR 14154, 14359 and 14360. Sixteen Montbeliard calves aged 17 to 18 months and weighing 316 to 468 kg were used in study ASR 13976.

iii. Housing: Individual or group pens. In ASR 13976 cattle were housed in group pens throughout the study. In two trials, ASR 14154 and 14360, cattle were housed in individual pens throughout the study. In ASR 14359, cattle were housed on a group pasture from Day 56 to Day 98 and in individual pens at other times.

iv. Infestations: In all studies the calves were assumed to be carrying Hypoderma spp infestations based on a history of exposure. In two studies (ASR 13976 and ASR 14154) the calves were also tested for Hypoderma spp antibodies using an ELISA test.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Doses: 500 mcg eprinomectin per kg body weight administered once on Day 0 when larvae were at the L1 stage (Treatment Group 2) or once between Days 31 and 102 when larvae were at the L2/L3 stage (Treatment Group 3). In ASR 13976 there was only one eprinomectin-treated group with treatment administered when larvae were at the L2/L3 stage.

viii. Controls: Control animals were untreated.

ix. Test Duration: Last observations were made 122 to 168 days after the first treatments were administered (Day 0), except for ASR 13976 where last observations were made 72 days after treatment.

x. Pertinent Parameters Measured: Counts of Hypoderma spp lesions at regular intervals until all lesions had resolved. All emerging larvae were identified to the species level.

d. Results: Cattle treated with eprinomectin when Hypoderma spp were at the L1 stage had fewer larvae emerging than control animals. Efficacy against L1 was 100% in all studies. In cattle treated when Hypoderma spp were at the L2/L3 stage, resolution of lesions took longer in the control group compared with the eprinomectin-treated group. The results for each study are summarized in Tables IV.B.13. to IV.B.16. Studies ASR 14154, 14359 and 14360 provided pivotal data for H. lineatum, which was identified in at least eight control animals in each of these studies. Studies ASR 13976 and 14360 provided pivotal data for H. bovis which was identified in at least eight control animals in each study.

Table IV. B.13. Arithmetic mean Hypoderma spp. lesion counts and % efficacy on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 13976).
Count Week 1 2 3 4 5 6 7 8 9 10
Mean Trt 1
Control
16.25 16.08 12.88 10.00 7.50 6.04 4.75 3.25 0.83 0.19
Mean Trt 3
Eprinomectin, L2/3/
% Efficacy
18.25/
NA
16.92/
0.0
1.38/
89.3
0.92/
90.8
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
Table IV. B.14. Arithmetic mean Hypoderma spp. lesion counts and % efficacy on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14154).
Count Week 1 2 3 4 5 6 7 8 9 10 11 12
Mean Trt 1
Control
14.0 16.1 19.8 19.2 22.1 21.6 20.9 16.5 11.1 6.1 3.5 0.6
Mean Trt 2
Eprinomectin L1/
% Efficacy
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
Mean Trt 3
Eprinomectin L2/3/
% Efficacy
14.6/
NA
7.5/
53.1
0.8/
96.2
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
Table IV. B.15. Arithmetic mean Hypoderma spp. lesion counts and % efficacy on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14359).
Count Week 1 2 3 4 5 6 7 8 9 10
Mean Trt 1
Control
5.7 6.7 7.1 6.2 4.8 3.9 3.9 2.5 1.8 0.8
Mean Trt 2
Eprinomectin,L1/
% Efficacy
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
Mean Trt 3
Eprinomectin, L2/3/
% Efficacy
6.3/
NA
4.1/
39.0
0.8/
89.2
0.2/
97.3
0/
100
0/
100
0/
100
0/
100
0/
100
Table IV. B.16. Arithmetic mean Hypoderma spp. lesion counts and % efficacy on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14360).
Count Week 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Mean Trt 1
Control
12.5 13.8 16.0 16.2 15.8 17.0 15.7 13.0 9.9 8.4 6.1 5.2 3.3 1.2
Mean Trt 2
Eprinomectin, L1/
% Efficacy
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
Mean Trt 3
Eprinomectin, L2/3/
% Efficacy
5.3/
NA
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100
0/
100

e. Adverse Reactions: There were no adverse reactions to treatment.

