Date of Approval: FREEDOM OF INFORMATION SUMMARY ORIGINAL NEW ANIMAL DRUG APPLICATION LONGRANGE (eprinomectin) Extended-Release Injectable Parasiticide for the treatment and control of internal and external parasites of cattle on pasture with persistent effectiveness Sponsored by: Merial Ltd.
TABLE OF CONTENTS I. GENERAL INFORMATION:...1 II. EFFECTIVENESS:...3 A. Dosage Characterization:...3 B. Substantial Evidence for Endoparasite Indications:...3 III. TARGET ANIMAL SAFETY:...65 A. Toxicity Study:...65 B. Reproductive Safety in Female Cattle of Breeding Age:...67 C. Reproductive Safety in Pregnant Cattle:...69 IV. HUMAN FOOD SAFETY:...71 A. Toxicology:...71 B. Residue Chemistry:...84 C. Microbial Food Safety:...93 D. Analytical Methods for Residues:...93 V. USER SAFETY:...94 VI. AGENCY CONCLUSIONS:...94 i
Page 1 I. GENERAL INFORMATION: A. File Number: B. Sponsor: Merial Ltd. 3239 Satellite Blvd. Bldg 500 Duluth, GA 30096-4640 Drug Labeler Code: 050604 C. Proprietary Name: LONGRANGE D. Established Name: Eprinomectin E. Pharmacological Category: Antiparasitic F. Dosage Form: Injectable solution G. Amount of Active Ingredients: 5% w/v eprinomectin (50 mg eprinomectin per ml) H. How Supplied: 50 ml rubber-capped glass bottles I. How Dispensed: Prescription (Rx) J. Dosage: 1 mg eprinomectin per kg body weight (1 ml/110 lb body weight) K. Route of Administration: Subcutaneous injection L. Species/Class: Cattle/pastured
Page 2 M. Indications: For the treatment and control of the following parasites: Gastrointestinal Roundworms Cooperia oncophora Adults and L 4 Cooperia punctata Adults and L 4 Cooperia surnabada Adults and L 4 Haemonchus placei Adults Oesophagostomum radiatum Adults Ostertagia lyrata Adults Ostertagia ostertagi Adults, L 4, and inhibited L 4 Trichostrongylus axei Adults and L 4 Trichostrongylus colubriformis - Adults Lungworms Dictyocaulus viviparus Adults Grubs Hypoderma bovis Mites Sarcoptes scabiei var. bovis Persistent Activity LONGRANGE (eprinomectin) has been proven to effectively protect cattle from reinfection with the following parasites for the indicated amounts of time following treatment: Parasites Gastrointestinal Roundworms Cooperia oncophora Cooperia punctata Haemonchus placei Oesophagostomum radiatum Ostertagia lyrata Ostertagia ostertagi Trichostrongylus axei Lungworms Dictyocaulus viviparus Duration of Persistent Effectiveness 100 days 100 days 120 days 120 days 120 days 120 days 100 days 150 days
Page 3 II. EFFECTIVENESS: A. Dosage Characterization: A dose titration study (PR&D 0011301) evaluated five formulations of Eprinomectin extended-release injectable (ERI) for the control of endoparasites in cattle at doses of 0.5, 0.75, and 1.0 mg of eprinomectin per kg body weight. Included in this study were 48 male-castrate Holstein cattle, approximately 4 to 6 months old and weighing 126 to 223 kg on Day -4. All treatments were given once on Day 0 by subcutaneous injection at 1 ml/110 lb (50 kg) body weight. On Day 120, cattle were inoculated orally with infective third-stage nematode larvae of Ostertagia ostertagi, Trichostrongylus axei, Cooperia oncophora/surnabada, Haemonchus placei, Nematodirus helvetianus, and Dictyocaulus viviparus. Cattle were necropsied for worm recoveries, and liver and injection site tissues were collected for eprinomectin assay by replicate on Days 148 and 149. Cattle treated with all doses of Eprinomectin ERI had significantly (p<0.05) fewer of the following parasites than the control animals: Cooperia oncophora, Cooperia surnabada, Dictyocaulus viviparus, Haemonchus spp. (identified to genus only), Nematodirus helvetianus, Ostertagia ostertagi, and Trichostrongylus axei. Percent effectiveness was 95% for all parasites. However, only the cattle treated with 1.0 mg eprinomectin/kg body weight with the formulation containing 5% poly-lactide-co-glycolic-acid (PLGA) had 100% effectiveness, therefore this formulation and dose were selected for development. B. Substantial Evidence for Endoparasite Indications: Eleven dose confirmation studies were performed, evaluating a 1 mg eprinomectin/kg body weight dose (1 ml/110 lb) and using natural and artificially induced infections. Studies were conducted using common protocols in multiple geographic locations throughout the United States and Europe. All protocols were reviewed and accepted by CVM. Effectiveness against 4th stage larvae (L4) was evaluated in three studies using artificially induced infections. Effectiveness in adults was evaluated in eight studies using both natural and artificially induced infections. A claim could only be granted in an artificial infection study if the isolate for a given species of parasite was 10 years old or less. DATA ANALYSIS: In all effectiveness studies, the Wilcoxon rank sum test was used to compare the distribution of speciated parasite counts for the treated group to that of the control group. A two-sided test was used at α=0.05. Speciated parasite counts for each animal were transformed to the natural logarithm of (count + 1) for analysis and calculation of geometric means. Effectiveness was calculated as 100[(C-T)/C], where C is the geometric mean for the control group and T is the geometric mean for the treated group. An indication was granted if there was a minimum of two studies (with at least one of the studies conducted in the United States) that fulfilled the following requirements: an adequate level of
