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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 141-095 Dectomax® Pour-On solution - original approval

Approval Date: September 16, 1997

I. GENERAL INFORMATION:

NADA141-095
Sponsor:Pfizer, Inc.
235 East 42nd Street
New York, New York 10017
Generic Name:doramectin 0.5% pour-on solution
Trade Name:Dectomax® Pour-On solution
Marketing Status:Over the Counter (OTC)

 

II. INDICATIONS FOR USE:

Gastrointestinal roundworms

  • Ostertagia ostertagi (adults and L4, including inhibited larvae)
  • Ostertagia lyrata (adults)
  • Haemonchus placei (adults and L4)
  • Trichostrongylus axei (adults)
  • Trichostrongylus colubriformis (adults and L4)
  • Cooperia oncophora (adults1 and L4)
  • Cooperia pectinata (adults)
  • Cooperia punctata (adults and L4)
  • Cooperia surnabada (adults)
  • Bunostomum phlebotomum (adults)
  • Oesophagostomum radiatum (adults and L4)
  • Trichuris spp. (adults) 1Efficacy below 90% was observed against adult Cooperia oncophora in some clinical studies

Lungworms

  • Dictyocaulus viviparus (adults and L4)

Eyeworms

  • Thelazia gulosa (adults)
  • Thelazia skrjabini (adults)

Grubs

  • Hypoderma bovis
  • Hypoderma lineatum

Lice

  • Biting Lice
    • Damalinia bovis
  • Sucking Lice
    • Haematopinus eurysternus
    • Linognathus vituli
    • Solenopotes capillatus

Mange Mites

  • Chorioptes bovis
  • Sarcoptes scabiei

DECTOMAX® pour-on solution has been proved to effectively control infections and to protect cattle from re-infection with Cooperia oncophora and Dictyocaulus viviparus for 21 days, and Ostertagia ostertagi, Cooperia punctata and Oesophagostomum radiatum for 28 days after treatment.
 

 

III. DOSAGE

A.DOSAGE FORMDECTOMAX® Pour-On Solution contains 5 mg doramectin/mL
B.
C.
ROUTE OF ADMINISTRATION
RECOMMENDED DOSAGES:
A single topical dose of 500 mcg/kg BW. Each mL contains 5 mg of doramectin, sufficient to treat 22 lb (10 kg) of body weight.

 

IV. TARGET SPECIES EFFICACY:

A. Preclinical Investigation:

Results from preclinical evaluation of doramectin pour-on in experimental formulations indicated that a dose of 500 mcg/kg bodyweight was required for efficacy against the provisionally identified dose-limiting species, Cooperia oncophora and Trichostrongylus colubriformis. This dose was selected for clinical evaluation in a prototype commercial formulation and a program of clinical studies was initiated to evaluate efficacy against a broader range of nematode and arthropod species. Based on this information, C. oncophora and T. colubriformis were confirmed as the key dose-limiting species for dose determination studies.

B. Dose Determination:

Summary

Three dose determination studies were conducted against C. oncophora and T. colubriformis (other nematodes were present in each study), each using three dosages of doramectin pour-on (i.e., 250, 500, and 750 ug/kg of bodyweight). In addition, a study was carried out against the potentially dose limiting arthropod, Damalinia bovis, using the same dosages.

STUDY DESIGN - NEMATODES

One natural and two artificial-infection studies were conducted to good clinical practice standards. Forty (40) to forty-eight (48) cattle were used per study. In the artificial-infection studies, calves were inoculated per os on day 0 with L3 C. oncophora plus L3 T. colubriformis or a mixed L3 nematode inoculum, including L3 of C. oncophora and T. colubriformis. Study animals were treated with either saline or doramectin pour-on at a dosage of 250, 500, or 750 mcg/kg. All treatments were applied topically in a single passage along the midline of the back from the withers to the tailhead.

STUDY DESIGN - DAMALINIA BOVIS

One artificial infection study was conducted to good clinical practice standards. Forty (40) calves previously infested with lice were treated on day 0 with either saline or doramectin pour-on solution. All treatments were applied topically in a single passage along the midline of the back from the withers to the tailhead. Lice counts were performed weekly for five weeks after treatment.

DATA ANALYSIS

Nematode percentage efficacies were calculated at each dose level using the following formula:

[(Arithmetic mean number of nematodes in non-medicated cattle) - (Arithmetic mean number of nematodes in doramectin-treated cattle)] ÷ [Arithmetic mean number of nematodes in non-medicated cattle] X 100 = Percentage Efficacy

Lice (D. bovis) percentage efficacies were calculated at each dosage level by determining the percentage reductions in lice counts on study Day 35 for the treated groups compared with the non-medicated group, using the following formula:

[(Arithmetic mean number of lice in non-medicated cattle) - (Arithmetic mean number of lice in doramectin-treated cattle)] ÷ [Arithmetic mean number of lice in non-medicated cattle] X 100 = Percentage efficacy

RESULTS:

Results are presented on an individual study basis in the section following (see Tables 1 to 4). Only the parasite species and life stage for which there was an adequate number of infected controls (minimum of six) are included in these tables.

OVERALL CONCLUSIONS:

A dosage of 250 mg/kg was not sufficiently effective in some instances for the dose-limiting species. In contrast, doramectin at 500 mg/kg was effective against the dose-limiting species, as well as all other claimed species present in these studies, including the louse D. bovis. These data indicate that 500 mcg/kg of doramectin administered as a pour-on solution is an appropriate dosage for the treatment and control of cattle arthropod and nematode parasites.

INDIVIDUAL DOSE DETERMINATION STUDIES

1. Dose determination study #1231C-60-94-019, Dr. L.R. Ballweber, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi

Forty (40) artificially infected calves were randomly allocated to four groups each of 10 animals (a negative control and three doramectin groups). Animals were treated topically with either doramectin pour-on or saline and slaughtered 14 to 16 days later for determination of worm burdens. The results are summarized in Table 1.

Table 1 Therapeutic Efficacy of Doramectin Against Adult Nematodes - Percentage Reduction Relative to Controls
Treatment/Dosage
(mcg/kg)
Arithmetic MeanPercentage Efficacy

Cooperia oncophora - Adults

 
 
 

Non-medicated442.5---
Doramectin (250)302.536
Doramectin (500)75.583
Doramectin (750)20.096
Trichostrongylus colubriformis - Adults
 
 
 
Non-medicated400.0---
Doramectin (250)70.067
Doramectin (500)0.0100
Doramectin (750)0.0100

2. Dose determination study #1232C-60-94-153, Dr. T.A. Yazwinski, Farm of Homer Featherston, Fayetteville, Arkansas

Forty-eight (48) naturally infected calves were randomly allocated to four groups each of 12 animals (a negative control and three doramectin groups). Animals were treated topically with either doramectin pour-on or saline and slaughtered 14 to 17 days later for determination of worm burdens. The results are summarized in Table 2.