4. Dose Confirmation Against Hornfly

Types of Studies: Dose confirmation in cattle with infestations of Haematobia irritans. There was one pen study (ASR 14276) in which animals were housed in individual pens. There were three studies (ASR 14439, ASR 14538 and ASR 14545) in which animals were housed by treatment groups at pasture.

4.1 Pen Study

a. Investigator:

Dr. R. K. Fulton
Merck Research Laboratories
Springdale, Arkansas 72766
USA

b. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against H. irritans.

ii. Animals: Twelve Holstein cattle aged 7 to 10 months and weighing 157 to 185 kg.

iii. Housing: Individual stanchions in individual environmentally controlled rooms during fly challenge periods (48 hours). Animals were housed in individual stalls between fly challenge periods.

iv. Infestations: Each animal was challenged with 200 flies before treatment and then at 7-day intervals from the day of treatment (Day 0) through Day 28.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Topical vehicle administered at 1 ml per 10 kg body weight.

ix. Test Duration: Last fly challenge was made 28 days after treatment.

x. Pertinent Parameters Measured: Counts of live flies recovered 48 hours after challenge.

c. Results: Cattle treated with eprinomectin had fewer H. irritans than control cattle from Day 0 to Day 21. Efficacy of greater than 98% was obtained through Day 14. The results are summarized in Table IV.B.17.

Table IV. B.17. Arithmetic mean H. irritans counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14276).
Count Day -7 0 7 14 21 28
Controls 159 134 160 139 170 185
Eprinomectin
500 mcg/kg
167 0 <1 2 58 142
% Efficacy - 100 >99 98.7 65.8 23.7

d. Adverse Reactions: There were no adverse reactions to treatment.

4.2 Dose Confirmation Against Hornfly - Pasture Studies

a. Type of Study: Dose confirmation in cattle with infestations of H. irritans. There were three studies (ASR 14439, ASR 14538 and ASR 14545) in which animals were housed by treatment groups at pasture.

b. Investigators:

ASR 14439
Dr. H. G. Kinzer
5065 Ocotillo
Las Cruces, NM
USA

ASR 14545
Dr. R. D. Hall
University of Missouri
Columbia, MO 65201
USA

ASR 14538
Dr. M. J. Kennedy
Symbiotica Research and Publication
Edmonton, Alberta T6J 6G8
Canada

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against H. irritans.

ii. Animals: Sixty cattle. Twenty Holstein or crossbred cattle aged from 14 months to adult and weighing 208 to 787 kg were used in each study.

iii. Housing: Each treatment group was housed in a separate paddock at least 500 yards from each other and from other cattle.

iv. Infestations: Cattle were exposed to natural infestation with H. irritans.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Topical vehicle administered at 1 ml per 10 kg body weight.

ix. Test Duration: Last fly counts were made 21 or 27/28 days after treatment.

x. Pertinent Parameters Measured: Counts of H. irritans on each animal on Days 0, 3 or 5, 6/7, 13/14, 20/21 and 27/28.

d. Results: Efficacy was >90% on Day 6/7 but declined thereafter. The results are summarized in Tables IV.B.18. to IV.B.20.

Table IV. B.18. Arithmetic mean H. irritans counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14439).
Count Day 0 3 6 13 20 27
Controls 966 1068 1503 981 485 581
Eprinomectin
500 mcg/kg
793 8 33 419 446 590
% Efficacy - >99 97.8 57.3 8.1 0
Table IV. B.19. Arithmetic mean H. irritans counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14538).
Count Day 0 5 7 14 21 28
Controls 62 17 40 42 71 146
Eprinomectin
500 mcg/kg
90 0 3 12 77 220
% Efficacy - 100 92.7 72.4 0 0
Table IV. B.20. Arithmetic mean H. irritans counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14545).
Count Day 0 3 7 14 21
Controls 253 178 734 332 321
Eprinomectin
500 mcg/kg
620 <1 10 171 185
% Efficacy - >99 98.7 48.6 42.4

e. Adverse Reactions: There were no adverse reactions to treatment.