Page 4 infection in 6 control animals, a statistically significant difference between treated and control animals at P<0.05, and 90% or greater effectiveness using geometric means for each species of parasite. If there were more than 2 studies with an adequate level of infection for a species, then the geometric means of the percent effectiveness against that species of parasite from each study was added together and divided by the number of studies with that species of parasite. If this average was greater than or equal to 90%, then the claim was granted. A treatment and control claim is granted for Cooperia oncophora (Adults and L 4 ), Cooperia punctata (Adults and L 4 ), Cooperia surnabada (Adults and L 4 ), Haemonchus placei (Adults), Oesophagostomum radiatum (Adults), Ostertagia lyrata (Adults), Ostertagia ostertagi (Adults, L 4, and inhibited L 4 ), Trichostrongylus axei (Adults and L 4 ), Trichostrongylus colubriformis (Adults), Dictyocaulus viviparus (Adults), Hypoderma bovis, and Sarcoptes scabiei var. bovis. The individual studies are summarized below. B.1 Study Number PR&D 0052101 1) Type of Study: Dose confirmation study in cattle with artificially-induced nematode infections. 2) Investigator: A. Marchiondo, Ph.D., G.C. Royer, D.V.M. Merial, Missouri Research Center Fulton, MO 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of fourth stage nematode larvae in cattle. b. Animals: Sixteen male Holstein calves, approximately 5.5 months of age and weighing 148.0 to 167.4 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two groups. c. Housing: Individual pens d. Infection: The inoculation schedule was designed so that nematodes were fourth stage larvae (L4) on Day 0.
Page 5 Table IIB.1.1: Inocula Number of Day of Age of Strain Species infective inoculation (Yrs) Nematodirus helvetianus 5,124 larvae -14 5 Bunostomum phlebotomum 1,092-14 4 Oesophagostomum radiatum 1,014-14 4 Haemonchus rarradiatumradiatum placei 5,072-7 5 Ostertagia ostertagi 10,020-7 5 Trichostrongylus axei 15,020-7 5 Cooperia oncophora, and 10,144-7 5 Cooperia surnabada Cooperia punctata 10,130-7 4 Trichostrongylus colubriformis 10,054-5 5 Dictyocaulus viviparus 1,014-5 4 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body. i. Test Duration: All cattle were necropsied either 21 or 22 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified.
Page 6 4) Results: Effectiveness against parasite species with an adequate level of infection in at least six control animals is summarized in the following table: Table IIB.1.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia oncophora 6 377.6 0.0 100.0 Cooperia punctata 8 2422.8 0.0 100.0 Cooperia surnabada 7 245.3 0.0 100.0 Ostertagia ostertagi 7 801.7 0.0 100.0 Trichostrongylus axei 8 1135.3 0.0 100.0 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.2 Study Number PR&D 0052102 1) Type of Study: Dose confirmation study in cattle with artificially-induced nematode infections. 2) Investigator: S. Rehbein, Dr. med. vet. habil., DipEVPC Merial GmbH, Kathrinenhof Research Center Rhordorf, Germany 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of fourth stage nematode larvae in cattle. b. Animals: Sixteen male Braunvieh calves, approximately 5.5 months of age and weighing 109 to 159 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Individually stanchioned
Page 7 d. Infection: The inoculation schedule was designed so that nematodes were fourth stage larvae (L4) on Day 0. Table IIB.2.1: Inocula Species Number of Infective Larvae Day of Inoculation Age of Strain (Yrs) Bunostomum phlebotomum 1,500-14 3 Nematodirus helvetianus 4,000-14 4 Oesophagostomum radiatum 1,500-14 unknown Cooperia oncophora/surnabada 10,000-8 4 Cooperia punctata 10,000-8 4 Haemonchus contortus 5000-8 4 Oesophagostomum venulosum 1,500-8 4 Ostertagia leptospicularis 10,000-8 5 Trichostrongylus axei 10,000-8 4 Cooperia curticei 10,000-5 4 Dictyocaulus viviparus 1,500-5 4 Ostertagia ostertagi 10,000-5 4 Ostertagia spp. (sheep) 8,000-5 2 Strongyloides papillosus 200,000-5 <1 Trichostrongylus colubriformis 10,000-5 4 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front ofthe shoulder.g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 100 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0mL per 110 lb (50 kg) body weight.i. Test Duration: All cattle were necropsied either 21 or 22 days posttreatment.
