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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                  ASR 14359
    Dr. D. D. Colwell          Dr. J. E. Holste
    Agriculture Canada         Merck Research Laboratories
    Lethbridge, Alberta        Fulton, MO
    Canada                     USA
    
    ASR 14360                  ASR 13976
    Dr. J. E. Lloyd            Dr. N.P.M. Pinkall
    University of Wyoming      Merck Research Laboratories
    Laramie, WY                Highfield Farm
    USA                        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 Week12345678910
Mean Trt 1
Control
16.2516.0812.8810.007.506.044.753.250.830.19
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 Week123456789101112
Mean Trt 1
Control
14.016.119.819.222.121.620.916.511.16.13.50.6
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 Week12345678910
Mean Trt 1
Control
5.76.77.16.24.83.93.92.51.80.8
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 Week1234567891011121314
Mean Trt 1
Control
12.513.816.016.215.817.015.713.09.98.46.15.23.31.2
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-707142128
Controls159134160139170185
Eprinomectin
500 mcg/kg
1670<1258142
% Efficacy-100>9998.765.823.7

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             ASR 14538
    Dr. H. G. Kinzer      Dr. M. J. Kennedy
    5065 Ocotillo         Symbiotica Research and Publication
    Las Cruces, NM        Edmonton, Alberta T6J 6G8
    USA                   Canada

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

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 Day036132027
Controls96610681503981485581
Eprinomectin
500 mcg/kg
793833419446590
% Efficacy->9997.857.38.10

 

 

Table IV. B.19. Arithmetic mean H. irritans counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14538).
Count Day057142128
Controls6217404271146
Eprinomectin
500 mcg/kg
90031277220
% Efficacy-10092.772.400

 

 

Table IV. B.20. Arithmetic mean H. irritans counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14545).
Count Day0371421
Controls253178734332321
Eprinomectin
500 mcg/kg
620<110171185
% Efficacy->9998.748.642.4

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,       ASR 14153
    14357, 14707, 14709            Dr. J. A. DiPietro
    Dr. B. N. Kunkle               University of Illinois
    Merck Research Laboratories    Urbana, IL  61801
    Fulton, MO  65251              USA
    USA 
    
    ASR 14162 and 14356            ASR 14256
    Dr. E. G. Johnson              Dr. R. K. Fulton
    Johnson Research               Merck Research Laboratories
    Parma, ID  83660               Springdale, AR  72762
    USA                            USA
    
    ASR 14263 and 14264            ASR 14364
    Dr. R. E. Plue                 Dr. D. R. Thompson
    Merck Research Laboratories    Merck Research Laboratories
    Springdale, AR  72762          Fulton, MO  65251
    USA                            USA
    
    ASR 14441                      ASR 14549
    Dr. J. A. Hair                 Dr. J. E. Holste
    Nu-Era Research Farms          Merck Research Laboratories
    Stillwater, OK  74074          Fulton, MO  65251
    USA                            USA
    
    ASR 14559                      ASR 15078
    Dr. D. D. Bowman               Dr. A. Paul
    Cheri-Hill R&D                 University of Illinois
    Stanwood, MI  49346            Urbana, IL  61801
    USA                            USA
    
    ASR 15186
    Dr. L. Cruthers
    Prof. Lab and Res. Services
    Corapeake, NC  27926
    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
ParasiteNumber of Larvae
Days before Treatment- ImmatureDays before Treatment- Adult
Haemonchus placei5000-70005-721-35
Ostertagia ostertagi3800- 200005-721-35
Trichostrongylus axei400-200005-721-35
Trichostrongylus colubriformis15000-300005-721-35
Cooperia oncophora10000-200005-721-35
Cooperia punctata15000-200005-721-35
Cooperia spp11800-19000530
Nematodirus helvetianus5700-100007-821-30
Bunostomum phlebotomum100-20001756
Oesophagostomum radiatum100-200016-1730-41
Dictyocaulus viviparus1000-60005-828-30

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).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiL486980100
Cooperia oncophoraL454830100
Cooperia punctataL439090100
Cooperia surnabadaL417780100
Nematodirus helvetianusL411900100
Bunostomum phlebotomumL4900100
Oesophagostomum radiatumL41970100
Dictyocaulus viviparusL43610100

 

 

Table IV. B.23. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14146).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiL42030100
Ostertagia ostertagiL488630100
Trichostrongylus axeiL426980100
Oesophagostomum radiatumL4430100
Dictyocaulus viviparusL41310100

 

 

Table IV. B.24. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14153).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiL411240100
Ostertagia ostertagiL473550100
Trichostrongylus axeiL47657<1>99
Trichostrongylus colubriformisL431551>99
Cooperia oncophoraL474003>99
Cooperia punctataL4162813>99
Nematodirus helvetianusL412371>99
Oesophagostomum radiatumL41750100
Dictyocaulus viviparusL4340100