5. Dose Confirmation Against Induced Endoparasite Infections

a. Type of Study: Dose confirmation in cattle with induced endoparasite infections. There were 15 studies (ASR 14146, ASR 14153, ASR 14162, ASR 14263, ASR 14264, ASR 14356, ASR 14357, ASR 14364, ASR 14441, ASR 14549, ASR 14559, ASR 14707, ASR 14709, ASR 15078 and ASR 15186). Pivotal data were also obtained from the animals treated at the selected therapeutic dose level in three dose selection studies (ASR 14145, ASR 14165 and ASR 14256).

b. Investigators:

ASR 14145, 14146, 14165, 14357, 14707, 14709
Dr. B. N. Kunkle
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 14162 and 14356
Dr. E. G. Johnson
Johnson Research
Parma, ID 83660
USA

ASR 14263 and 14264
Dr. R. E. Plue
Merck Research Laboratories
Springdale, AR 72762
USA

ASR 14441
Dr. J. A. Hair
Nu-Era Research Farms
Stillwater, OK 74074
USA

ASR 14559
Dr. D. D. Bowman
Cheri-Hill R&D
Stanwood, MI 49346
USA

ASR 15186
Dr. L. Cruthers
Prof. Lab and Res. Services
Corapeake, NC 27926
USA

ASR 14153
Dr. J. A. DiPietro
University of Illinois
Urbana, IL 61801
USA

ASR 14256
Dr. R. K. Fulton
Merck Research Laboratories
Springdale, AR 72762
USA

ASR 14364
Dr. D. R. Thompson
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 14549
Dr. J. E. Holste
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 15078
Dr. A. Paul
University of Illinois
Urbana, IL 61801
USA

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against induced endoparasite infections.

ii. Animals: The studies included 149 cattle treated with eprinomectin at the selected therapeutic dose level and 137 control cattle. Each study used 12, 16, 18 or 20 Holstein or crossbred cattle aged 3 to 12 months and weighing 78 to 335 kg.

iii. Housing: In 17 of the studies, animals were housed in individual pens or stanchions. In one study (ASR 14441) animals were penned together by treatment group. Two of the studies (ASR 14364 and ASR 14441) included separate eprinomectin-treated groups housed indoors under shelter and outdoors exposed to prevailing climatic conditions.

iv. Infections: Infectious third-stage endoparasite larvae (L3) were administered to each animal at times before treatment selected to ensure that the majority of parasites were at either the L4 or the adult stage at the time of treatment. Bunostomum phlebotomum larvae were administered topically in the ear. Larvae of all other species were administered orally. The number of larvae and days of administration for each species are summarized in Table IV.B.21.

Table IV. B.21. Approximate number of endoparasite L3 and days of administration in induced infection pivotal studies
Parasite Number of Larvae
Days before Treatment- Immature Days before Treatment- Adult
Haemonchus placei 5000-7000 5-7 21-35
Ostertagia ostertagi 3800- 20000 5-7 21-35
Trichostrongylus axei 400-20000 5-7 21-35
Trichostrongylus colubriformis 15000-30000 5-7 21-35
Cooperia oncophora 10000-20000 5-7 21-35
Cooperia punctata 15000-20000 5-7 21-35
Cooperia spp 11800-19000 5 30
Nematodirus helvetianus 5700-10000 7-8 21-30
Bunostomum phlebotomum 100-2000 17 56
Oesophagostomum radiatum 100-2000 16-17 30-41
Dictyocaulus viviparus 1000-6000 5-8 28-30

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Topical vehicle administered at 1 ml per 10 kg body weight.

ix. Test Duration: The animals were necropsied for nematode recovery between 14 and 28 days after treatment.

x. Pertinent Parameters Measured: Counts of pulmonary and gastrointestinal nematodes in 5% to 100% aliquots of material recovered at necropsy.

d. Results: Cattle treated with eprinomectin had fewer nematodes recovered compared with control animals. Nematode counts were reduced by >95% for each species and stage against which efficacy is claimed. The arithmetic mean nematode counts and percentage efficacy for each nematode species in each study are summarized in Tables IV.B.22. to IV.B.39.