Page 8 j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection in at least six controls is summarized in the following table: Table IIB.2.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Geometric Mean Eprinomectin Effectiveness (%) Cooperia oncophora 8 2625.8 1.1 99.9 Cooperia punctata 8 6982.0 0.0 100.0 Cooperia surnabada 8 443.3 1.1 99.7 Dictyocaulus viviparus 8 282.3 0.0 100.0 Haemonchus contortus 8 696.1 0.0 100.0 Nematodirus helvetianus 8 228.1 0.0 100.0 Oesophagostomum radiatum 8 521.3 0.0 100.0 Ostertagia leptospicularis 8 4264.2 0.0 100.0 Ostertagia ostertagi 8 4769.0 0.0 100.0 Strongyloides papillosus 8 943.2 1.0 99.9 Trichostrongylus axei 8 2719.8 0.0 100.0 Trichostrongylus colubriformis 7 166.4 0.0 100.0 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.3 Study Number PR&D 0052103 1) Type of Study: Dose confirmation study in cattle with artificially-induced nematode infections. 2) Investigator: S.R. Pitt, BvetMed, Ph.D., MRCVS Merial, Highfield Research Center Hertford, Hertfordshire, UK
Page 9 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of fourth stage nematode larvae in cattle. b. Animals: Sixteen male castrate continental-cross breed calves, approximately 4 to 6 months of age and weighing 122.5 to 152.5 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Individually penned d. Infection: The inoculation schedule was designed so that nematodes were fourth stage larvae (L4) on Day 0. Table IIB.3.1: Inocula Species Number of infective larvae Day of inoculation Age of Strain (Yrs) Bunostomum phlebotomum 1,500-13 3.5 Nematodirus helvetianus 5,000-12 4 Oesophagostomum radiatum 1,500-12 10-20 Cooperia oncophora 11,000-7 6 Haemonchus contortus 5,000-7 4 Ostertagia ostertagi 11,000-7 6 Trichostrongylus axei 10,000-7 4 Dictyocaulus viviparus 1,500-5 > 20 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 21 or 22 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified.
Page 10 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table: Table IIB.3.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Geometric Mean Eprinomectin Effectiveness (%) Dictyocaulus viviparus 7 244.1 0.0 100.0 Ostertagia ostertagi 7 5894.6 0.0 100.0 Cooperia oncophora 7 5753.9 0.0 100.0 Cooperia surnabada 7 460.6 0.0 100.0 Nematodirus helvetianus 6 72.7 0.0 100.0 Oesophagostomum radiatum 7 170.5 0.0 100.0 adult 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.4 Study Number PR&D 0052001 1) Type of Study: Dose confirmation study in cattle with artificially-induced nematode infections. 2) Investigator: A. Marchiondo, Ph.D., G.C. Royer, D.V.M. Merial, Missouri Research Center Fulton, MO 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of adult nematodes in cattle. b. Animals: Sixteen Holstein calves, approximately 5.5 months of age and weighing 157.6 to 177.4 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Individually penned
Page 11 d. Infection: Cattle were inoculated according to the following schedule: Table IIB.4.1: Inocula Number of Day of Species infective larvae inoculation Bunostomum phlebotomum 1,024-56 4 Oesophagostomum radiatum 1,004-49 4 Haemonchus placei 5,130-35 5 Cooperia 10,087-28 5 Cooperia oncophora/surnabada punctata 10,023-28 4 Age of Strain (Yrs) Dictyocaulus viviparus 1,017-28 4 Nematodirus helvetianus 5,046-28 5 Ostertagia ostertagi 10,123-28 5 Trichostrongylus axei 15,143-28 5 Trichostrongylus colubriformis 10,048-28 4 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 14 or 15 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table:
Page 12 Table IIB.4.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia oncophora 7 669.2 1.6 99.8 Cooperia punctata 7 261.1 0.6 99.8 Cooperia surnabada 7 141.9 0.6 99.6 Dictyocaulus viviparus 8 21.0 0.0 100.0 Haemonchus placei 8 394.9 0.0 100.0 Oesophagostomum radiatum 8 51.2 0.0 100.0 Ostertagia ostertagi 8 3367.3 0.3 99.9 Trichostrongylus axei 8 1767.7 0.0 100.0 Trichostrongylus colubriformis 6 40.5 0.0 100.0 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.5 Study Number PR&D 0052002 1) Type of Study: Dose confirmation study in cattle with artificially-induced nematode infections. 2) Investigator: S. Rehbein, Dr. med. vet. habil., DipEVPC Merial GmbH, Kathrinenhof Research Center Rohrdorf, Germany 3) General Design: a.purpose: This study was designed to confirm the effective dose for the treatment of adult nematodes in cattle. b. Animals: Sixteen Braunvieh calves, approximately 5 months of age and weighing 124.5 to 186.5 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to separate treatment groups. c.housing: Individually stanchioned