 

 

Table IV. B.25. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14162).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiL4500530>99
Trichostrongylus axeiL47800100
Cooperia oncophoraL424480100
Cooperia punctataL447980100
Cooperia surnabadaL46390100
Oesophagostomum radiatumL41350100
Dictyocaulus viviparusL47382097.3

 

 

Table IV. B.26. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14165).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdult114980100
Trichostrongylus axeiAdult96000100
Trichostrongylus colubriformisAdult46920100
Nematodirus helvetianusL412270100
Oesophagostomum radiatumAdult1840100
Dictyocaulus viviparusAdult1700100

 

 

Table IV. B.27. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14256).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiL43530100
Cooperia punctataL4177801>99

 

 

Table IV. B.28. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14263).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiL48860100
Ostertagia ostertagiL4112000100
Trichostrongylus axeiL417580100
Trichostrongylus colubriformisL46700100
Oesophagostomum radiatumL42490100
Dictyocaulus viviparusL4100100

 

 

Table IV. B.29. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14264).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiAdult8570100
Ostertagia ostertagiAdult70973>99
Ostertagia ostertagiL4930100
Trichostrongylus axeiAdult15930100
Cooperia oncophoraAdult274825>99
Cooperia punctataAdult31410100
Cooperia surnabadaAdult14290100
Oesophagostomum radiatumAdult1910100

 

 

Table IV. B.30. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14356).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiAdult11030100
Ostertagia ostertagiAdult377513>99
Trichostrongylus axeiAdult6250100
Cooperia oncophoraAdult19020100
Cooperia punctataAdult56900100
Bunostomum phlebotomumAdult430100
Oesophagostomum radiatumAdult3380100

 

 

Table IV. B.31. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14357).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiAdult11000100
Ostertagia ostertagiAdult42900100
Ostertagia ostertagiL41750100
Trichostrongylus axeiAdult40380100
Cooperia oncophoraAdult5922>99
Cooperia punctataAdult

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).
NematodeStageHousingMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdultOutdoor
Indoor
22470
0
100
100
Ostertagia ostertagiL4Outdoor
Indoor
630
0
100
100
Trichostrongylus axeiAdultOutdoor
Indoor
18730
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).
NematodeStageHousingMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdultOutdoor
Indoor
1576<1
<1
>99
>99
Cooperia oncophoraAdultOutdoor
Indoor
4207190
98
95.5
97.7
Cooperia punctataAdultOutdoor
Indoor
839<1
1
>99
>99
Oesophagostomum radiatumAdultOutdoor
Indoor
270
0
100
100

 

 

Table IV. B.34. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14549).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Bunostomum phlebotomumL41450100

 

 

Table IV. B.35. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14559).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Bunostomum phlebotomumAdult109<1>99

 

 

Table IV. B.36. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14707).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiL410130100
Trichostrongylus axeiL4600100
Cooperia oncophoraL413370100
Cooperia punctataL49760100
Cooperia surnabadaL43050100
Nematodirus helvetianusL49230100
Oesophagostomum radiatumL4610100

 

 

Table IV. B.37. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14709).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Nematodirus helvetianusL421353>99
Dictyocaulus viviparusL4230100

 

 

Table IV. B.38. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 15078).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Trichostrongylus colubriformisAdult60232>99
Dictyocaulus viviparusAdult2910100


 

Table IV. B.39. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 15186).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Bunostomum phlebotomumL4760100
Dictyocaulus viviparusL4 <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                        ASR 14281
    Dr. J. A. Stuedemann             Dr. T. A. Yazwinski
    USDA                             University of Arkansas
    Watkinsville, GA  30677          Fayetteville, AR  72701
    USA                              USA
    
    ASR 14374                        ASR 14548
    Dr. D. R. Thompson               Dr. E. G. Johnson
    Merck Research Laboratories      Johnson Research
    Fulton, MO  65251                Parma, ID  83660
    USA                              USA
    
    ASR 14613
    Dr. M. D. Drag
    Merck Research Laboratories
    Fulton, MO  65251
    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).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Haemonchus placeiAdult5040100
Ostertagia ostertagiAdult47600100
Ostertagia ostertagiIL4136300100
Trichostrongylus axeiAdult61270100
Cooperia oncophoraAdult21730100
Cooperia punctataAdult16930100
Oesophagostomum radiatumAdult250100

 

 