Table IV. B.22. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14145).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi L4 8698 0 100
Cooperia oncophora L4 5483 0 100
Cooperia punctata L4 3909 0 100
Cooperia surnabada L4 1778 0 100
Nematodirus helvetianus L4 1190 0 100
Bunostomum phlebotomum L4 90 0 100
Oesophagostomum radiatum L4 197 0 100
Dictyocaulus viviparus L4 361 0 100
Table IV. B.23. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14146).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei L4 203 0 100
Ostertagia ostertagi L4 8863 0 100
Trichostrongylus axei L4 2698 0 100
Oesophagostomum radiatum L4 43 0 100
Dictyocaulus viviparus L4 131 0 100
Table IV. B.24. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14153).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei L4 1124 0 100
Ostertagia ostertagi L4 7355 0 100
Trichostrongylus axei L4 7657 <1 >99
Trichostrongylus colubriformis L4 3155 1 >99
Cooperia oncophora L4 7400 3 >99
Cooperia punctata L4 16281 3 >99
Nematodirus helvetianus L4 1237 1 >99
Oesophagostomum radiatum L4 175 0 100
Dictyocaulus viviparus L4 34 0 100
Table IV. B.25. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14162).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi L4 5005 30 >99
Trichostrongylus axei L4 780 0 100
Cooperia oncophora L4 2448 0 100
Cooperia punctata L4 4798 0 100
Cooperia surnabada L4 639 0 100
Oesophagostomum radiatum L4 135 0 100
Dictyocaulus viviparus L4 738 20 97.3
Table IV. B.26. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14165).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult 11498 0 100
Trichostrongylus axei Adult 9600 0 100
Trichostrongylus colubriformis Adult 4692 0 100
Nematodirus helvetianus L4 1227 0 100
Oesophagostomum radiatum Adult 184 0 100
Dictyocaulus viviparus Adult 170 0 100
Table IV. B.27. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14256).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei L4 353 0 100
Cooperia punctata L4 17780 1 >99
Table IV. B.28. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14263).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei L4 886 0 100
Ostertagia ostertagi L4 11200 0 100
Trichostrongylus axei L4 1758 0 100
Trichostrongylus colubriformis L4 670 0 100
Oesophagostomum radiatum L4 249 0 100
Dictyocaulus viviparus L4 10 0 100
Table IV. B.29. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14264).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei Adult 857 0 100
Ostertagia ostertagi Adult 7097 3 >99
Ostertagia ostertagi L4 93 0 100
Trichostrongylus axei Adult 1593 0 100
Cooperia oncophora Adult 2748 25 >99
Cooperia punctata Adult 3141 0 100
Cooperia surnabada Adult 1429 0 100
Oesophagostomum radiatum Adult 191 0 100
Table IV. B.30. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14356).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei Adult 1103 0 100
Ostertagia ostertagi Adult 3775 13 >99
Trichostrongylus axei Adult 625 0 100
Cooperia oncophora Adult 1902 0 100
Cooperia punctata Adult 5690 0 100
Bunostomum phlebotomum Adult 43 0 100
Oesophagostomum radiatum Adult 338 0 100
Table IV. B.31. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14357).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei Adult 1100 0 100
Ostertagia ostertagi Adult 4290 0 100
Ostertagia ostertagi L4 175 0 100
Trichostrongylus axei Adult 4038 0 100
Cooperia oncophora Adult 592 2 >99
Cooperia punctata Adult

11012>99Cooperia surnabadaAdult5252>99Bunostomum phlebotomumAdult160100Oesophagostomum radiatumL4100100  

Table IV. B.32. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg with separate groups housed indoors and outdoors (ASR 14364).
Nematode Stage Housing Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult Outdoor
Indoor
2247 0
0
100
100
Ostertagia ostertagi L4 Outdoor
Indoor
63 0
0
100
100
Trichostrongylus axei Adult Outdoor
Indoor
1873 0
7
100
>99
Table IV. B.33. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg with separate groups housed indoors and outdoors (ASR 14441).
Nematode Stage Housing Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult Outdoor
Indoor
1576 <1
<1
>99
>99
Cooperia oncophora Adult Outdoor
Indoor
4207 190
98
95.5
97.7
Cooperia punctata Adult Outdoor
Indoor
839 <1
1
>99
>99
Oesophagostomum radiatum Adult Outdoor
Indoor
27 0
0
100
100
Table IV. B.34. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14549).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Bunostomum phlebotomum L4 145 0 100
Table IV. B.35. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14559).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Bunostomum phlebotomum Adult 109 <1 >99
Table IV. B.36. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14707).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi L4 1013 0 100
Trichostrongylus axei L4 60 0 100
Cooperia oncophora L4 1337 0 100
Cooperia punctata L4 976 0 100
Cooperia surnabada L4 305 0 100
Nematodirus helvetianus L4 923 0 100
Oesophagostomum radiatum L4 61 0 100
Table IV. B.37. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14709).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Nematodirus helvetianus L4 2135 3 >99
Dictyocaulus viviparus L4 23 0 100
Table IV. B.38. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 15078).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Trichostrongylus colubriformis Adult 6023 2 >99
Dictyocaulus viviparus Adult 291 0 100
Table IV. B.39. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 15186).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Bunostomum phlebotomum L4 76 0 100
Dictyocaulus viviparus L4   <1 >99

