Animal & Veterinary

NADA 141-079 Ivomec® Eprinex™ Pour-On - original approval

Approval Date: April 16, 1997

I. GENERAL INFORMATION:

NADA

141-079

Sponsor:

Merck Research Laboratories
Division of Merck & Co., Inc.
P. O. Box 2000
Rahway, New Jersey 07065-0914

Generic Name:

eprinomectin

Trade Name:

Ivomec® Eprinex™ Pour-On

Marketing Status:

Over the Counter (OTC)

II. INDICATIONS FOR USE

IVOMEC EPRINEX Pour-On for Beef and Dairy Cattle is indicated for treatment and control of:

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.

III. DOSAGE

A.

DOSAGE FORM

IVOMEC EPRINEX Pour-On is a clear non-aqueous solution containing 5 mg per ml of eprinomectin. The product is available in 250 ml, 1 liter, 2.5 liter and 5 liter plastic bottles.

B.

ROUTE OF ADMINISTRATION

IVOMEC EPRINEX Pour-On should be applied topically along the backline from the withers to the tailhead.

C.

APPROVED DOSAGES:

The recommended dose of IVOMEC EPRINEX Pour-On is 1 ml per 10 kg body weight to deliver 500 mcg per kg body weight of eprinomectin.

IV. EFFECTIVENESS

A clinical development program was conducted which supports the efficacy of eprinomectin applied topically at 500 mcg/kg bodyweight against a wide range of endo- and ectoparasites in cattle. In all clinical studies the results from the eprinomectin-treated group(s) were compared with results from an untreated or placebo-treated group. In some studies infections were induced while in others they were naturally acquired. Each claim for the control of a parasite species and stage is supported by at least two well-controlled studies. Efficacy is expressed as percentage (%) reduction compared to controls calculated as follows:

                     AM

C-AMT % Reduction = ------- X 100 AMC where

% Reduction = Percentage reduction of the parasite species
AMC = Arithmetic mean number of parasites in control cattle
AMT = Arithmetic mean number of parasites in treated cattle

Eprinomectin provided >= 90% reduction for each endo- and ectoparasite listed in the INDICATIONS section. Data from the development program supports the use of eprinomectin applied topically at 500 mcg/kg for treatment and control of endo- and ectoparasites in cattle.

A. Dose Determination

Dose selection studies were conducted against a wide range of important ecto- and endoparasites of cattle. There were four studies with ectoparasites and seven studies with endoparasites. Each study included an untreated control group and groups treated with three dose levels within the range of 125 to 750 mcg/kg body weight. All formulations were delivered in the commercial vehicle but the concentration of active drug varied with the dose level. Four studies examined efficacy against natural ectoparasite infestations including two studies with Chorioptes bovis mites and two studies with lice. Five studies examined efficacy against induced endoparasite infections including three studies in which the parasites were immature at the time of treatment and two studies where they were adults. A further two studies evaluated efficacy against natural endoparasite infections including inhibited fourth-stage Ostertagia ostertagi larvae.

1. Dose Selection Against Chorioptes bovis

a. Type of Study: Dose selection in cattle with infestations of Chorioptes bovis. There were two studies (ASR 14095 and ASR 14098).

b. Investigator:

Dr. D. Barth
Merck Research Laboratories
Kathrinenhof Farm
8201 Lauterbach, Germany

c. General Design:

i. Purpose: To determine the optimal dose level of eprinomectin against infestations of C. bovis mites.

ii. Animals: Forty-eight Fleckvieh and Rotbunte cows aged 3 to 10 years and weighing 447 to 766 kg. There were 24 cows in each study.

iii. Housing: Individual stanchions.

iv. Infestations: All cattle were carrying natural C. bovis infestations confirmed by pretreatment skin scrapings.

v. Dosage Form: Non-aqueous solution containing 2.5, 5 or 7.5 mg eprinomectin per ml.

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

vii. Doses: 250, 500 or 750 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Control animals were untreated.

ix. Test Duration: Final skin scrapings were taken 56 days after treatment.

x. Pertinent Parameters Measured: Mite counts in skin scrapings collected from six sites on each animal at approximately weekly intervals.

d. Results: In ASR 14095, mite counts were reduced in all eprinomectin-treated cattle and efficacy was sustained through Day 56. The results are summarized below in Table IV.A.1.