Page 13 d. Infection: Cattle were inoculated according to the following schedule: Table IIB.5.1: Inocula Number of Day of Age of Strain Species L3/Eggs Inoculation (Yrs) Bunostomum phlebotomum 1,500-56 4 Chabertia ovina 1,500-56 4 Trichuris spp. 300-56 <1 Oesophagostomum radiatum 1,500-49 Unknown Cooperia punctata 10,000-28 5 Dictyocaulus viviparus 1,500-28 4 Haemonchus contortus 5,000-28 4 Nematodirus helvetianus 4,000-28 4 Oesophagostomum venulosum 1,500-28 4 Ostertagia leptospicularis 10,000-28 6 Cooperia curticei 10,000-21 4 Cooperia 10,000-21 5 oncophora/surnabada Ostertagia ostertagi 10,000-21 4 Ostertagia spp. (sheep) 8,000-21 2 Trichostrongylus axei 10,000-21 5 Trichostrongylus capricola 10,000-21 5 Trichostrongylus colubriformis 10,000-21 5 Strongyloides papillosus 200,000-12 <1 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 14 or 15 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table:
Page 14 Table IIB.5.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Bunostomum phlebotomum 8 345.6 0.0 100.0 Cooperia oncophora 8 3518.5 2.0 99.9 Cooperia punctata 8 4215.9 2.6 99.9 Cooperia surnabada 8 574.1 1.1 99.8 Dictyocaulus viviparus 8 198.0 0.0 100.0 Haemonchus contortus 8 1002.8 0.0 100.0 Nematodirus helvetianus 8 309.6 0.0 100.0 Oesophagostomum radiatum 8 590.2 0.0 100.0 Ostertagia leptospicularis 8 3262.6 0.0 100.0 Ostertagia ostertagi 8 3160.5 0.0 100.0 Ostertagia spp. L4 inhibited 8 900.0 0.0 100.0 Strongyloides papillosus 8 6651.8 111.8 98.3 Trichostrongylus axei 8 1971.7 0.0 100.0 Trichostrongylus colubriformis 8 231.9 0.0 100.0 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.6 Study Number PR&D 0052003 1) Type of Study: Dose confirmation study in cattle with artificially-induced nematode infections. 2) Investigator: D.G. Baggott, BVSc, Ph.D., MRCVS Merial, Highfield Research Center Hertford, Hertfordshire, UK 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment with adult nematodes in cattle.
Page 15 b. Animals: Sixteen Limousin (or Limousin cross) calves, approximately 4 to 7 months of age and weighing 129 to 153.5 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Individually stanchioned d. Infection: Cattle were inoculated according to the following schedule: Table IIB.6.1: Inocula Species Number of Infective Larvae Day of Inoculation Age of Strain (Yrs) Bunostomum phlebotomum 1,700-55 3.5 Oesophagostomum radiatum 1,500-47 10-20 Cooperia oncophora/surnabada 11,000-28 6 Dictyocaulus viviparus 1,500-28 >20 Haemonchus contortus 5,000-28 4 Nematodirus helvetianus 6,000-28 4 Ostertagia ostertagi/lyrata 11,000-28 6 Trichostrongylus axei 10,000-28 4 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front ofthe shoulder.g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0mL per 110 lb (50 kg) body weight.i. Test Duration: All cattle were necropsied either 14 or 15 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered fromanimals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table:
Page 16 Table IIB.6.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia oncophora 8 8117.1 1.9 99.9 Cooperia surnabada 8 717.1 0.6 99.9 Dictyocaulus viviparus 8 112.8 0.0 100.0 Nematodirus helvetianus 7 170.7 0.0 100.0 Oesophagostomum radiatum 8 436.8 0.0 100.0 Ostertagia ostertagi 8 5896.7 0.3 99.9 Ostertagia lyrata 6 26.4 0.3 98.7 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.7 Study Number PR&D 0045601 1) Type of Study: Dose confirmation study in cattle with naturally-acquired nematode infections. 2) Investigator: D. Reddick, M. Sc., B.Sc. Moredun Scientific Ltd. Penucuik, Midlothian, Scotland, UK 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of nematodes in cattle. b. Animals: Twenty male Holstein Friesian, Friesian, or Friesian-cross cattle, between 11 and 15 months of age and weighing 195 to 315 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Pasture d. Infection: Cattle had naturally-acquired nematode infections.
Page 17 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied 14 days post-treatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table: Table IIB.7: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Geometric Mean Eprinomectin Effectiveness (%) Cooperia oncophora 10 1475.8 68.1 95.4 Cooperia surnabada 7 78.8 3.7 95.4 Ostertagia ostertagi 10 7029.9 1.4 99.9 O. ostertagi L4 inhibited 10 201123.9 1422.2 99.3 Trichostrongylus axei 8 141.1 0.0 100.0 Trichostrongylus colubriformis 8 162.6 0.0 100.0 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.8 Study Number PR&D 0045602 1) Type of Study: Dose confirmation study in cattle with naturally-acquired nematode infections.
