Why Do Cattlemen De-worm?

Extended-Release Injection Available from Veterinarians by Prescription Hoyt Cheramie, DVM, MS,DACVS Large Animal Veterinary Services Merial Limited 1 2 Seven Factors that Drive Profit in Cow/Calf 11 Weaned calf crop Sale weight Calf price Feed cost Interest Cull cow weight Cull cow price Why Do Cattlemen De-worm? Better weight gain Higher weaning weight: calves Improved body condition: cows Improved feed conversion Increased reproductive efficiency: cow & bull Increased milk production Improved carcass quality Greater immunity Decreased morbidity & mortality 3 4 What is Parasite Control Benefit? $201 per cow in breakeven cost Improvements in reproduction Increased weaned calf crop Earlier calving Decreased time from calving to conception by 12 days 20% more 1 st calf heifers pregnant after 1 st service Calf weaning weights More efficient average daily gains Earlier weight gains Lawrence JD, Ibarburu MA. Economic analysis of pharmaceutical technologies in modern beef production in a bioeconomy era. 2009. Iowa State University. Manage Cows for Reproduction 12 Length of Calving Season 140 Days 60 Days Calves Born in Number Weight Number Weight 1 st 20 days 25 540 50 540 2 nd 20 days 22 510 30 510 3 rd 20 days 18 480 20 480 4 th 20 days 12 450 5 th 20 days 10 420 6 th 20 days 8 390 7 th 20 days 5 360 Overall 100 478 lbs. 100 519 lbs. 1994 41 lbs $1.75 $7175 5 6 1

Cows Keep the Life-cycle Going Until the Calves are Grazing Well Deworming Cows in the Fall has Minimal Impact on Spring & Summer Infection Rates Dr Mike Hildreth South Dakota State University Dr Mike Hildreth South Dakota State University 7 8 Spring Treatment of Calves has Minimal Impact Parasite Management Effort and Focus 10% of the parasite population is in the animal 90% of the parasite population is on the pasture Spring Treatment of Cows Reduces Risk for Calves Throughout the Summer Dr Mike Hildreth South Dakota State University 9 10 What is the Opportunity Since 1949, we ve known that if parasite burdens are controlled in the pasture, they will be controlled in the herd 8 For decades, producers have treated cattle with products that include avermectins, levamisoles and benzimidazoles, none of which have provided adequate control without. multiple treatments necessitating extra handling of the cattle on pasture increasing the level of stress in the cattle creating more work and expense for the producer. Extended-Release Injection Available from Veterinarians by Prescription 11 12 2

This product opens a whole new parasite control category Contains eprinomectin and Theraphase An entirely new way to think about parasite control in cattle Treating cattle Treating pasture 100 to 150 days of parasite control with a single treatment 1 * *Dependent upon parasite species, as referenced in FOI summary and product label. Long enough to break the parasite life cycle uses the animal to help clean up the pasture 13 14 A list of firsts is the first product in this 100 to 150-day injection category In fact, is the first Extended-Release Injection approved by FDA is the first and only product with dual pharmacokinetic peaks is the first Extended-Release endectocide that can be used in beef cows as well as calves and stockers EPRINEX (eprinomectin) Pour-On Why EPRINOMECTIN? Arguably the best anthelmintic on the market >99-100% efficacy against 8 major economically relevant parasites of cattle (Eprinex FOI) >99% efficacy against cooperia sp Very good against external parasites A number of new parasite claims Broadest spectrum (39 species & stages) Not highly lipophilic 15 16 THERAPHASE 1-2,7 With LongRange we introduce Theraphase Technology Poly-Lactide-coGlycolic Acid PLGA organic biodegradable polymer The unique THERAPHASE Technology in creates one initial therapeutic peak of eprinomectin in the bloodstream immediately following injection Systemic levels then begin to decline, but remain well above the effective levels for approximately 70 days as the THERAPHASE matrix slowly releases eprinomectin Beginning around 70 days, the THERAPHASE matrix releases a second bolus of eprinomectin, creating a second peak of eprinomectin plasma levels As a result, is effective immediately and continues to provide effective levels against susceptible parasite species for up to 100 to 150 days* (eprinomectin) Theraphase Video *Dependent upon parasite species, as referenced in FOI summary and product label. 17 17 18 3