Table 2 Therapeutic Efficacy of Doramectin Against Nematodes - Percentage Reduction Relative to Controls
Treatment/Dosage (mcg/kg)Arithmetic MeanPercentage Efficacy
Cooperia oncophora - Adults 
 
 
 
Non-medicated926.6---
Doramectin (250)73.392
Doramectin (500)0.0100
Doramectin (750)42.795
Haemonchus placei - Adults
 
 
 
Non-medicated437.5---
Doramectin (250)0.0100
Doramectin (500)0.0100
Doramectin (750)0.0100
Ostertagia ostertagi - Adults
 
 
 
Non-medicated1262.5---
Doramectin (250)0.0100
Doramectin (500)0.0100
Doramectin (750)0.0100
Trichostrongylus axei - Adults
 
 
 
Non-medicated683.3---
Doramectin (250)0.0100
Doramectin (500)0.0100
Doramectin (750)0.0100
Cooperia punctata - Adults
 
 
 
Non-medicated806.2---
Doramectin (250)10.899
Doramectin (500)0.0100
Doramectin (750)3.2>99
Cooperia surnabada - Adults
 
 
 
Non-medicated155.0---
Doramectin (250)17.589
Doramectin (500)0.8>99
Doramectin (750)0.0100

3. Dose determination study #5032C-03-94-076, Dr. R.N. Titchener, West of Scotland School of Agriculture, Brickrow Farm, Auchincruive, Ayr, Scotland

Forty (40) artificially infected calves were randomly allocated to four groups each of 10 animals (a negative control and three doramectin groups). Animals were treated topically with doramectin pour-on or did not receive any treatment. Lice counts were conducted at 7, 14, 21 and 35 days after treatment. The results are summarized in Table 3.

Table 3 Therapeutic Efficacy of Doramectin Against Damalinia bovis - Arithmetic means for each group and Percentage Reduction Relative to Controls
Tx
Group
Day -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
control
420288248261171337136
T2
250 µg/kg
4932720 (100%)1 (99.6%)2 (98.8%)4 (98.8%)2 (98.5%)
T3
500 µg/kg
4362710 (100%)0 (100%)0 (100%)0 (100%)0 (100%)
T4
750 µg/kg
4732280 (100%)0 (100%)0 (100%)0 (100%)0 (100%)

4. Dose determination study #5232C-03-93-089, Dr. D.J. Burden, Park Farm, St. Briavels, Coleford, Gloucester, England

Forty-two (42) artificially infected calves were randomly allocated to either a non-medicated group (12 animals) or one of three treated groups (10 animals each). Animals were treated topically with either doramectin pour-on or did not receive any treatment. All animals were slaughtered 14 or 15 days later for determination of worm burdens. The results are summarized in Table 4.

Table 4 Therapeutic Efficacy of Doramectin Against Nematodes - Percentage Reduction Relative to Controls
Treatment/Dosage
(mcg/kg)
Arithmetic MeansPercentage Efficacy
Cooperia oncophora - Adults 
 
 
 
Non-medicated12,656---
Doramectin (250)6,97245
Doramectin (500)1,16591
Doramectin (750)22498
Trichostrongylus colubriformis Adults
 
 
 
Non-medicated1,348---
Doramectin (250)132076
Doramectin (500)5>99
Doramectin (750)0100
Dictyocaulus viviparus - Adults
 
 
 
Non-medicated334---
Doramectin (250)0100
Doramectin (500)0100
Doramectin (750)0100
Ostertagia ostertagi - Adults
 
 
 
Non-medicated1,808---
Doramectin (250)4>99
Doramectin (500)0100
Doramectin (750)0100
Trichostrongylus axei - Adults
 
 
 
Non-medicated616---
Doramectin (250)0100
Doramectin (500)0100
Doramectin (750)0100

C. Efficacy Confirmation - Nematodes

SUMMARY

A series of controlled efficacy studies, involving cattle with both naturally- and artificially-acquired infections, were conducted. These studies evaluated the efficacy of doramectin pour-on at 500 mcg/kg bodyweight against eyeworms, adult/immature lungworms, and adult/immature gastrointestinal nematodes. Studies were conducted to common protocols in various geographic locations throughout North America in order to obtain broad strain representation of each nematode species.

STUDY DESIGNS

Studies were designed to estimate efficacy against parasites in the adult stage as well as against normally developing and inhibited fourth-stage larvae. Experimental approaches and techniques were standardized sufficiently to allow data from individual studies to be pooled to produce an efficacy estimate for each parasite species/stage tested. Efficacy against adult nematodes was assessed using both naturally- and artificially-acquired infections. Efficacy against fourth-stage larvae was assessed using only artificially-induced infections so that the age of the nematode species under test was known at the time of treatment. Efficacy against inhibited larvae of Ostertagia ostertagi was assessed in naturally-infected cattle.

DATA ANALYSIS

In each study, worm burdens of each species/stage were determined for each animal. Arithmetic mean worm burdens were calculated from the worm counts and used to estimate efficacy as follows:

[(Arithmetic mean number of nematodes in non-medicated cattle) - (Arithmetic mean number of nematodes in doramectin-treated cattle)] ÷ [Arithmetic mean number of nematodes in non-medicated cattle] X 100 = Percentage Efficacy

RESULTS

Results are presented on an individual study basis in the section following (see Tables 5 to 24). All studies had or exceeded the minimum required six adequately infected controls for each species and life stage represented.

OVERALL CONCLUSIONS

A single topical application of doramectin pour-on at a dosage of 500 mcg/kg was highly efficacious against adult nematodes of the following species: O. ostertagi, O. lyrata, H. placei, T. axei, T. colubriformis, C. oncophora, C. pectinata, C. punctata, C. surnabada, B. phlebotomum, O. radiatum, Trichuris spp., D. viviparus, T. gulosa and T. skrjabini; against L4 of O. ostertagi, H. placei, T. colubriformis, C. oncophora, C. punctata, O. radiatum; and D. viviparus; and against inhibited L4 of O. ostertagi. No significant adverse reaction to treatment was observed in any study.

INDIVIDUAL NEMATODE DOSE CONFIRMATION STUDIES

1. Dose confirmation study #1231C-60-93-016, Dr. T.A. Yazwinski, Farm of Homer Featherston, Fayetteville, Arkansas

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 5.

Table 5 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Bunostomum phlebotomum (Adults)332.80.1>99

2. Dose confirmation study #1231C-60-93-017, Dr. L.R. Ballweber, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 6.

Table 6 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Haemonchus placei (L4 stage)7500100
Trichostrongylus colubriformis (L4 stage)4400100
Oesophagostomum radiatum (L4 stage)4510100

3. Dose confirmation study #1231C-60-94-152, Dr. T.A. Yazwinski, Farm of Homer Featherston, Fayetteville, Arkansas

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 7.

Table 7 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)6,0140100
Ostertagia lyrata (Adults)2120100
Cooperia oncophora (Adults)3,84413697
Cooperia punctata (Adults)8542>99
Cooperia surnabada (Adults)3203091
Bunostomum phlebotomum (Adults)2920100
Trichuris spp. (Adults)63198

4. Dose confirmation study #1231C-02-94-168, Dr. A. Villeneuve, University of Montreal, St. Hyacinthe, Quebec, Canada

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 8.