Page 18 2) Investigator: T.A. Yazwinski, Ph.D. University of Arkansas Fayetteville, AR 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of nematodes in cattle. b. Animals: Twenty male castrate Holstein cattle, approximately 6 months of age and weighing 79 to 182 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Pasture d. Infection: Cattle had naturally-acquired nematode infections. e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 14 or 15 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table:
Page 19 Table IIB.8: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Geometric Mean Eprinomectin Effectiveness (%) Cooperia oncophora 10 7685.8 208.4 97.3 Cooperia punctata 10 557.6 1.7 99.7 Cooperia surnabada 10 533.7 27.8 94.8 Haemonchus placei 10 652.9 0.4 99.9 Ostertagia lyrata 10 138.5 0.3 99.8 Ostertagia ostertagi 10 4746.9 2.0 99.9 Ostertagia spp. L4 inhibited 10 2182.0 0.5 99.9 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.9 Study Number PR&D 0045603 1) Type of Study: Dose confirmation study in cattle with naturally-acquired nematode infections. 2) Investigators: S. Rehbein, Dr. med. vet. habil., DipEVPC Merial GmbH, Kathrinenhof Research Center Rohrdorf, Germany 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of nematodes in cattle. b. Animals: Twenty intact male Holstein-Friesian cattle, approximately 12 months of age and weighing 353 to 491 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to separate treatment groups. c. Housing: Pasture
Page 20 d. Infection: Cattle had naturally-acquired nematode infections. e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied 14 days post-treatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection is summarized in the following table: Table IIB.9: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle Eprinomectin Effectiveness (Control) (%) Geometric Means Cooperia oncophora 10 808.8 4.4 99.5 Dictyocaulus viviparus 9 30.3 0.0 100.0 Ostertagia ostertagi 10 1650.5 0.0 100.0 O. ostertagi L4 inhibited 10 10803.4 907.7 91.6 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.10 Study Number PR&D 0045604 1) Type of Study: Dose confirmation study in cattle with naturally-acquired nematode infections.
2) Investigator: J.C. Williams, Ph.D. Louisiana State University Baton Rouge, LA 3) General Design: Freedom of Information Summary Page 21 a. Purpose: This study was designed to confirm the effective dose for the treatment of nematodes in cattle. b. Animals: Twenty crossbred beef cattle (15 females, 3 male castrates and 2 males), approximately 9 to 14 months of age and weighing 137 to 224 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: Pasture d. Infection: Cattle had naturally-acquired nematode infections. e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied 14 days post-treatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite genus species with an adequate level of infection is summarized in the following table:
Page 22 Table IIB.10: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia pectinata 9 799.5 0.0 100.0 Cooperia punctata 10 4221.9 0.0 100.0 Oesophagostomum radiatum 10 185.2 0.0 100.0 Ostertagia ostertagi 10 9236.0 0.6 99.9 O. ostertagi L4 inhibited 10 30773.2 5726.1 81.4 Trichostrongylus axei 10 3930.7 0.0 100.0 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. B.11 Study Number PR&D 0045606 1) Type of Study: Dose confirmation study in cattle with naturally-acquired nematode infections. 2) Investigator: J.C. Hunter, III, M.S., Ph.D. Merial, Missouri Research Center Fulton, MO 3) General Design: a. Purpose: This study was designed to confirm the effective dose for the treatment of nematodes in cattle. b. Animals: Twenty crossbred Angus cattle (12 male castrates and 8 females), approximately 9 to 15 months of age and weighing 142 to 239 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to separate treatment groups. c. Housing: Pasture d. Infection: Cattle had naturally-acquired nematode infections. e. Dosage Form: Eprinomectin ERI
Page 23 f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied 14 days post-treatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite genus species with an adequate level of infection is summarized in the following table: Table IIB.11: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia punctata 9 336.6 0.4 99.9 Oesophagostomum 10 101.2 0.0 100.0 Ostertagia radiatum ostertagi 10 30158.4 0.8 99.9 Ostertagia lyrata 9 702.4 0.0 100.0 Ostertagia spp. L4 inhibited 10 5665.5 9.8 99.8 Trichostrongylus axei 10 53639.6 1.0 99.9 5) Adverse Reactions: There were no drug related health problems or adverse drug events observed during the study. C. Substantial Evidence for Endoparasite Persistent Activity Fourteen studies were conducted to evaluate the persistent effect of Eprinomectin ERI against artificial and natural nematode infections. Studies were conducted using common protocols in multiple geographic locations throughout North America and Europe. Seven studies were conducted to confirm the persistent
Page 24 effect against infections with third-stage larvae (L3) and/or eggs of gastrointestinal and pulmonary nematodes of cattle induced 100 or 120 days after treatment. Four studies were conducted to confirm the persistent effect against natural infections with third-stage larvae (L3) and/or eggs of gastrointestinal and pulmonary nematodes of cattle for 120 days after treatment. One study was conducted to confirm the persistent effect against both natural and induced infections; cattle grazed on infected pasture for 120 days and then received an inoculation with infective third-stage larvae (L3) at Day 120. Two studies were conducted to confirm the persistent effect against infections with third-stage larvae (L3) of gastrointestinal and pulmonary nematodes of cattle induced 150 days after treatment. A claim could only be granted in an artificial infection study if the isolate for a given genus species of parasite