e. Adverse Reactions: There were no adverse reactions to treatment.

6. Dose Confirmation Against Natural Endoparasite Infections

a. Type of Study: Dose confirmation in cattle with natural endoparasite infections. There were four studies (ASR 14281, ASR 14374, ASR 14548 and ASR 14613). Pivotal data were also obtained from the animals treated at the selected therapeutic dose level in one dose selection study (ASR 14018).

b. Investigators:

ASR 14018
Dr. J. A. Stuedemann
USDA
Watkinsville, GA 30677
USA

ASR 14374
Dr. D. R. Thompson
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 14613
Dr. M. D. Drag
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 14281
Dr. T. A. Yazwinski
University of Arkansas
Fayetteville, AR 72701
USA

ASR 14548
Dr. E. G. Johnson
Johnson Research
Parma, ID 83660
USA

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against natural endoparasite infections.

ii. Animals: The studies included 37 cattle treated with eprinomectin at the selected therapeutic dose level and 37 control cattle. Four studies used 12 or 16 cattle 6 to 14 months old and weighing 96 to 267 kg at treatment. In two of these studies (ASR 14018 and 14281), the cattle were beef breeds and in the other two studies (ASR 14374 and 14548) they were Holsteins. The fifth study (ASR 14613) used 14 lactating Holstein cows aged 4 to 8 years and weighing 487 to 776 kg at the time of treatment.

iii. Housing: Individual pens or stanchions.

iv. Infections: Based on grazing history all animals were expected to be carrying natural nematode infections. In four studies infections were confirmed by fecal nematode egg counts before treatment. In the fifth study (ASR 14018), two animals from the herd were necropsied to confirm the presence of inhibited O. ostertagi larvae (IL4). In four studies, the animals were housed under conditions that precluded further nematode infection for at least 21 days before treatment. In the fifth study (ASR 14018), they were housed under these conditions for 8 days before treatment.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: In four studies control animals were treated with topical vehicle administered at 1 ml per 10 kg body weight. In the fifth study (ASR 14018), the controls were untreated.

ix. Test Duration: The animals were necropsied for nematode recovery between 14 and 27 days after treatment.

x. Pertinent Parameters Measured: Gastrointestinal and pulmonary nematodes in 5% to 100% aliquots of material recovered at necropsy.

d. Results: Cattle treated with eprinomectin had fewer nematodes recovered compared with control animals. Nematode counts were reduced by >98% for each species and stage against which efficacy is claimed. The arithmetic mean nematode counts and percentage efficacy for each nematode species in each study are summarized in Tables IV.B.40. to IV.B.44.