THERAPHASE 1,2 Pharmacokinetic Curve for IVOMEC EPRINEX (eprinomectin) Pour-On 8 Provides 100 to 150 days of parasite control* Helps address resistance concerns Calves and stockers can t grow away from the dose *Dependent upon parasite species, as referenced in FOI summary and product label. Plasma Concentration (ng/ml) 10.00 9.00 8.00 7.00 6.00 5.00 4.00 3.00 2.00 1.00 0.00 0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 Time Post-Treatment (Days) 19 20 versus Conventional Product Plasma Concentration (ng/ml) 30 25 20 15 10 Peak is 2.5 times higher; driving 4 fold increase in AUC Persistency Persistent activity Macrocyclic lactone cattle de-worming products have varying levels of persistency None approach the persistent activity of against eight economically important species of parasites SAFE-GUARD (fenbendazole) has not demonstrated persistent activity against cattle parasites 2-6 5 0 EPRINEX 0 20 40 60 80 100 120 140 Time Post Treatment (Days) 21 22 Persistency 7 (efficacy against incoming larvae) Persistency 7-8 (efficacy against incoming larvae) CYDECTIN (moxidectin) Injectable DECTOMAX (doramectin) Injectable TM Injectable CYDECTIN (moxidectin) Injectable DECTOMAX (doramectin) Injectable SMALL INTESTINAL WORM (C. oncophora) SMALL INTESTINAL WORM (C. punctata) STOMACH HAIRWORM BARBER S POLE WORM NODULAR WORM BROWN STOMACH WORM (O. ostertagi) BROWN STOMACH WORM (O. lyrata) LUNGWORM LUNGWORM SMALL INTESTINAL WORM (C. oncophora) SMALL INTESTINAL WORM (C. punctata) STOMACH HAIRWORM BARBER S POLE WORM NODULAR WORM BROWN STOMACH WORM (O. ostertagi) BROWN STOMACH WORM (O. lyrata) LUNGWORM 23 24 4

Persistent Claims against incoming L3s 100 Days: 120 Days: 150 Days: Cooperia oncophora Cooperia punctata Trichostrongylus axei Haemonchus placei Osophagostomum radiatum Ostertagia ostertagi Ostertagia lyrata Dictyocaulus viviparus Resistance What we do know: In 1983, some said because ivermectin is so effective, it would drive resistance Not until 2004 was the first of two well-documented cases reported 12 A stocker operation, intensive rotational grazing with 75 head per acre Today, they are grazing 700 head per acre Some will claim will drive resistance Others will point to the data 25 26 Resistance Pharmacokinetic Curve for IVOMEC EPRINEX (eprinomectin) Pour-On 8 Scientific articles show Extended Release products are effective against otherwise resistant parasites 13-15 These products increase the parasites exposure to the drug By either having a large Area Under the Curve Or by having a very high initial PK peak has both a high initial peak and a large AUC Plasma Concentration (ng/ml) 10.00 9.00 8.00 7.00 Head 6.00 5.00 Tail 4.00 3.00 2.00 1.00 0.00 0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 Time Post-Treatment (Days) 27 28 30.00 25.00 20.00 15.00 PK peak 2.5 times and AUC 4 times greater than that of EPRINEX. is no more likely to select for resistance than a single treatment with a conventional dewormer 16-17 However, with its high peak and large area under the curve, it s likely to be more effective against otherwise resistant parasites 16 10.00 5.00 Same short tail 0.00 0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 29 30 5

120-day Parasite Control Studies 7 Time Period Analysis of Variance Results for Body Weight Gain Control Mean (lbs.) Mean (lbs.) Weight Gain (lbs.) P-value * 0 to 28 Days 46.2 58.9 12.7 <0.0001 0 to 56 Days 85.3 109.9 24.6 <0.0001 0 to 84 Days 106.9 138.9 32.0 <0.0001 0 to 120 Days 151.1 190.2 39.1 <0.0001 *P-value from ANOVA F-test Average gains from 7 studies conducted in Idaho, Louisiana, Arkansas, Missouri, Minnesota, Oregon and Wisconsin in stocker weight calves Control calves received no treatment Dosing and Safety Administration and dosing 1 Body weight (lbs.) Dose volume (ml) 110 1 220 2 330 3 440 4 550 5 660 6 770 7 880 8 990 9 1,100 1,210 1,320 10 11 12 31 32 Dosing Proper injection site 2 BQA guidelines Packaging 50 ml 12/case 250 ml 6/case 500 ml 6/case 33 34 Dosing and Safety 50mL Extended-Release Injection Available from Veterinarians by Prescription is only for SC administration. Only use polypropylene syringes. Not for use with polycarbonate syringe material. If you do not know the material of your syringe equipment, contact the manufacturer before use with. Using a 16 or 18 gauge needle, ½-inch to ¾-inch needle, should be injected under the loose skin in front of the shoulder, as seen on the previous slide. Be sure animals are properly restrained to ensure correct SC administration. 50mL bottle sizes: Do not use beyond three months after the stopper has been punctured. Discard after 15 stopper punctures. Use sterile equipment and sanitize the injection site by applying a suitable disinfectant. Clean, properly disinfected needles should be used to reduce the potential for injection site reactions. No special handling or protective clothing is necessary. 35 36 6