In ASR 14098, two animals of the six treated at 250 mcg/kg had positive mite counts at each post-treatment observation and had mite counts similar to the control animals from Day 35 through Day 56. Five of six animals treated at 500 mcg/kg had zero mite counts from Day 21 onwards, and all six animals had zero mite counts from Day 35 through Day 56. The results are summarized below in Table IV.A.2.

Lesion scores were also compiled in these studies. Lesion scores, although reduced for treated cattle over controls, did not appear to be useful in distinguishing the best treatment level.

Table IV.A.l. Arithmetic mean C. bovis mite counts on cattle treated with eprinomectin administered topically (ASR 14095).
Count Day 0 7 14 21/22 28 35 42 49 56
Untreated Controls 444 413 343 371 344 303 270 259 228
Eprinomectin 250 mcg/kg 469 49 18 3 <1 9 <1 <1 <1
Percent Efficacy - 88 95 >99 >99 97 >99 >99 >99
Eprinomectin 500 mcg/kg 427 33 5 3 0 0 0 <1 0
Percent Efficacy - 92 99 >99 100 100 100 >99 100
Eprinomectin 750 mcg/kg 424 9 0 <1 0 0 0 <1 0
Percent Efficacy - 98 100 >99 100 100 100 >99 100
Table IV. A.2. Arithmetic mean C. bovis mite counts on cattle treated with eprinomectin administered topically (ASR 14098).
Count Day -1/0 7 14 21 28 35 42 49 56
Untreated Controls 307 327 301 253 200 149 206 282 233
Eprinomectin 250 mcg/kg 335 102 61 10 4 42 59 31 66
Percent Efficacy - 69 80 96 98 72 71 89 72
Eprinomectin 500 mcg/kg 377 94 3 <1 <1 0 0 0 0
Percent Efficacy - 71 99 >99 >99 100 100 100 100
Eprinomectin 750 mcg/kg 319 46 14 4 <1 4 0 <1 0
Percent Efficacy - 86 96 99 >99 97 100 >99 100

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

2. Dose Selection Against Lice

a. Type of Study: Dose selection in cattle with infestations of lice. One study was conducted (ASR 14150).

b. Investigator:

Dr. L. L. Smith
Smith Research and Development
Lodi, Wisconsin 53555
USA

c. General Design:

i. Purpose: To determine the optimal dose level of eprinomectin against infestations of lice.

ii. Animals: Twenty-four beef crossbred calves aged 3 to 8.5 months and weighing 96 to 253 kg.

iii. Housing: Individual stanchions.

iv. Infestations: All cattle were carrying natural lice infestations confirmed by pretreatment counts in selected sites.

v. Dosage Form: Non-aqueous solution containing 2.5, 5 or 7.5 mg eprinomectin per ml.

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

vii.Doses: 250, 500 or 750 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Control animals were untreated.

ix. Test Duration: Final lice counts were made 56 days after treatment.

x. Pertinent Parameters Measured: Lice counts and identification to species in eight pre-selected sites on each animal at approximately weekly intervals.

d. Results: No live lice were found on any eprinomectin-treated animal after treatment. Lice numbers were maintained on control animals through Day 28 but decreased thereafter. The results are summarized in Tables IV.A.3. and IV.A.4.

Table IV. A.3. Arithmetic mean Solenopotes capillatus counts on cattle treated with eprinomectin administered topically (ASR 14150).
Count Day -1 7 14 21 28
Untreated Controls 699 746 552 544 449
Eprinomectin 250 mcg/kg 854 0 0 0 0
Percent Efficacy - 100 100 100 100
Eprinomectin 500 mcg/kg 882 0 0 0 0
Percent Efficacy - 100 100 100 100
Eprinomectin 750 mcg/kg 688 0 0 0 0
Percent Efficacy - 100 100 100 100
Table IV. A.4. Arithmetic mean Damalinia bovis counts on cattle treated with eprinomectin administered topically (ASR 14150).
Count Day -1 7 14 21 28 35
Untreated Controls 506 542 867 548 392 177
Eprinomectin 250 mcg/kg 370 0 0 0 0 0
% Efficacy - 100 100 100 100 100
Eprinomectin 500 mcg/kg 297 0 0 0 0 0
% Efficacy - 100 100 100 100 100
Eprinomectin 750 mcg/kg 406 0 0 0 0 0
% Efficacy - 100 100 100 100 100