Table IV. B.40. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14018).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Haemonchus placei Adult 504 0 100
Ostertagia ostertagi Adult 4760 0 100
Ostertagia ostertagi IL4 13630 0 100
Trichostrongylus axei Adult 6127 0 100
Cooperia oncophora Adult 2173 0 100
Cooperia punctata Adult 1693 0 100
Oesophagostomum radiatum Adult 25 0 100
Table IV. B.41. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14281).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult 5970 18 >99
Ostertagia ostertagi IL4 51 0 100
Trichostrongylus axei Adult 362 0 100
Cooperia oncophora Adult 2994 29 >99
Cooperia punctata Adult 3530 1 >99
Cooperia surnabada Adult 424 3 >99
Nematodirus helvetianus Adult 3914 8 >99
Nematodirus helvetianus L4 375 0 100
Oesophagostomum radiatum Adult 86 0 100
Trichuris spp Adult 73 1 98.6
Table IV. B.42. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14374).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult 2795 0 100
Cooperia oncophora Adult 832 13 98.4
Trichuris spp Adult 105 <1 >99
Table IV. B.43. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14548).
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult 33 0 100
Cooperia oncophora Adult 297 0 100
Cooperia punctata Adult 734 0 100
Cooperia surnabada Adult 55 0 100
Nematodirus helvetianus Adult 168 0 100
Dictyocaulus viviparus Adult 64 0 100
Table IV. B.44. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14613)
Nematode Stage Mean Count % Efficacy
Control Eprinomectin
Ostertagia ostertagi Adult 1303 0 100
Ostertagia ostertagi L4 744 0 100
Trichostrongylus axei Adult 93 0 100

e. Adverse Reactions: There were no adverse reactions to treatment.

7. Dose Confirmation of Persistent Efficacy Against Dictyocaulus viviparus

a. Type of Study: Dose confirmation to demonstrate control against Dictyocaulus viviparus for 21 days following treatment. There were two studies (ASR 14701 and ASR 15074).

b. Investigators:

ASR 14701
Dr. D. D. Bowman
Cheri-Hill R&D
Stanwood, MI 49346
USA

ASR 15074
Dr. R. L. Sifferman
Bradford Park Veterinary Hospital
Springfield, MO 65804
USA

c. General Design: i. Purpose: To confirm the persistent efficacy of eprinomectin administered topically at 500 mcg/kg against D. viviparus.

ii. Animals: The studies included 28 cattle treated with eprinomectin and 28 control cattle. In one study the cattle were Holsteins and in the other they were beef crossbred. The cattle were less than 6 months of age and weighed 51 to 104 kg at the time of treatment.

iii. Housing: The animals were housed in individual outdoor pens exposed to prevailing climatic conditions.

iv. Infections: Forty or 50 D. viviparus infectious L3 were administered to each animal once daily for 14 or 21 days after treatment.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Control animals were untreated in one trial (ASR 14701) and were treated with topical vehicle administered at 1 ml per 10 kg body weight in the other trial (ASR 15074).

ix. Test Duration: The animals were necropsied for nematode recovery 28 days after the last administration of larvae, that is, 42 or 49 days after treatment.

x. Pertinent Parameters Measured: Number of D. viviparus recovered at necropsy.

d. Results: Cattle treated with eprinomectin had fewer D. viviparus recovered than control cattle. D. viviparus counts were reduced by >94% in cattle challenged with infectious larvae for 14 days or for 21 days after treatment. The arithmetic mean D. viviparus counts and percentage efficacy from each study are summarized in Table IV.B.45.

Table IV. B.45. Nematode count data for cattle treated with eprinomectin at 500 mcg/kg and challenged with D. viviparus L3 after treatment.
Trial Challenge
Interval
(Days)
Mean D. viviparus Count % Efficacy
Control Eprinomectin
14701 21 112 5 96.0
15074 14
21
122
156
1
9
>99
94.4

e. Adverse Reactions: There were no adverse reactions to treatment.

8. Effect of Weather

a. Type of Study: Confirmation of efficacy against internal parasites in cattle exposed to prevailing weather conditions or to simulated rainfall before or after treatment. There were six dose confirmation studies. Four of the studies provided pivotal data confirming therapeutic (ASR 14364 and ASR 14441) or persistent (ASR 14701 and ASR 15074) efficacy. These studies are summarized in Sections IV.B.5 and IV.B.7, respectively. Additional data are provided by two corroborative studies (ASR 14384 [simulated rainfall] and 14385).

b. Investigators:

ASR 14364
Dr D.R. Thompson
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 14385
Dr R.P. Gogolewski
Merck Research Laboratories
Ingleburn, NSW
Australia

ASR 14701
Dr D.D. Bowman
Cheri-Hill R&D
Stanwood, MI 49346
USA

ASR 14384
Mr G.R. Allerton
Merck Research Laboratories
Ingleburn, NSW
Australia

ASR 14441
Dr J.A. Hair
Nu-Era Research Farms
Stillwater, OK 74074
USA

ASR 15074
Dr R.L. Sifferman
Bradford Park Veterinary Hospital
Springfield, MO 65804
USA