was 10 years old or less. In addition, a persistent effect claim could only be granted for those parasite species for which a treatment and control claim was already established. DATA ANALYSIS: In all effectiveness studies, the Wilcoxon rank sum test was used to compare the distribution of speciated parasite counts for the treated group to that of the control group. A two-sided test was used at α=0.05. Speciated parasite counts for each animal were transformed to the natural logarithm of (count + 1) for analysis and calculation of geometric means. Effectiveness was calculated as 100[(C-T)/C], where C is the geometric mean for the control group and T is the geometric mean for the treated group. An indication was granted if there was a minimum of two studies (with at least one of the studies conducted in the United States) that fulfilled the following requirements: an adequate level of infection in 6 control animals, a statistically significant difference between treated and control animals at P<0.05, and 90% effectiveness using geometric means for each genus species of parasite and at each persistent effect period. If there were more than two studies, then the reported percent against a genus species of parasite was the arithmetic mean of the percent effectiveness for all studies with that genus species of parasite. If this average was greater than or equal to 90%, then the claim was granted. If this average was less than 90%, the claim was not granted. A persistency claim is granted for Dictyocaulus viviparus for 150 days after treatment, for Haemonchus placei, Oesophagostomum radiatum, Ostertagia lyrata, and Ostertagia ostertagi for 120 days after treatment and for Cooperia oncophora, Cooperia punctata, and Trichostrongylus axei for 100 days after treatment based on the above criteria. The fourteen studies are summarized as follows. C1. Study Number PR&D 0073701 1) Type of Study: Dose confirmation study in cattle with induced gastrointestinal roundworm and lungworm infections.
Page 25 2) Investigators: R.E. Plue, D.V.M, M.S. G.C. Royer, D.V.M. Merial, Missouri Research Center Fulton, MO 3) General Design: J.E. Holste, D.V.M. Holste Biological and Pharmaceutical Services Columbia, MO a.purpose: This study was designed to determine the effectiveness of Eprinomectin ERI against nematode infections induced at 100 and 120 days post-treatment. b. Animals: Thirty Holstein male calves, aged approximately 4 months and weighing 87 to 121 kg, were ranked by decreasing body weights and allocated consecutively to 10 replicates of three animals each. Animals within each replicate were randomly assigned to one of three treatment groups. c. Housing: These cattle were maintained in pens by treatment group. d. Infection: Each animal was inoculated per os with infective larvae of Trichostrongylus axei, Cooperia oncophora, Cooperia surnabada, and Cooperia punctata. The age of the nematode strains used in this experiment were 6 years old, 6 years old, 6 years old, and 5 years old, respectively. e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 148 or 149 days posttreatment.
Page 26 j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection at 100 and 120 days is summarized in the following table: Table IIC.1: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Day 120 (Eprinomectin Day 100 (Eprinomectin Control Parasite n ERI on Day 0) 1 ERI on Day 20) 2 GM GM Effectiveness GM Effectiveness Cooperia oncophora 9 1850.9 38.4 97.9% 2.5 99.9% Cooperia punctata 10 8005.7 45.9 99.4% 2.1 99.9% Cooperia surnabada 9 671.9 3.4 99.5% 1.0 99.9% Trichostrongylus axei 1 10 2596.9 408.1 84.3% 3.8 99.9% Animals were treated once with Eprinomectin ERI on Day 0 and artificially infected with nematode larvae (L3) on Day 120. 2 Animals were treated once with Eprinomectin ERI on Day 20 and artificially infected with nematode larvae (L3) on Day 120. 5) Adverse Reactions: No adverse reactions to treatment were noted. C2. Study Number PR&D 0073702 1) Type of Study: Dose confirmation study in cattle with induced gastrointestinal roundworm and lungworm infections. 2) Investigator: T.A. Yazwinski, Ph.D. University of Arkansas Fayetteville, AR 3) General Design: a.purpose: This study was designed to determine the effectiveness of Eprinomectin ERI against nematode infections induced at 100 and 120 days post-treatment. b. Animals: Thirty female Angus calves, approximately 5 months of age and weighing 168 to 257 kg, were ranked by decreasing body weights and allocated consecutively to 10 replicates of three animals each. Animals within each replicate were randomly assigned to one of three treatment groups. c.housing: These cattle were maintained in pens by treatment group. d. Infection: Each animal was inoculated per os with infective larvae of Trichostrongylus axei, Cooperia oncophora, and Cooperia
Page 27 punctata. A mixed culture was used for inoculation, which also included Ostertagia ostertagi, Haemonchus placei, and Oesophagostomum radiatum larvae. All nematode strains used in this experiment were 1 to 3 months old. e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 148 or 149 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection at 100 and 120 days is summarized in the following table: Table IIC.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Day 120 (Eprinomectin ERI on Day 0) 1 Day 100 (Eprinomectin ERI on Day 20) 2 Control Parasite n GM GM Effectiveness GM Effectiveness Cooperia oncophora 9 226.8 2.0 99.1% 6.8 97.0% Cooperia punctata 10 1143.2 2.2 99.8% 4.9 99.6% Ostertagia ostertagi 10 205.0 0.4 99.8% 0.6 99.7% Trichostrongylus axei 10 159.3 0.8 99.5% 0.5 99.7% 1 Animals were treated once with Eprinomectin ERI on Day 0 and artificially infected with nematode larvae (L3) on Day 120. 2 Animals were treated once with Eprinomectin ERI on Day 20 and artificially infected with nematode larvae (L3) on Day 120. 5) Adverse Reactions: No adverse reactions to treatment were noted.