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

3. Dose Selection Against Endoparasites

a. Type of Study: Dose selection in cattle with infections of gastrointestinal and pulmonary nematodes. Two studies are summarized (ASR 13953 and ASR 14000).

b. Investigators:

ASR 13953
Dr. S. R. Pitt
Merck Research Laboratories
Highfield Farm
Hertford SG 138QJ, UK

ASR 14000
Dr. J. C. Williams< br /> Louisiana State University
Baton Rouge, LA 70803
USA

c. General Design:

i. Purpose: To determine the optimal dose level of eprinomectin against infections of gastrointestinal and pulmonary nematodes including inhibited Ostertagia ostertagi L4.

ii. Animals: Fifty-one Friesian and crossbred beef calves aged 7 to 10 months and weighing 149 to 248 kg. There were 24 calves used in ASR 13953 and 27 calves used in ASR 14000.

iii. Housing: Tethered in individual pens.

iv. Infections: In ASR 13953 the calves were helminth free as demonstrated by fecal nematode egg counts. Infective third-stage nematode larvae (L3) were administered to each calf on Day -28 and calves were assumed to be carrying adult nematode infections at the time of treatment. In ASR 14000, three calves were necropsied before treatment to confirm that the animals were carrying natural nematode infections including inhibited L4 (IL4) O. ostertagi.

v. Dosage Form: Non-aqueous solution containing 1.25, 2.5 or 5 mg eprinomectin per ml.

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

vii. Doses: 125, 250 or 500 mcg eprinomectin per kg body weight administered once on Day 0.

viii. Controls: Control animals were untreated.

ix. Test Duration: Calves were necropsied for nematode recovery 14 to 16 days after treatment.

x. Pertinent Parameters Measured: Counts of nematodes recovered from the gastrointestinal and pulmonary tracts.

d. Results: Efficacy was >90% against O. ostertagia including IL4, T. axei, C. oncophora, N. helvetianus and D. viviparus at the 250 and 500 mcg per kg body weight dose levels. The results are summarized in Tables IV.A.5. and IV.A.6.

Table IV. A.5. Arithmetic mean nematode counts from cattle treated with eprinomectin administered topically (ASR 13953).
Nematode (Adult) Control
Eprinomectin (mcg/kg) 125 Eprinomectin (mcg/kg) 250 Eprinomectin (mcg/kg) 500
Ostertagia ostertagi 4460 0
100%
0
100%
0
100%
Trichostrongylus axei 2490 283
89%
3
>99%
3
>99%
Cooperia oncophora 4977 1257
75%
360
93%
57
99%
Nematodirus helvetianus 1560 67
96%
0
100%
0
100%
Dictyocaulus viviparus 52 0
100%
0
100%
0
100%
Table IV. A.6. Arithmetic mean nematode counts from cattle treated with eprinomectin administered topically (ASR 14000).
Nematode Control
Eprinomectin (mcg/kg) 125 Eprinomectin (mcg/kg) 250 Eprinomectin (mcg/kg) 500
Ostertagia ostertagi
(Adult)
18920 0
100%
18
>99%
0
100%
Ostertagia ostertagi
(IL4)
60884
-
23493
61%
838
99%
309
>99%

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

4. Additional Dose Selection Studies

Six additional dose selection studies were conducted, five against endoparasites, L4 and adult stages, (ASR 14018, 14134, 14145, 14165 and 14256) and one against lice (ASR 14096), with similar results to those presented above. Since the results duplicated those already presented, individual study summaries were not included.

5. Conclusions

Chorioptes bovis is the dose limiting parasite. Although there was high efficacy against C. bovis mites at the 250 mcg/kg body weight dose level, infestations recurred in some animals within the eight-week observation period of the studies. The 500 mcg/kg dose level showed optimal efficacy against C. bovis mites and was also effective against the other endo- and ectoparasite species examined.

B. Dose Confirmation

Each claim is supported by data from at least two studies in which cattle were treated with eprinomectin administered topically at 500 mcg per kg body weight. The commercial formulation was used in all studies.