Table 8 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (L4 Stage)677.21.794
Cooperia oncophora (L4 Stage)265.08.597

5. Dose confirmation study #1231C-60-95-175, Dr. L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 9.

Table 9 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Trichostrongylus colubriformis (L4 Stage)5,8000100
Cooperia punctata (L4 Stage)3250100
Oesophagostomum radiatum (L4 Stage)570100
Dictyocaulus viviparus (L4 Stage)940100

6. Dose confirmation study #1231C-60-95-176, Dr. T.A. Yazwinski, Farm of Homer Featherston, Fayetteville, Arkansas

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 10.

Table 10 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (L4 Stage)4,8782>99
Haemonchus placei (L4 Stage)7920100
Trichostrongylus colubriformis (L4 Stage)3700100
Cooperia punctata (L4 Stage)6880100
Oesophagostomum radiatum (L4 Stage)1,9150100

7. Dose confirmation study #1231C-60-95-193, Dr. T.A. Yazwinski, Farm of Homer Featherston, Fayetteville, Arkansas

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 11.

Table 11 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (L4 Stage)7740100
Haemonchus placei (L4 Stage)4220100
Cooperia oncophora (L4 Stage)383896
Cooperia punctata (L4 Stage)2240100
Oesophagostomum radiatum (L4 Stage)19150100

8. Dose confirmation study #1231C-60-95-220, Dr. R. Corwin, Middlebush Veterinary Research Farm, Columbia, Missouri

Twenty (20) artificially infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 12.

Table 12 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (L4 Stage)5,7705>99
Dictyocaulus viviparus (L4 Stage)800100

9. Dose confirmation study #1232C-60-93-015, Dr. H. Ciordia, Southern Piedmont Experiment Station, Watkinsville, Georgia

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 13.

Table 13 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)17,3100100
Ostertagia ostertagi (Inhibited L4 larvae)23,05517599
Haemonchus placei (Adults)4,2110100
Trichostrongylus axei (Adults)5,2900100
Cooperia oncophora (Adults)2700100
Cooperia pectinata (Adults)2250100
Cooperia punctata (Adults)1,1300100

10. Dose confirmation study #1232C-60-93-016, Dr. L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 14.

Table 14 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)2,89410>99
Cooperia punctata (Adults)2,73327090

11. Dose confirmation study #1232C-02-93-017, Dr. M.J. Kennedy, Alberta Agricultural Animal Health Division, Edmonton, Alberta, Canada

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 15.

Table 15 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Thelazia gulosa (Adults)5.10100
Thelazia skrjabini (Adults)5.70.296

12. Dose confirmation study #1232C-02-94-018, Dr. M.J. Kennedy, Ronald Johnson Farm, Wetaskiwin, Alberta, Canada

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 16.

Table 16 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Thelazia gulosa (Adults)3.20100
Thelazia skrjabini (Adults)1.30100

13. Dose confirmation study #1232C-02-94-019, Dr. M.J. Kennedy, Ronald Johnson Farm, Wetaskiwin, Alberta, Canada

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 17.

Table 17 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Thelazia gulosa (Adults)1.00100
Thelazia skrjabini (Adults)7.80100

14. Dose confirmation study #1232C-60-94-150, Dr. E.G. Johnson, Johnson Research, Parma, Idaho

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 18.

Table 18 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)3,2605898
Ostertagia ostertagi (Inhibited L4 Stages)1,94413293
Cooperia surnabada (Adults)3353291

15. Dose confirmation study #1232C-60-94-154, Dr. L. Smith, Research and Development Inc., Readstown, Wisconsin

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 19.

Table 19 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)2,55010>99
Cooperia punctata (Adults)5905691
Dictyocaulus viviparus (Adults)260100

16. Dose confirmation study #1232C-60-94-155, Dr. J.A. Stuedemann, USDA/ARS, Southern Piedmont Conservation Research Center, Watkinsville, Georgia

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 20.

 

Table 20 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)2,5452899
Ostertagia ostertagi (Inhibited L4 larvae)1,2300100
Haemonchus placei (Adults)1,5100100
Trichostrongylus axei (Adults)8164>99
Cooperia pectinata (Adults)2,6709097
Cooperia punctata (Adults)4,07233492

17. Dose confirmation study #1232C-60-94-163, Dr. T.A. Yazwinski, Farm of Homer Featherston, Fayetteville, Arkansas

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 21.

Table 21 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)2,9686>99
Cooperia oncophora (Adults)1,9782499
Cooperia punctata (Adults)1,4761499
Oesophagostomum radiatum (Adults)2980100
Trichuris spp. (Adults)381>99

18. Dose confirmation study #1232C-60-94-167, Dr. J.E. Miller, School of Veterinary Medicine, Louisiana State University Agriculture & Mechanical College, Baton Rouge, Louisiana

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 22.

Table 22 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)1,3670100
Ostertagia lyrata (Adults)540100
Haemonchus placei (Adults)262299
Trichostrongylus colubriformis (Adults)3120100
Cooperia punctata (Adults)2,5980100
Oesophagostomum radiatum (Adults)3670100
Trichuris spp. (Adults)150100
Dictyocaulus viviparus (Adults)1020100

19. Dose confirmation study #1232C-60-95-183, Dr. J.A. Stuedemann, USDA/ARS Southern Piedmont Conservation Research Center, Watkinsville, Georgia

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 23.

Table 23 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Ostertagia ostertagi (Adults)5,0580100
Ostertagia ostertagi (Inhibited L4 Larvae)1,4080100
Haemonchus placei (Adults)1,3780100
Trichostrongylus axei (Adults)3,0480100
Trichostrongylus colubriformis (Adults)1220100
Cooperia oncophora (Adults)1,5710100
Cooperia pectinata (Adults)1,4540100
Cooperia punctata (Adults)2,9000100

20. Dose confirmation study #1232C-60-95-192, Dr. J.A. Stuedemann, USDA/ARS Southern Piedmont Conservation Research Center, Watkinsville, Georgia

Twenty (20) naturally infected calves were assigned to two equal groups (negative control and doramectin). At necropsy, worm counts in the two groups were compared to determine doramectin efficacy. The results are summarized in Table 24.

Table 24 Arithmetic means and Therapeutic Efficacy of Doramectin at 500 mcg/kg Against Cattle Nematodes
ParasiteControlDoramectin% Efficacy
Trichostrongylus colubriformis (Adults)2360.5>99
Cooperia oncophora (Adults)1,13513>99
Cooperia pectinata (Adults)3830100
Cooperia punctata (Adults)1,5190100
Bunostomum phlebotomum (Adults)137199

 

SUMMARY OF COOPERIA ONCOPHORA PIVOTAL DOSE CONFIRMATION STUDIES
Study NumberStudy LocationC. oncophora stage% Efficacy
1231C-60-94-152ArkansasAdult97
1232C-60-93-015GeorgiaAdult100
1232C-60-93-016WisconsinAdult70
1232C-60-94-150IdahoAdult86
1232C-60-94-154WisconsinAdult75
1232C-60-94-155GeorgiaAdult82
1232C-60-94-163ArkansasAdult99
1232C-60-95-183GeorgiaAdult100
1232C-60-95-192GeorgiaAdult99
1231C-02-94-168Quebec, CanadaL4s97
1231C-60-95-176ArkansasL4s>99
1231C-60-95-193ArkansasL4s96

D. Efficacy Confirmation - Grubs:

SUMMARY

A series of studies involving cattle with naturally-acquired infections of Hypoderma lineatum and/or Hypoderma bovis were conducted to evaluate the efficacy of doramectin pour-on, administered topically at a dosage of 500 mcg/kg bodyweight, against 1st-instar larvae. Studies were carried out under field conditions to common protocols at various locations in North America.