Page 28 C.3 Study Number PR&D 0047301 1) Type of Study: Dose confirmation study in cattle with induced gastrointestinal roundworm and lungworm infections. 2) Investigators: S.R. Pitt, BVetMed, Ph.D., MRCVS B.J. Timms, MPhil., MSc., CBiol, MIBiol Merial, Highfield Research Centre Hertford, Hertfordshire, UK 3) General Design S. Rehbein, Dr. med. vet. habil., DipEVPC Merial GmbH, Kathrinenhof Research Center Rohrdorf, Germany a.purpose: This study was designed to determine the effectiveness of Eprinomectin ERI against nematode infections induced at 120 days posttreatment. b. Animals: Twenty male castrate Limousin and Limousin cross calves, approximately 5 to 7 months of age and weighing 154 to 191 kg, were ranked by decreasing body weights and allocated consecutively to 10 replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: These cattle were maintained in pens by treatment group. d. Infection: Experimentally induced nematode infections were used. Each animal was inoculated on Day 120 with infective third-stage larvae (L3) from the nematode species listed below: Table IIC.3.1: Inocula Number of infective Age of Strain Species larvae (Yrs) Cooperia oncophora/surnabada 10,700 7 Dictyocaulus viviparus 1,257 >20 Haemonchus contortus 6,830 5 Nematodirus helvetianus 5,010 5 Oesophagostomum radiatum 1,403 20 Ostertagia ostertagi/lyrata 10,760 7 Trichostrongylus axei 2,925 5 e. Dosage Form: Eprinomectin ERI
Page 29 f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 148 or 149 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection at 120 days is summarized in the following table: Table IIC.3.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia oncophora 9 2440.3 6.6 99.7 Cooperia surnabada 7 95.3 3.7 96.1 Dictyocaulus viviparus 9 77.4 0.0 100.0 Nematodirus helvetianus 9 965.8 8.7 99.1 Ostertagia ostertagi 9 3983.6 2.8 99.9 5) Adverse Reactions: No adverse reactions to treatment were noted. C.4 Study Number PR&D 0047302 1) Type of Study: Dose confirmation study in cattle with induced gastrointestinal roundworm and lungworm infections. 2) Investigator: S. Rehbein, Dr. med. vet. habil., DipEVPC Merial GmbH, Kathrinenhof Research Center Rohrdorf, Germany
Page 30 3) General Design: a. Purpose: This study was designed to determine the effectiveness of Eprinomectin ERI against nematode infections induced at 120 days posttreatment. b. Animals: Twenty male Pinzgauer calves, approximately 5 to 6 months of age and weighing 152 to 210 kg, were ranked by decreasing body weights and allocated consecutively to 10 replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: These cattle were maintained in pens by treatment group. d. Infection: Experimentally induced nematode infections were used. Each animal was inoculated on Day 120 with infective third-stage larvae (L3) or eggs (Trichuris spp. [ovine]) from the nematode species listed below: Table IIC.4.1: Inocula Species Number of infective larvae/eggs Age of Strain (Yrs) Bunostomum phlebotomum 1,500 4 C. curticei 10,000 4 C. punctata 10,000 5 Cooperia oncophora/surnabada 10,000 5 Haemonchus contortus 5,000 4 Nematodirus helvetianus 4,000 4 Ostertagia leptospicularis 10,000 6 Oesophagostomum radiatum 1,500 Unknown Oesophagostomum venulosum 1,500 4 Ostertagia ostertagi 10,000 4 Ostertagia spp. (ovine) 10,000 2 Strongyloides papillosus 200,000 <1 Trichostrongylus colubriformis 10,000 4 Trichostrongylus axei 10,000 5 Trichuris spp. (ovine) 1,000 <1 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight.