1. Dose Confirmation Against Mites

a. Type of Study: Dose confirmation in cattle with infestations of C. bovis or Sarcoptes scabiei mites. There were four studies with C. bovis (ASR 14432, ASR 15067, ASR 15072 and ASR 15076) and two studies with S. scabiei (ASR 14115 and ASR 14608).

b. Investigators:

ASR 14432
Dr. J. A. Hair
Nu-Era Farms
Stillwater, OK 74074
USA

ASR 15072
Dr. K. E. Sterner
821 N. Jefferson St.
Ionia, MI 48846
USA

ASR 14608
Dr. A. Villeneuve
University of Montreal
St-Hyacinthe, Quebec
Canada

ASR 15067
Dr. R. E. Schmidt
106 Meadow Street
Lodi, WI 53555
USA

ASR 15076
Dr. D. Bowman
Cheri-Hill R&D
Stanwood, MI 49346
USA

ASR 14115
Dr. E. Kutzer
University of Vienna
A-1030 Vienna
Austria

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against infestations of C. bovis or S. scabiei mites.

ii. Animals: One hundred and eight cattle. Sixteen or 20 adult Holstein cows weighing 419 to 791 kg were used in each of the studies with C. bovis. Sixteen or 20, Fleckvieh, Braunvieh or Holstein cattle aged from 3 months to adult and weighing 127 to 912 kg were used in each of the studies with S. scabiei.

iii. Housing: Individual stanchions, tie stalls or pens.

iv. Infestations: In the trials with C. bovis and in one trial with S. scabiei (ASR 14608), the cattle were carrying natural mite infestations. In the remaining trial with S. scabiei, infestations were induced by application of mites at selected times before treatment. All infestations were confirmed by pretreatment skin scrapings.

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: Final skin scrapings were taken 28 or 56/57 days after treatment.

x. Pertinent Parameters Measured: Mite counts in skin scrapings collected from two, four or six sites on each animal at approximately weekly intervals.

d. Results: Cattle treated with eprinomectin had fewer mites than control cattle at each post-treatment observation. The results of each study are summarized in Tables IV.B.1. to IV.B.6.

Table IV. B.1. Arithmetic mean C. bovis mite counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14432).
Count Day -1/0 7/8 14/15 21 28 35 42 49 56
Controls 198 426 237 163 191 219 60 58 111
Eprinomectin
500 mcg/kg
191 0 0 0 0 0 0 0 0
% Efficacy - 100 100 100 100 100 100 100 100
Table IV. B.2. Arithmetic mean C. bovis mite counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 15067).
Count Day -1 7 14 21 28 35 42 49 56
Controls 296 330 375 519 310 237 290 299 388
Eprinomectin
500 mcg/kg
171 52 28 39 2 2 3 0 0
% Efficacy - 84 93 93 >99 >99 99 100 100
Table IV. B.3. Arithmetic mean C. bovis mite counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 15072).
Count Day -3 7 14 21 28 35 42 49 56
Controls 311 66 481 302 457 1461 1169 741 465
Eprinomectin
500 mcg/kg
317 0 0 0 0 0 0 0 0
% Efficacy - 100 100 100 100 100 100 100 100
Table IV. B.4. Arithmetic mean C. bovis mite counts on cattle treated with eprinomectin administered at 500 mcg/kg (ASR 15076).
Count Day -2 7 14 21 28 35 42 49 56
Controls 1056 2702 3002 3111 1674 2383 1569 1445 661
Eprinomectin 500 mcg/kg 1353 39 8 7 <1 1 0 <1 0
% Efficacy - 99 >99 >99 >99 >99 100 >99 100
Table IV. B.5. Arithmetic mean S. scabiei mite counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14115).
Count Day -1 7 14 21 27/28 35 42 48/49 56/57
Controls 262 451 421 775 1008 1473 1594 3162 3103
Eprinomectin
500 mcg/kg
150 30 <1 0 0 0 0 0 0
% Efficacy - 93 >99 100 100 100 100 100 100
Table IV. B.6. Arithmetic mean S. scabiei mite counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14608).
Count Day -1 7 14 21 28
Controls 85 73 48 44 47
Eprinomectin
500 mcg/kg
77 <1 0 <1 0
% Efficacy - >99 100 >99 100

e. Adverse Reactions: Two control animals and two eprinomectin-treated animals died or were removed from studies for non-trial related reasons. There were no adverse reactions to treatment.