STUDY DESIGNS

In each study, 30 to 60 cattle were selected from herds considered likely to harbor natural infections of Hypoderma spp. The studies were conducted when the Hypoderma spp. larvae were expected to be in the 1st-instar stage. On day -1 or day 0 (treatment day), animals were randomly allocated in a tiered manner based on bodyweight to a saline-treated (non-medicated in study 1032C-60-93-037) or a doramectin-treated group. All treatments were applied topically in a single passage along the midline of the back from the withers to the tailhead. Subsequently, during the period of Hypoderma spp. emergence, the numbers of warbles appearing on the backs of animals were determined at approximately 14-day intervals and larvae were expressed from as many fully developed warbles as possible. Expressed larvae were identified where possible, to stage and species.

DATA ANALYSIS

In each study, warbles were counted for each animal. Percentage efficacy was determined by the percentage of doramectin-treated animals with no warbles on any observation day.

RESULTS

Results are presented on an individual study basis in the section following (see tables 25 to 29).

OVERALL CONCLUSIONS

A single application of doramectin pour-on, administered to cattle at a dosage of 500 mcg/kg, was highly effective in the treatment of 1st-instars of H. bovis and H. lineatum. No adverse reaction directly attributable to doramectin administration or to larval Hypoderma spp. death or disintegration as a result of doramectin treatment was seen in any animal.

INDIVIDUAL GRUB DOSE CONFIRMATION STUDIES

1. Dose confirmation study #1032C-60-93-037, Dr. J.E. Lloyd, Beef Livestock Research Facility, University of Wyoming, Laramie, Wyoming

Sixty (60) calves with natural Hypoderma spp. infections were divided into two equal groups (doramectin or control). Animals were examined at regular intervals after treatment from Day 40 to Day 180 and warbles were enumerated to determine efficacy. The mean number of warbles in the control group varied from 1.1 on Day 40 to a peak of 18.5 on Day 110. The doramectin-treated animals had no warbles from Day 40 to Day 180. The results are summarized in Table 25.

Table 25 Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Hypoderma spp.
Parasite% Efficacy
Hypoderma bovis100
Hypoderma lineatum100

2. Dose confirmation study #1032C-02-94-039, Dr. D. Colwell, Bovatech Veterinary Services, Shaughnessy, Alberta, Canada

Thirty (30) calves with natural Hypoderma spp. infections were divided into two equal groups (doramectin or control). Animals were examined at regular intervals after treatment from Day 37 to Day 107 and warbles were enumerated to determine efficacy. The mean number of warbles in the control group varied from 1.0 on Day 37 to a peak of 13.6 on Day 79. The doramectin-treated animals had no warbles from Day 37 to Day 107. The results are summarized in Table 26.

Table 26 Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Hypoderma spp.
Parasite% Efficacy
Hypoderma lineatum100

3. Dose confirmation study #1032C-60-94-041, Dr. C. Jones, Dixon Springs Agricultural Center, Dixon Springs, Illinois

Forty (40) calves with natural Hypoderma spp. infections were divided into two equal groups (doramectin or control). Animals were examined at regular intervals after treatment from Day 41 to Day 181 and warbles were enumerated to determine efficacy. The mean number of warbles in the control group varied from 2.9 on Day 41 to a peak of 19.5 on Day 83. The doramectin-treated animals had no warbles from Day 41 to Day 181. The results are summarized in Table 27.

Table 27 Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Hypoderma spp.
Parasite% Efficacy
Hypoderma bovis100
Hypoderma lineatum100

4. Dose confirmation study #1032C-60-94-162, Dr. L.L. Smith, Research and Development, Inc., Readstown, Wisconsin

Forty (40) calves with natural Hypoderma spp. infections were divided into two equal groups (doramectin or control). Animals were examined at regular intervals after treatment from Day 72 to Day 156 and warbles were enumerated to determine efficacy. The mean number of warbles in the control group varied from 1.7 on Day 72 to a peak of 6.3 on Day 100. The doramectin-treated animals had no warbles from Day 72 to Day 156. The results are summarized in Table 28.

Table 28 Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Hypoderma spp.
Parasite% Efficacy
Hypoderma bovis100
Hypoderma lineatum100

E. Efficacy Confirmation - Lice:

SUMMARY

A series of studies were conducted under field conditions to evaluate the efficacy of doramectin pour-on administered topically at a dosage of 500 mcg/kg bodyweight to cattle harboring naturally-acquired infestations of one or more species of lice. All studies were conducted following a common protocol at various locations throughout North America in order to obtain broad strain representation for each of the economically important species over a range of climatic conditions and husbandry systems.

STUDY DESIGNS

In each of the studies, 20 cattle harboring infestations of one or more species of lice were selected. The species responsible for the infestation were identified and the animals were randomly allocated in a tiered manner to either a saline-treated/non-medicated group or a doramectin-treated group. All treatments were applied topically in a single passage along the midline of the back from the withers to the tailhead.

Prior to the start of each study, body sites were designated for counts on the basis of louse species present and their distribution on the animals. On day 0, lice counts were carried out on all animals, after which cattle received either saline or doramectin pour-on topically, according to their treatment group, except in study 1033C-60-94-009 where animals in group T1 received no treatment. Further lice counts were carried out at weekly intervals thereafter for five weeks.

DATA ANALYSIS

In each study, lice were counted for each animal. Efficacy was calculated based on the percentage reduction of lice in doramectin-treated cattle compared with the control group at each time point post-treatment. Percent efficacy was calculated using the following formula:

[(Arithmetic mean number of lice in non-medicated cattle) - (Arithmetic mean number of lice in doramectin-treated cattle)] ÷ [Arithmetic mean number of lice in non-medicated cattle] X 100 = Percentage Efficacy

RESULTS

Results are presented on an individual study basis in the section following (see tables 30 to 38).

OVERALL CONCLUSIONS

A single application of doramectin pour-on, administered to cattle at a dosage of 500 mcg/kg, was effective against natural infestations of Damalinia bovis, Haematopinus eurysternus, Linognathus vituli, and Solenopotes capillatus. No adverse reactions to treatment were observed.

1. Dose confirmation study #1032C-60-94-161, Dr. J. Lancaster, 4K Farms, Tontitown, Arkansas

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 30.

Table 30 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Linognathus vituli
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1 (saline)26332621191510
T2 (dora)26460
100%
0
100%
0
100%
0
100%
0
100%

2. Dose confirmation study #1032C-60-95-170, Dr. T.N. TerHune, Health Management Services, Corcoran, California

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 31.