Page 31 h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied either 148 or 149 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection at 120 days is summarized in the following table: Table IIC.4.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Bunostomum phlebotomum 10 173.2 0.4 99.8 Cooperia oncophora 9 733.1 219.0 70.1 Cooperia punctata 10 2854.8 870.8 69.5 Cooperia surnabada 9 164.1 43.5 73.5 Dictyocaulus viviparus 10 202.2 0.6 99.7 Nematodirus helvetianus 10 587.5 89.1 84.8 Oesophagostomum 8 45.4 0.5 99.0 Ostertagia radiatum leptospicularis 10 5553.7 39.6 99.3 Ostertagia ostertagi 10 7433.4 42.2 99.4 Trichostrongylus axei 10 1382.8 349.3 74.7
Page 32 5) Adverse Reactions: No adverse reactions to treatment were noted. C5. Study Number PR&D 0047303 1) Type of Study: Dose confirmation study in cattle with inducedgastrointestinal roundworm and lungworm infections. 2) Investigators: R.E. Plue, D.V.M., M.S. G.C. Royer, D.V.M. Merial, Missouri Research Center Fulton, MO 3) General Design: J.E. Holste, D.V.M. Holste Biological and Pharmaceutical Services Columbia, MO a. Purpose: This study was designed to determine the effectiveness of Eprinomectin ERI against nematode infections induced at 120 days posttreatment. b. Animals: Twenty Holstein male calves, approximately 5.5 months of age and weighing 153 to 194 kg, were ranked by decreasing body weights and allocated consecutively to 10 replicates of two animals each. Animals within each replicate were randomly assigned to one of two treatment groups. c. Housing: These cattle were maintained in pens by treatment group. d. Infection: Experimentally induced nematode infections were used. Each animal was inoculated on Day 120 with infective third-stage larvae (L3) from the nematode species listed below. Table IIC.5.1: Inocula Number of Age of Strain Species infective larvae (Yrs)
Page 33 Bunostomum phlebotomum 1,545 5 Cooperia punctata 15,037 5 Cooperia oncophora/surnabada 15,111 6 Dictyocaulus viviparus 1,999 5 Haemonchus placei 7,048 6 Nematodirus helvetianus 6,029 6 Oesophagostomum radiatum 2,003 5 Ostertagia ostertagi 20,016 6 Trichostrongylus colubriformis 20,137 6 Trichostrongylus axei 15,061 6 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Vehicle containing no eprinomectin was administered at 1.0 ml per 110 lb (50 kg) body weight to provide 0 mg eprinomectin/kg body weight. i. Test Duration: All cattle were necropsied either 148 or 149 days posttreatment. j. Pertinent Measurements/Observations: Nematodes recovered from animals at necropsy were counted and identified. 4) Results: Effectiveness against parasite species with an adequate level of infection at 120 days is summarized in the following table: Table IIC.5.2: Therapeutic Effectiveness of Eprinomectin ERI Against Nematodes Parasite Number of Infected Control Animals Vehicle (Control) Eprinomectin Effectiveness (%) Geometric Mean Cooperia punctata 9 1708.2 3.7 99.8 Dictyocaulus viviparus 9 220.7 0.0 100.0 Haemonchus placei 9 650.3 49.2 92.4
Page 34 Oesophagostomum radiatum 9 101.1 0.4 99.6 Ostertagia ostertagi 9 7251.7 7.3 99.9 Trichostrongylus axei 9 415.1 141.9 65.8 5) Adverse Reactions: No adverse reactions to treatment were noted. C.6 Study Number PR&D 0128701 1) Type of Study Dose confirmation study in cattle with induced gastrointestinal roundworm infections.
Page 35 2) Investigator: M. Visser, Biol. Merial GmbH, Kathrinenhof Research Center Rohrdorf, Germany 3) General Design: a. Purpose: This study was designed to determine the effectiveness of Eprinomectin ERI against nematode infections induced at 120 days posttreatment. b. Animals: Sixteen Fleckvieh (Simmental) male calves, between 5 and 6 months of age and weighing 164 to 197.5 kg, were ranked by decreasing body weights and allocated consecutively to eight replicates of two animals each. Animals within each replicate were randomly assigned to separate groups. c. Housing: Individually stanchioned. d. Infection: Experimentally induced nematode infections were used. Each animal was inoculated on Day 120 with infective third-stage larvae (L3) from the nematode species listed below: Table IIC.6.1: Inocula Species Number of infective larvae Age of Strain (Years) Cooperia oncophora/surnabada 10,000 9 Cooperia punctata 10,000 9 Nematodirus battus 6,125 9 Ostertagia ostertagi/lyrata 10,000 9 Trichostrongylus axei 10,000 9 e. Dosage Form: Eprinomectin ERI f. Route of Administration: Single subcutaneous injection in the front of the shoulder. g. Dose: Eprinomectin ERI was administered once on Day 0 at 1.0 ml per 110 lb (50 kg) body weight to provide 1.0 mg/kg body weight. h. Controls: Saline was administered at 1.0 ml per 110 lb (50 kg) body weight. i. Test Duration: All cattle were necropsied 148 days post-treatment.