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against induced endoparasite infections in cattle exposed to prevailing weather conditions or to simulated rainfall.

ii. Animals: The studies included 120 cattle treated with eprinomectin at the selected therapeutic dose level and 78 control cattle. Each study used between 18 and 60 Holstein or beef crossbred cattle aged 3 to 10 months and weighing 51 to 335 kg.

iii. Housing: In five of the studies, animals were housed in individual pens. In one study (ASR 14441) animals were penned together by treatment group. Three of the studies (ASR 14364, 14385 and ASR 14441) included separate eprinomectin-treated groups housed inside under shelter and outside exposed to prevailing climatic conditions. In two of the studies (ASR 14701 and ASR 15074), all animals were housed outside. One study (ASR 14384) included groups exposed to simulated rainfall before treatment or at various intervals after treatment.

iv. Infections: Infectious third-stage endoparasite larvae (L3) were administered orally to each animal at selected times before or after treatment.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: In five studies topical vehicle was administered at 1 ml per 10 kg body weight. In one study (ASR 14701) the controls were untreated.

ix. Test Duration: The animals were necropsied for nematode recovery between 14 and 28 days after treatment in the therapeutic efficacy studies and 42, 49 or 56 days after treatment in the persistent efficacy studies.

x. Pertinent Parameters Measured: Counts of pulmonary and gastrointestinal nematodes in 5% to 100% aliquots of material recovered at necropsy.

d. Results: Cattle treated with eprinomectin had fewer nematodes recovered compared with control animals. Nematode counts were reduced by >90% for each species and stage against which efficacy is claimed. The results of the pivotal studies are summarized in Tables IV.B.32, IV.B.33 and IV.B.45. The arithmetic mean nematode counts and percentage efficacy for each nematode species in corroborative studies, ASR 14384 and ASR 14385, are summarized in Tables IV.B.46. to IV.B.47.

Table IV. B.46. Arithmetic mean nematode counts on cattle exposed to simulated rain before or after treatment with eprinomectin administered topically at 500 mcg/kg (ASR 14384).
Nematode Species Control No Rain Rain
-1 hour
Rain
+1 hour
Rain
+3 hours
Rain
+6 hours
Osertagia ostertagi 3342 0 0 17 8 4
Percent Efficacy
 
100 100 >99 >99 >99
Trichostrongylus axei 1496 0 0 0 0 0
% Efficacy
 
100 100 100 100 100
Table IV. B.47. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg with separate groups housed indoors and outdoors (ASR 14385).
Nematode Stage Housing Mean Count
Control
Mean Count
Eprinomectin
% Efficacy
Ostertagia ostertagi Adult Outdoor
Indoor
7088 0
8
100
>99
Ostertagia ostertagi L4 Outdoor
Indoor
458 4
0
>99
100
Trichostrongylus axei Adult Outdoor
Indoor
5000 25
0
>99
100
Cooperia pectinata Adult Outdoor
Indoor
10017 17
0
>99
100

9. Conclusions: Eprinomectin administered topically at 500 mcg/kg is effective against the following endo- and ectoparasites.

Gastrointestinal nematodes (adults and fourth-stage larvae, L4)

Haemonchus placei
Ostertagia ostertagi (including inhibited L4)
Trichostrongylus axei
Trichostrongylus colubriformis
Cooperia oncophora
Cooperia punctata
Cooperia surnabada
Nematodirus helvetianus
Bunostomum phlebotomum
Oesophagostomum radiatum
Trichuris spp. (adults)

Lungworms (adults and L4)

Dictyocaulus viviparus

Cattle grubs (all parasitic stages)

Hypoderma lineatum
Hypoderma bovis

Lice

Damalinia bovis
Linognathus vituli
Haematopinus eurysternus
Solenopotes capillatus

Mange Mites

Chorioptes bovis
Sarcoptes scabiei

Flies

Haematobia irritans

IVOMEC EPRINEX (eprinomectin) Pour-On for Beef and Dairy Cattle has been proved to control infections of Dictyocaulus viviparus for 21 days after treatment and Haematobia irritans for 7 days after treatment.