Table 31 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Haematopinus eurysternus
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(saline)
18191316691
T2
(dora)
17170.4
97%
0
100%
0
100%
0
100%
0
100%

3. Dose confirmation study #1032C-60-95-173, Dr. J.J. Arends, Bagwell Farm, Garner, North Carolina

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 32.

Table 32 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Linognathus vituli
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(saline)
73493830333835
T2
(dora)
64410
100%
0
100%
0
100%
0
100%
0
100%

4. Dose confirmation study #1032C-60-95-174, Dr. J.J. Arends, Tony Coats Farm, Clayton, North Carolina

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Tables 33 and 34.

Tables 33 & 34 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Lice
 GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
Damalinia bovis T1
(saline)
256369877176159
T2 (dora)25980
100%
0
100%
0
100%
0
100%
0
100%
Haematopinus eurysternusT1
(saline)
16363946454061
T2 (dora)16270
100%
0
100%
0
100%
0
100%
0
100%

5. Dose confirmation study #1032C-60-95-177, Dr. D.G. Meyer, Lucerne Enterprise Research Feedlot, Colon, Nebraska

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Tables 35 and 36.

Tables 35 & 36 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Lice
 GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
Damalinia bovis T1
(saline)
212460488253133
T2 (dora)1280
100%
0
100%
0
100%
0
100%
0
100%
Solenoptes capillatusT1
(saline)
17347463475778
T2 (dora)16310
100%
0
100%
0
100%
0
100%
0
100%

6. Dose confirmation study #1032C-60-95-221, Dr. L.L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Tables 37 and 38.

Tables 37 and 38 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Lice
 GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
Damalinia bovis T1
(saline)
4766939309261003511232
T2 (dora)3305713
>99%
.4
>99%
.1
>99%
0
100%
0
100%
Solenoptes capillatusT1
(saline)
1112925694681594583570
T2 (dora)10078410
100%
0
100%
0
100%
0
100%
0
100%

7. Dose confirmation study #1033C-60-94-009, Dr. J.E. Lloyd, University of Wyoming, Laramie, Wyoming

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 39.

Table 39 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Damalinia bovis
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(nonmedicated)
1081531931791518957
T2 (dora)1061290
100%
0
100%
0
100%
0
100%
0
100%

8. Dose confirmation study #1033C-60-94-157, Dr. L.L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 40.

Table 40 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Linognathus vituli
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(nonmedicated)
540564568439294204103
T2 (dora)5165760
100%
0
100%
0
100%
0
100%
0
100%

9. Dose confirmation study #1033C-60-94-158, Dr. L.L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) cattle with natural lice infestations were divided into two equal groups (doramectin or control). Lice counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 41.

Table 41 Mean Lice Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Haematopinus eurysternus
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(saline)
446535462348228285222
T2 (dora)2373990
100%
0
100%
0
100%
0
100%
0
100%

F. Efficacy Confirmation - Mange Mites:

SUMMARY

A series of studies was conducted to evaluate the efficacy of doramectin pour-on, administered at a dosage of 500 mcg/kg, in cattle harboring natural or artificial infestations of mange mites under field conditions. The studies were conducted to a common protocol for each mite species at sites in North America and Europe, representative of a range of climatic conditions and husbandry systems.

STUDY DESIGN - CHORIOPTES BOVIS

Artificial-infestation and natural-infestation studies were conducted in North America and Europe to good clinical practice standards. In each study, a minimum of 20 cattle with confirmed, active mite infestations were randomly assigned to a saline-treated/non-medicated group or a doramectin-treated group (each of 10 or 11 animals) in a tiered manner. On day 0, mite counts were carried out on skin scrapings from all animals, after which the animals in each study received doramectin pour-on or saline or no treatment, according to their treatment group. Doramectin and saline treatments were applied topically in a single passage along the midline of the back between the withers and the tailhead. In all studies, mite counts were also made from skin scrapings obtained from each animal on Days 7, 14/15, 21, 28 and 35.

STUDY DESIGN - SARCOPTES SCABIEI

Natural infestation studies were conducted in Europe to good clinical practice standards. In these studies, a minimum of 14 cattle with confirmed, active mite infestations were randomly assigned to either a doramectin-treated group (11 or 6 animals) or a non-medicated group (12 or 8 animals). On day 0, mite counts were carried out on all non-medicated animals, after which the animals in the treated group in each study received doramectin pour-on (500 mcg/kg) topically in a single passage along the midline of the back between the withers and the tailhead. Animals in the non-medicated groups received no treatment. In both studies, mite counts also were made from skin scrapings taken from each animal on days 7, 14, 21, 28, and 35.

DATA ANALYSIS

In each study, mites were counted for each animal. . Efficacy was calculated based on the percentage reduction in live mites counts of doramectin-treated cattle compared with the control group at each time point post-treatment. Percent efficacy was calculated using the following formula:

[(Arithmetic mean number of mites in non-medicated cattle) - (Arithmetic mean number of mites in doramectin-treated cattle)] ÷ [Arithmetic mean number of mites in non-medicated cattle] X 100 = Percentage Efficacy

RESULTS

Results are presented on an individual study basis in the section following (see Tables 42 to 45).

OVERALL CONCLUSIONS

A single topical application of doramectin pour-on, administered to cattle at a dosage of 500 mcg/kg of body weight, was effective against infestations of Chorioptes bovis or Sarcoptes scabiei. No adverse reactions to treatment were observed.

1. Dose confirmation study #1031C-60-93-009, Dr. L.L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) cattle with artificial mite infestations were divided into two equal groups (doramectin or control). Live mite counts were conducted on Days -8, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 42.

Table 42 Mean Live Mite Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Chorioptes bovis
GroupDay -8Day 0Day 7Day 14Day 21Day 28Day 35
T1
(nonmed)
164399376468576594908
T2 (dora)15416745
88%
29
94%
1
>99%
1
>99%
0.2
>99%

2. Dose confirmation study #1033C-60-94-159, Dr. L.L. Smith, Research and Development, Inc., Readstown, Wisconsin

Twenty (20) cattle with natural mite infestations were divided into two equal groups (doramectin or control). Live mite counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 43.

Table 43 Mean Lice Mite Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Chorioptes bovis
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(nonmed)
159187150157161217162
T2 (dora)1501031
>99%
0
100%
0
100%
0
100%
0
100%

3. Dose confirmation study #5032C-81-94-086, Dr. G. Gaina, S.C. Agrozootechnica S.A., Baracia, Romania

Twenty-three (23) cattle with natural mite infestations were allocated to a non-medicated group (12 animals) or a doramectin-treated group (11 animals). Live mite counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 44.

Table 44 Mean Live Mite Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Sarcoptes scabiei
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(nonmed)
9162624253129
T2 (dora)10161
98%
0
100%
0
100%
0
100%
0
100%

4. Dose confirmation study #5032C-10-94-089, Dr. G. Gräfner, Herr Sommer, Ruting, Germany

Fourteen (14) cattle with natural mite infestations were allocated to a non-medicated group (8 animals) or a doramectin-treated group (6 animals). Live mite counts were conducted on Days -7, 0, 7, 14, 21, 28, and 35. The results are summarized in Table 45.