Table IV. B.41. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14281).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdult597018>99
Ostertagia ostertagiIL4510100
Trichostrongylus axeiAdult3620100
Cooperia oncophoraAdult299429>99
Cooperia punctataAdult35301>99
Cooperia surnabadaAdult4243>99
Nematodirus helvetianusAdult39148>99
Nematodirus helvetianusL43750100
Oesophagostomum radiatumAdult860100
Trichuris sppAdult73198.6

 

 

Table IV. B.42. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14374).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdult27950100
Cooperia oncophoraAdult8321398.4
Trichuris sppAdult105<1>99

 

 

Table IV. B.43. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14548).
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdult330100
Cooperia oncophoraAdult2970100
Cooperia punctataAdult7340100
Cooperia surnabadaAdult550100
Nematodirus helvetianusAdult1680100
Dictyocaulus viviparusAdult640100

 

 

Table IV. B.44. Nematode count data from cattle treated with eprinomectin at 500 mcg/kg (ASR 14613)
NematodeStageMean Count% Efficacy
ControlEprinomectin
Ostertagia ostertagiAdult13030100
Ostertagia ostertagiL47440100
Trichostrongylus axeiAdult930100

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               ASR 15074
    Dr. D. D. Bowman        Dr. R. L. Sifferman
    Cheri-Hill R&D          Bradford Park Veterinary Hospital
    Stanwood, MI  49346     Springfield, MO  65804
    USA                     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.
TrialChallenge
Interval
(Days)
Mean D. viviparus Count% Efficacy
ControlEprinomectin
1470121112596.0
1507414
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                     ASR 14384
    Dr D.R. Thompson              Mr G.R. Allerton
    Merck Research Laboratories   Merck Research Laboratories
    Fulton, MO  65251             Ingleburn, NSW
    USA                           Australia
    
    ASR 14385                     ASR 14441
    Dr R.P. Gogolewski            Dr J.A. Hair
    Merck Research Laboratories   Nu-Era Research Farms
    Ingleburn, NSW                Stillwater, OK  74074
    Australia                     USA
    
    ASR 14701                     ASR 15074
    Dr D.D. Bowman                Dr R.L. Sifferman
    Cheri-Hill R&D                Bradford Park Veterinary Hospital
    Stanwood, MI  49346           Springfield, MO  65804
    USA                           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 SpeciesControlNo RainRain
-1 hour
Rain
+1 hour
Rain
+3 hours
Rain
+6 hours
Osertagia ostertagi3342001784
Percent Efficacy
 
100100>99>99>99
Trichostrongylus axei149600000
% Efficacy
 
100100100100100

 

 

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).
NematodeStageHousingMean Count
Control
Mean Count
Eprinomectin
% Efficacy
Ostertagia ostertagiAdultOutdoor
Indoor
70880
8
100
>99
Ostertagia ostertagiL4Outdoor
Indoor
4584
0
>99
100
Trichostrongylus axeiAdultOutdoor
Indoor
500025
0
>99
100
Cooperia pectinataAdultOutdoor
Indoor
1001717
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                  ASR 14329
    Dr. J. A. Stuedemann       Dr. C. H. Courtney
    USDA                       University of Florida
    Watkinsville, GA  30677    Gainesville, FL  32611
    USA                        USA
    
    ASR 14618                  ASR 14694
    Dr. D. D. Bowman           Dr. R. Young
    Cheri-Hill R&D             Young Veterinary Research
    Stanwood, MI  49346        Modesto, CA  95356
    USA                        USA
    
    ASR 14810                  ASR 15068
    Dr. G. Myers               Dr. R. L. Sifferman
    Dr. Gil Myers, Inc.        Bradford Park Veterinary Hospital
    Magnolia, KY  42757        Springfield, MO  65804
    USA                        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
LocationNumber of
Cattle
BreedAgeLactatingBody Weighta
(kg)
14327GA125Angus,
Angus cross
14-16 moNo125-341
14329FL100Angus cross,
Brahman, Holstein
4-16 moNo207-425
14618MI55Holstein, Jersey6 mo-AdultNo/Yesb159-709
14694CA35HolsteinAdultYes675
14810KY80Beef Cross8-15 moNo125-349
15068MO90Beef Cross,
Holstein
9 moNo550
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
TreatmentNumber
of Cattle
EPG CountsaPercent
Efficacy
BeforeAfter
14327Control
Eprinomectin
25
100
91
86
95
<1

>99
14329bControl
Eprinomectin
14
56
56
86
24
<1

>99
Control
Eprinomectin
6
24
78
115
218
<1

>99
14618cControl
Eprinomectin
11
44
5
6
7
<1

>99
14694cControl
Eprinomectin
7
28
4
3
3
<1

>99
14810bControl
Eprinomectin
3
12
150
167
60
<1

>99
Control
Eprinomectin
13
52
107
98
119
<1

>99
15068Control
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