2. Dose Confirmation Against Lice

a. Type of Study: Dose confirmation in cattle with biting and/or sucking lice. There were six studies (ASR 14273, ASR 14274, ASR 14362, ASR 14366, ASR 14367 and ASR 14375).

b. Investigators:

ASR 14273
Dr. J. A. Hair
Nu-Era Research Farms
Stillwater, OK 74074
USA

ASR 14362
Dr. J. E. Lloyd
University of Wyoming
Laramie, WY 82071
USA

ASR 14367 and 14375
Dr. J. E. Holste
Merck Research Laboratories
Fulton, MO 65251
USA

ASR 14274
Dr. J. L. Lancaster
3076 N. Lancaster Lane
Fayetteville, AR 72703
USA

ASR 14366
Dr. L. L. Smith
Smith Research and Development
Lodi, WI 53555
USA

c. General Design:

i. Purpose: To confirm the efficacy of eprinomectin administered topically at 500 mcg/kg against infestations of biting and sucking lice.

ii. Animals: Ninety-six cattle. Sixteen Holstein or beef crossbred calves aged 5 to 12 months and weighing 113 to 338 kg were used in each study.

iii. Housing: Individual pens. In one trial (ASR 14273) the pens were outdoors exposed to climatic conditions.

iv. Infestations: All cattle were carrying natural lice infestations confirmed by pretreatment counts in selected sites.

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: Final lice counts were made 56 days after treatment.

x. Pertinent Parameters Measured: Lice counts and identification to species in six, seven or nine preselected sites on each animal at approximately weekly intervals.

d. Results: Cattle treated with eprinomectin had fewer lice than control cattle at each posttreatment observation. The results to 28 days are summarized in Tables IV.B.7. to IV.B.12. Data collected beyond 28 days was not used in the determination of efficacy against lice.

Table IV. B.7. Arithmetic mean lice counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14273).
Lice Species Count Day -1 7 14 21 28
Linognathus vituli Control 52 51 20 9 13
Eprinomectin 500 mcg/kg 40 0 0 0 0
% Efficacy - 100 100 100 100
Solenopotes capillatus Control 679 486 492 559 664
Eprinomectin 500 mcg/kg 694 0 0 0 0
% Efficacy - 100 100 100 100
Table IV. B.8. Arithmetic mean lice counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14274).
Lice Species Count Day 0 7 14 21 28
Linognathus vituli Control 51 37 34 27 25
Eprinomectin
500 mcg/kg
68 0 0 0 0
% Efficacy - 100 100 100 100
Damalinia bovis Control 14 16 9 15 12
Eprinomectin
500 mcg/kg
24 0 0 0 0
% Efficacy - 100 100 100 100
Table IV. B.9. Arithmetic mean lice counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14362).
Lice Species Count Day -1 7 14 21 28
Linognathus vituli Control 49 73 74 68 66
Eprinomectin
500 mcg/kg
26 1 1 0 0
% Efficacy - 98.5 98.8 100 100
Damalinia bovis Control 34 32 28 49 72
Eprinomectin
500 mcg/kg
32 2 3 0 0
% Efficacy - 92.9 91.1 100 100
Haematopinus eurysternus Control 54 47 51 46 54
Eprinomectin
500 mcg/kg
33 2 1 0 0
% Efficacy - 96.3 97.3 100 100
Table IV. B.10. Arithmetic mean lice counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14366).
Lice Species Count Day -1 7 14 21 28
Linognathus vituli Control 46 45 49 34 18
Eprinomectin
500 mcg/kg
28 0 0 0 0
% Efficacy - 100 100 100 100
Damalinia bovis Control 70 84 55 77 38
Eprinomectin
500 mcg/kg
170 0 0 0 0
% Efficacy - 100 100 100 100
Haematopinus eurysternus Control 227 301 343 385 505
Eprinomectin
500 mcg/kg
324 0 0 0 0
% Efficacy - 100 100 100 100
Table IV. B.11. Arithmetic mean lice counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14367).
Lice Species Count Day 0 7 14 21 28
Damalinia bovis Control 248 127 130 148 272
Eprinomectin
500 mcg/kg
183 0 0 0 0
% Efficacy - 100 100 100 100
Table IV. B.12. Arithmetic mean lice counts on cattle treated with eprinomectin administered topically at 500 mcg/kg (ASR 14375).
Lice Species Count Day 0 7 14 21 28
Linognathus vituli Control 136 155 116 81 30
Eprinomectin
500 mcg/kg
123 0 0 0 0
% Efficacy - 100 100 100 100
Solenopotes capillatus Control 365 631 360 194 147
Eprinomectin
500 mcg/kg
539 0 0 0 0
% Efficacy - 100 100 100 100

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

continued

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