Table 45 Mean Live Mite Counts and Therapeutic Efficacy of Doramectin at 500 mcg/kg BW Against Sarcoptes scabiei
GroupDay -7Day 0Day 7Day 14Day 21Day 28Day 35
T1
(nonmed)
1401319041261518
T2 (dora)1461451
99%
0
100%
0
100%
0
100%
0
100%

G. Field Efficacy Against Nematodes:

SUMMARY

A series of studies were conducted under field conditions to confirm the effectiveness of doramectin pour-on, administered topically at 500 ug/kg, against naturally-acquired gastrointestinal nematode infections of cattle. Studies were conducted to a common protocol at different locations throughout North America, representative of a range of climatic conditions and management systems. The geographic locations of the studies are presented in Table 43.

EXPERIMENTAL METHOD

Animals were selected from grazing or feedlot herds in which gastrointestinal parasitism had been confirmed by the presence of nematode eggs in the feces. In each study, between 40 and 100 cattle were selected and randomly allocated to a saline- or doramectin-treated group and were treated topically with either doramectin pour-on or saline on day 0. All treatments were applied topically in a single passage along the midline of the back from the withers to the tailhead. Fecal egg counts were carried out using standard methods on samples collected from each animal at the time of treatment and at weekly intervals thereafter for three weeks.

Each animal was observed for abnormal clinical signs at regular intervals throughout the study. Weather conditions were recorded around the time of treatment and daily thereafter for six (one study) or seven days.
DATA ANALYSIS

In each study, fecal egg counts were made for each animal. Arithmetic mean fecal egg counts were calculated and used to estimate efficacy as follows:

[(Arithmetic mean number of eggs in non-medicated cattle) - (Arithmetic mean number of eggs in doramectin-treated cattle)] ÷ [Arithmetic mean number of eggs in non-medicated cattle] X 100 = Percentage Efficacy.

RESULTS

A summary of the results are presented in Table 46.

OVERALL CONCLUSIONS

A single topical application of doramectin, administered to cattle at a dosage of 500 mcg/kg, was effective in treatment of mixed infections of gastrointestinal nematodes, including Haemonchus spp., Ostertagia spp., Trichostrongylus spp., Bunostomum spp., Cooperia spp., and Oesophagostomum spp. No adverse reactions to treatment were observed.

Table 46 Summary of Nematode Field Efficacy Studies
Study NumberLocationNo. Doramectin
Treated Animals
% Reduction in EPG 21
Days Post Treatment
1233C-60-94-156Watkinsville, Georgia7593
1233C-60-94-166Baton Rouge, Louisiana3699
1233C-60-95-181Amarillo, Texas3099
1233C-60-95-184Clayton, North Carolina3696
1233C-60-95-186Corcoran, California39100
1233C-60-95-187Colon, Nebraska6096
1233C-60-95-188Parma, Idaho6099

H. Duration of Activity - Nematodes:

SUMMARY

Two studies were conducted to evaluate the persistent efficacy of doramectin, administered at a dosage of 500 mcg/kg (1 mL/10 kg), against artificial infections of nematodes. Each study used larval nematode cultures isolated during 1994 or 1995.

STUDY DESIGN

In each study, calves were selected for use based on the absence of trichostrongyle-type eggs in fecal samples. The animals were randomly assigned to a saline-treated group, to one of three doramectin-treated groups, or as larval viability monitors.

On day 0, each calf in Groups T1 and T2 was treated topically with either saline or doramectin, respectively. Groups T3 and T4 were treated with doramectin in an identical manner on days 7 and 14, respectively. All treatments were applied in a single passage along the midline of the back, from the withers to the tailhead. All animals were observed after each treatment for a sufficient time to permit a reliable assessment of any abnormal clinical condition. Animals were challenged daily on days 14 to 35 by oral gavage with infective nematode larvae. The persistence interval was defined as the period from day of treatment to last day of challenge with infective larvae.

DATA ANALYSIS

In each study, nematodes were counted for each animal. Arithmetic mean nematode counts were calculated and used to estimate efficacy as follows:

[(Arithmetic mean number of nematodes in non-medicated cattle) - (Arithmetic mean number of nematodes in doramectin-treated cattle)] ÷ [Arithmetic mean number of nematodes in non-medicated cattle] X 100 = Percentage Efficacy

RESULTS

The results are presented in Tables 47 to 48.

OVERALL CONCLUSIONS

A single topical application of doramectin, administered at a dosage of 500 mcg/kg, provided persistent efficacy against challenge infections of Dictyocaulus viviparus and Cooperia oncophora for up to 21 days, and against challenge infections of Ostertagia ostertagi, Cooperia punctata and Oesophagostomum radiatum for up to 28 days after treatment. No adverse reaction to treatment was observed during these studies.

1. Dose confirmation study #1231C-60-95-199, Dr. E. Johnson, Johnson Research, Parma, Idaho

Forty-two (42) calves were allocated to one of four groups of 10 animals each, or as one of two larval viability monitor animals. Each animal was then artificially challenged with nematodes. At necropsy, worm counts between doramectin and saline groups were compared to determine doramectin efficacy. The results are summarized in Table 47.

Table 47 Arithmetic Means and Persistent Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Nematodes
ParasiteControlDoramectinDuration of
Activity
% Efficacy
Dictyocaulus viviparus40021100
Ostertagia ostertagi156028100
Cooperia punctata27262898
Cooperia oncophora656572191
Oesophagostomum radiatum6080.428>99

2. Dose confirmation study #1231C-02-95-204, Dr. R. Prichard, Institute of Parasitology, McGill University, Ste-Anne de Bellevue, Quebec, Canada

Forty-two (42) calves were allocated to one of four groups of 10 animals each, or as one of two larval viability monitor animals. Each animal was then artificially challenged with nematodes. At necropsy, worm counts between doramectin and saline groups were compared to determine doramectin efficacy. The results are summarized in Table 48.

Table 48 Arithmetic Means and Persistent Efficacy of Doramectin at 500 mcg/kg BW Against Cattle Nematodes
ParasiteControlDoramectinDuration of
Activity
% Efficacy
Dictyocaulus viviparus10021100
Ostertagia ostertagi1,410102899
Cooperia punctata870752891
Cooperia oncophora3,200222199
Oesophagostomum radiatum1,3281.228>99

 

VI. TARGET SPECIES SAFETY:

Doramectin target animal safety (cattle) has previously been established in the doramectin injectable solution for cattle file (see: FDA-approved NADA 141-061). Two additional studies were conducted for the doramectin pour-on solution for cattle file. A comparative pharmacokinetics study established lower systemic exposure to doramectin resulting from treatment of cattle with the intended label dose of doramectin pour-on compared with the label dose of doramectin injectable solution. A margin-of-safety study provided direct evaluation of doramectin pour-on solution administered at 1X, 3X and 5X the intended label dose.

A. COMPARATIVE BIOAVAILABILITY STUDY:

1. Experiment number: 1532N-60-94-160

2. Type of Study: Comparative bioavailability study comparing blood plasma levels in cattle treated with either doramectin injectable solution at the commercial dose of 200 mcg/kg BW, or doramectin pour-on solution at the proposed dose of 500 mcg/kg BW.