Varying weather conditions, including rainfall, do not affect the efficacy of IVOMEC EPRINEX Pour-On.

C. Field Trials

1. Endoparasites

a. Type of Study: Field trials in cattle with natural endoparasite infections. There were six trials (ASR 14327, ASR 14329, ASR 14618, ASR 14694, ASR 14810 and ASR 15068).

b. Investigators:

ASR 14327
Dr. J. A. Stuedemann
USDA
Watkinsville, GA 30677
USA

ASR 14618
Dr. D. D. Bowman
Cheri-Hill R&D
Stanwood, MI 49346
USA

ASR 14810
Dr. G. Myers
Dr. Gil Myers, Inc.
Magnolia, KY 42757
USA

ASR 14329
Dr. C. H. Courtney
University of Florida
Gainesville, FL 32611
USA

ASR 14694
Dr. R. Young
Young Veterinary Research
Modesto, CA 95356
USA

ASR 15068
Dr. R. L. Sifferman
Bradford Park Veterinary Hospital
Springfield, MO 65804
USA

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against endoparasites under field conditions.

ii. Animals: The studies included 388 cattle treated with eprinomectin and 97 control cattle. Sixty of the eprinomectin-treated cattle were lactating cows. Details of the trial animals are summarized in Table IV.C.1.

Table IV. C.1. Details of cattle used in field trials with eprinomectin administered topically at 500 mcg/kg.
Trial
Number
Location Number of
Cattle
Breed Age Lactating Body Weighta
(kg)
14327 GA 125 Angus,
Angus cross
14-16 mo No 125-341
14329 FL 100 Angus cross,
Brahman, Holstein
4-16 mo No 207-425
14618 MI 55 Holstein, Jersey 6 mo-Adult No/Yesb 159-709
14694 CA 35 Holstein Adult Yes 675
14810 KY 80 Beef Cross 8-15 mo No 125-349
15068 MO 90 Beef Cross,
Holstein
9 mo No 550
a Actual or estimated
b 40 adult females were lactating

iii. Housing: In five of the trials the animals were housed in group pastures or dry lots. In the sixth trial (ASR 14618), the animals were housed in stanchions, group pens or group pastures. Animals from the control and eprinomectin-treated groups were always housed separately.

iv. Infections: All animals were carrying natural nematode infections confirmed by fecal nematode egg counts before treatment.

v. Dosage Form: Non-aqueous solution containing 5 mg eprinomectin per ml.

vi. Route of Administration: Topical application along the backline from withers to tailhead.

vii. Dose: 1 ml per 10 kg body weight to provide 500 mcg eprinomectin per kg body weight. The dose was calculated and applied by a non-Company operator such as the investigator, the animals' owner or a herdsman.

viii. Controls: Control animals were untreated.

ix. Test Duration: The post-treatment fecal samples were collected 14/15 days after treatment.

x. Pertinent Parameters Measured: Fecal nematode egg per gram (epg) counts from samples collected before and after treatment.

d. Results: There was >99% reduction in strongylid eggs in all studies. The arithmetic mean epg counts and percentage efficacy for each study are summarized in Table IV.C.2.

Table IV. C.2. Mean strongylid epg counts and percentage efficacy for cattle treated with eprinomectin in field trials.
Trial
Number
Treatment Number
of Cattle
EPG Countsa Percent
Efficacy
Before After
14327 Control
Eprinomectin
25
100
91
86
95
<1

>99
14329b Control
Eprinomectin
14
56
56
86
24
<1

>99
Control
Eprinomectin
6
24
78
115
218
<1

>99
14618c Control
Eprinomectin
11
44
5
6
7
<1

>99
14694c Control
Eprinomectin
7
28
4
3
3
<1

>99
14810b Control
Eprinomectin
3
12
150
167
60
<1

>99
Control
Eprinomectin
13
52
107
98
119
<1

>99
15068 Control
Eprinomectin
18
72
118
122
99
<1

>99
a Samples collected Days -5 to 0 and Days 14/15
b Study conducted at two different sites; data from each site summarized separately
c Studies were conducted with mature lactating dairy cows, which generally carry lower burdens of internal parasites

e. Adverse Reactions: There were no adverse reactions to treatment.

continued

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