3. Study director: M.A. Nowakowski, Ph.D., Pfizer Central Research

4. General Design:

a. Objective: To compare the plasma kinetic profiles of doramectin administered at recommended doses to cattle by subcutaneous injection and by pour-on application.

b. Animals: 32 cross-bred beef cattle, 16 males and 16 females, weighing an average of 225 kg at study initiation.

c. Control: None

d. Dosage Form: DECTOMAX® injectable solution, 200 mcg/kg
Doramectin pour-on solution, 500 mcg/kg

e. Route of Administration: DECTOMAX® injectable solution, subcutaneous injection
Doramectin pour-on solution, topical

f. Test Duration: 56 days

g. Pertinent Measurements/Observations: Clinical observations were made daily. Blood was obtained for doramectin assay pre-dose and on days 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 21, 28, 35, 42, 49, and 56 after treatment.

5. Results:

Results (±1 SD) are summarized in Table 49.

Table 49: Comparative Pharmacokinetic Parameters - Doramectin Injectable Solution and Doramectin Pour-On Solution
ParameterDoramectin Injectable
Solution (200 mcg/kg)
Doramectin Pour-On
Solution (500 mcg/kg)
AUC0-infinity(ng-day/mL)*520±301210±302
Cmax (ng/mL)*35±29±2
Tmax (days)6±29±2
Mean half-life*5.8 days115 days2
*- Significant difference (P<0.05)
1- n=16 animals
2- n=12 animals

Because of the nature of drug absorption and elimination demonstrated by the topical route of administration, the elimination constant, kel and, therefore, AUC(0-infinity), could not be estimated for 4 of the 16 topically-treated animals. AUC(0-Tlast) accounted for 98% of AUC(0-infinity) for the animals dosed with the injectable formulation and for 89% of AUC(0-infinity) for the animals dosed with the topical formulation. The relative bioavailability of the topical formulation was estimated to be 42% of the injectable formulation.

6. Statistical Analysis: AUC, Tmax and Cmax were estimated for each route of administration and analyzed using analysis of variance of a one-period parallel design group. The 5% level of significance was used to determine whether the two routes differed.

7. Conclusion: Systemic exposure of cattle to doramectin was substantially lower when the drug was applied at the recommended dose topically as the pour-on formulation than when administered by subcutaneous injection as the injectable solution.

B. SAFETY MARGIN STUDY:

1. Experiment number: 1435N-60-94-002

2. Type of Study: A 16-day study in which a total of three topical administrations of doramectin pour-on solution at doses of 500, 1,500 or 2,500 mcg/kg BW were administered to beef cattle.

3. Study director: Dan C. Ronning, M.S.
Colorado Animal Research Enterprises, Inc.
Fort Collins, Colorado

4. General Design:

a. Objective: To assess the safety of 500, 1,500 or 2,500 mcg/kg BW doramectin when administered topically to cattle on three consecutive days.

b. Animals: Twenty-four (24) beef cattle, 12 males and 12 females, weighing approximately 142 to 194 kg at study initiation.

c. Control: Normal physiologic saline

d. Dosage Form: Doramectin pour-on solution, 500 mcg/kg

e. Route of Administration: Topical administration

f. Test Duration: 16 days

g. Pertinent Measurements/Observations: Clinical observations, physical examinations, rectal temperatures, feed consumption, body weights, hematology, serum chemistry, urinalysis, gross pathology, and histopathology.

5. Results:

a. Clinical Observations: Treatment-related changes were limited to superficial skin flaking at the site of administration in some animals. This observation occurred approximately two weeks post-dose, and was not highly dose-correlated.

b. Rectal temperatures: Rectal temperatures were normal and consistent among all animals throughout the study period.

c. Feed consumption: There was no significant difference in feed consumption among treatment groups.

d. Body weight: There was no significant difference in weight gain among treatment groups.

e. Hematology/serum chemistry: Hematologic and serum chemistry values were within the normal range in all treatment groups.

f. Urinalysis: Urinalysis results were within the normal range in all treatment groups.

g. Gross and histopathological observations: Superficial skin flaking at the administration site was correlated with microscopic observations of mild acanthosis and hyperkeratosis of the epidermis.

6. Statistical Analysis: For hematologic, serum chemistry, and rectal temperature variables, treatment means and animal within treatment standard deviations were estimated. Average daily weight gain and feed consumption were calculated for each treatment group and analysis of variance procedures was carried out.

7. Conclusions: Doramectin pour-on produced no significant systemic toxicological effects when administered topically at dosages of 500, 1,500, or 2,500 mcg/kg for three consecutive days. Treatment-related effects were limited to superficial skin flaking at the site of administration in some animals at approximately two weeks post-dose. It was concluded that use of doramectin pour-on as directed provides a wide margin of safety in cattle.

C. BREEDING ANIMAL SAFETY:

Safety in male and female breeding animals was determined by comparison with doramectin injectable solution for cattle. Data were previously presented to show that subcutaneous administration of doramectin at 600 mcg/kg (3X the intended SC dose) had no adverse effects on male and female breeding cattle.

To evaluate if topical application of doramectin posed any risk to breeding animals, a comparative bioavailability study was conducted. The results (summarized in study 1532N-60-94-160 above) indicate significantly lower systemic exposure to doramectin administered topically compared to subcutaneous injection. Therefore, doramectin pour-on solution for cattle will be safe in breeding cattle.

 

V. HUMAN FOOD SAFETY

A. Toxicology:

1. TOXICITY STUDIES

For a summary of the toxicology tests completed in support of doramectin, please consult the Freedom of Information (FOI) summary for NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle.

2. SAFE CONCENTRATION OF TOTAL RESIDUE

As discussed in the FOI summary for NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle, the safe concentration in muscle has been calculated from the no-observed-effect-level in the most sensitve study in the most sensitive species:

Safe concentration in muscle = (60 kg) (0.75 µg/kg/day) / 300 g/day = 150 ppb

The safe concentration of residues in liver, kidney and fat are determined from this number using appropriate food consumption values (food factor) for these tissues. Therefore, the safe concentrations are:

Liver: 150 ppb x 3 (food factor) = 450 ppb

Kidney: 150 ppb x 6 (food factor) = 900 ppb

Fat: 150 ppb x 6 (food factor) = 900 ppb

B. Total Residue and Metabolism:

For a summary of the total residue and metabolism studies completed in support of doramectin, please consult the Freedom of Information (FOI) summary for NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle.

C. Selection of Target Tissue and Marker Residue for Doramectin in Cattle:

The data from the total residue metabolism studies referenced above establish that liver contains the highest levels of total drug-related doramectin residues and it is the tissue in cattle from which residues are the last to deplete to the safe concentration. Similarly high concentrations occur in fat; however, these did not exceed the safe concentration at any time point tested. These observations suggested that liver was the most likely target tissue for doramectin in cattle.

The metabolism data confirmed liver as the target tissue and selection of the parent doramectin as the marker residue. Those data demonstrated that the parent was present in sufficiently high concentration and had the proper depletion characteristics in liver to serve as the marker residue in that tissue.

D. Tolerance for the Marker Residue:

A liver tolerance of 100 ppb was assigned for setting the withdrawal time in cattle under NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle. Since both injection and topical administration are considered to be parenteral routes of administration, a liver tolerance of 100 ppb is also applicable to doramectin pour-on solution for cattle.

E. Studies Establishing the Withdrawal Period:

Depletion of the marker residue was determined following topical administration of doramectin.

TITLE: Marker Residue Study of Edible Tissue from Cattle Treated Topically with Doramectin

STUDY NO.: 1531N-60-94-054

STUDY DESIGN:

Dose: 625 mcg/kg BW as a topical administration

Test animals: 32 adult, crossbred beef cattle (16 male, 16 female)

Withdrawal schedule: 14, 21, 28, 42 and 56 days post-dosing

Following treatment with doramectin, six animals were sacrificed at each collection time, and tissue samples of liver, muscle (longissimus dorsi and semimembranosus), kidney, and perirenal fat were collected and assayed for unchanged doramectin, the marker residue.

RESULTS:

The results from the study are shown in Table 50:

Table 50: Mean doramectin ( 1 SD) concentration in cattle tissue (study #1531N-60-94-054)
Withdrawal
period (days)
Liver
Levels
(ng/g)
Fat
Levels
(ng/g)
Kidney
Levels
(ng/g)
Muscle Levels
semimembranosus1
(ng/g)
Muscle Levels
longissimus
dorsi
2
(ng/g)
1490±40130±6020±87±39±4
2170±3090±2017±57±26±2
2860±3070±3013±6<4<4
4228±738±116±2<3<3
5615±818±9<4<lloq3<lloq3
1- semimembranosus muscle represents edible muscle
2- longissimus dorsi muscle represents tissue deep to the site of topical drug administration
3- value below the lower limit of assay quantitation

WITHDRAWAL TIME

Statistical analysis of the marker residue depletion study (1531N-60-94-054) using a liver-based tolerance of 100 ppb results in a withdrawal time of 45 days.

F. Regulatory Method:

DORAMECTIN DETERMINATIVE ASSAY PROCEDURE

For a summary of determinative analytical procedure, please consult the Freedom of Information (FOI) summary for NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle.

DORAMECTIN CONFIRMATORY ASSAY PROCEDURE

For a summary of confirmatory analytical procedure, please consult the Freedom of Information (FOI) summary for NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle.

METHOD VALIDATION

The determinative and confirmatory analytical methods were evaluated and accepted under NADA 141-061, DECTOMAX® (doramectin) 1% injectable solution for cattle.

 

VI. USER SAFETY

Potential for exposure to doramectin solution by end users was assessed under field conditions. Two commercialized dosing guns recommended for use with the product and the custom designed dosing cup to be provided with the smaller volume presentations of the product were employed by users to apply doramectin pour-on solution to cattle. User exposure to drug was then evaluated by quantitating drug exposure to the hands, arms and face during dosing.

USER SAFETY STUDY

TITLE: User Exposure for Doramectin Pour-On Application in Cattle

PROTOCOL NO.: 1530N-60-96-227

STUDY DESIGN: Dose: 500 mcg/kg BW as a topical administration

Test animals: 75 adult, crossbred beef

Five individuals (referred to as "users") each dosed a total of 15 cattle, 5 each with either a dosing cup or one of two commercially available dosing guns. Users wore a tyvek coverall, face mask, and gloves, each with absorbent patches affixed for the purpose of capturing ambient drug product as a measure of potential human exposure during normal drug use.

RESULTS:

Doramectin was detected on the outside gloves of four of the five users handling the dosing cup at quantities per glove of 0.05 mL or less of formulated product. Doramectin was detected on the outside gloves of four of the five users handling either dosing gun at quantities of 0.2 mL of formulated product. Doramectin was not detected on any inside gloves (separated from outside gloves by latex gloves), or on any of the absorbent pads.

Doramectin was detected on the outside of the outer gloves, but was not detected on any inside gloves (separated from the outer pair by latex gloves), nor on any absorbent pads. Latex gloves were judged to be impervious to the product, since doramectin was not detected on the inner gloves. Therefore, users are protected from exposure during product application, provided they comply with label precautions which recommend the use of rubber gloves, boots and a waterproof coat.

CONCLUSION

The label-recommended equipment, procedures and precautions eliminate potential for exposure to doramectin under normal handling of doramectin pour-on solution, thus preventing absorption of any toxicologically significant quantities of the drug. Accidental exposure through spillage is unlikely to result in any significant adverse reactions, since the product is only minimally irritating and recommended washing after contact should minimize the potential for irritation, which is largely due to the solvent.

Doramectin pour-on solution presents no unusual risks to the handler under normal conditions of use in compliance with recommended procedures and precautions.

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this original NADA satisfy the requirements of section 512 of the Federal Food, Drug and Cosmetic Act and 21 CFR Part 514 of the implementing regulations. The data demonstrate that DECTOMAX® pour-on solution is safe and effective for the treatment and control of gastrointestinal roundworms, lungworms, kidneyworms, biting and sucking lice, and mange mites in cattle, when administered topically at a dose of 500 mcg/kg bodyweight.

The safe concentrations of doramectin residues assigned in association with the original DECTOMAX® injectable solution for cattle NADA are 150 ppb in muscle, 450 ppb in liver, 900 ppb in kidney, and 900 ppb in fat. Based on metabolism studies in cattle, a tolerance of 100 ppb for marker residue, parent doramectin, has been established in liver. The tolerance (Rm) refers to the residue measured by the regulatory method described herein.

A pre-slaughter withdrawal period of 45 days was calculated from the residue depletion study of doramectin residues in cattle, following topical administration of DECTOMAX® pour-on solution. Statistical analysis of the marker residue depletion study using a liver-based tolerance of 100 ppb gave a withdrawal time of 45 days.

The data submitted for DECTOMAX® pour-on solution for cattle support the marketing of the product as an over-the-counter new animal drug. Adequate directions for use have been written for the layman, and the conditions for use prescribed on the label are likely to be followed in practice. Therefore, the Center for Veterinary Medicine (CVM) has concluded that this product shall have the over-the-counter marketing status.

The agency has carefully considered the potential environmental effects of this action and has concluded that the action will not have significant impact on the human environment and that an environmental impact statement is not required. The agency's finding of no significant impact (FONSI) and the evidence supporting that finding contained in an environmental assessment may be seen in the Dockets Management Branch (HFV-305), Park Building (Room 1-23), 12420 Parklawn Dr., Rockville, Maryland 20855.

Under section 512(c)(2)(F)(ii) of the FFDCA, this approval for food producing animals qualifies for THREE years of marketing exclusivity beginning on the date of approval because the supplemental application contains substantial evidence of the effectiveness of the drug involved, any studies of animal safety, or, in the case of food producing animals, human food safety studies (other than bioequivalence or residue studies) required for the approval of the application and conducted or sponsored by the applicant. DECTOMAX® pour-on solution is under U.S. patent number 5,089,480, which expires on February 18, 2009.

 

VIII. LABELS (Attached)

  1. Facsimile label for the 250 mL, 1 liter and 2.5 liter containers and package insert.

Copies of applicable labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855