Dosing and Safety 250 ml & 500 ml Dosing and Safety target animal safety 2 250 ml and 500 ml bottle sizes: Use only automatic syringe equipment provided by Merial. should not be stored in automatic syringe equipment. Discard bottle after one stopper puncture with draw-off spike. Automatic syringe equipment should be thoroughly cleaned after each use. No special handling or protective clothing is necessary. Clinical studies have demonstrated the wide margin of safety of Overdosing with at three to five times the recommended dose resulted in a statistically significant reduction in average weight gain when compared to the group treated with at the recommended label dose Treatment-related lesions observed in cattle treated with three and five times the labeled dose rate of included swelling, hyperemia or necrosis in the subcutaneous tissue of the skin No adverse reproductive effects were observed following administration of at three times the recommended therapeutic dose to beef cows at all stages of breeding, pregnancy or nursing calves 37 38 Dosing and Safety Not for use in bulls, as reproductive safety testing has not been conducted in males intended for breeding or that are actively breeding Not for use in calves less than three months of age because safety testing has not been conducted in calves younger than three months This drug product is not approved for use in female dairy cattle 20 months of age or older, including dry cows A withdrawal period has not been established for pre-ruminating calves. Do not use in calves to be processed for veal Animals intended for human consumption must not be slaughtered with in 48 days of the last treatment Dosing and Safety Environmental Hazards 2 As with other avermectins, eprinomectin is excreted in the dung of treated animals and can inhibit the reproduction and growth of pest and beneficial insects that use dung as a source of food and for reproduction. The magnitude and duration of such effects are species and life-cycle specific. When used according to label directions, the is not expected to have an adverse affect on populations of dung-dependent insects. 39 40 Feedlot and Management-Intensive Grazing Disclaimer for feedlots and intensive rotational grazing operations Cattle managed in feedlots and intensive rotational grazing operations should not be treated with the environmental impact for these scenarios has not been evaluated Merial believes the market will have very little interest in using in cattle confined to a dry lot feeding situation Management-intensive rotational grazing operations can be defined as grazing strategies employing grazing periods of fewer than four days and stocking densities greater than 50,000 pounds of live weight per acre The Ultimate Parasite Solution The ultimate goal of any parasite control program should be to allow your cattle the best performance possible while managing the persistent parasite threat on your pasture makes it possible with a single treatment that lasts up to 100 to 150 days 41 42 7

REFERENCES 1 Dependent upon parasite species, as referenced in FOI summary and product label. 2 product label. 3 CYDECTIN Injectable product label. 4 DECTOMAX Injectable product label. When used at turnout, protects cattle against infective larvae on the pasture longer than any other product. 2 5 SAFE-GUARD product label. 6 SAFE-GUARD product label and FOI summary. 7 Based on competitive product labels and FOI summaries. 8 Rehbein S, Visser M, Kellermann M, Letendre L. Reevaluation of efficacy against nematode parasites and pharmacokinetics of topic eprinomectin in cattle. Parasitol Res. 2012; DOI 10.1007/s00436-012-2970-2. 9 Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers. 2011;3:1377-1397. 10 Lewis, DH. Biodegradable polymers as drug delivery systems, controlled release of bioactive agents from Lactide/Glycolide polymers, in biodegradable polymers as drug delivery systems. (Ed) M. Chasin, and R. Langer, Marcel Dekker: New York. 1990;1-43. 11 Crotts G, Park TG. Protein delivery from poly(lactic-co-glycolic acid) biodegradable microspheres: release kinetics and stability issues. J. Microencapsulation. 1998;15(6):699-713 12 Smith LL, Gasbarre LC. Evaluation of individual or a combination of anthelmintics in a commercial cattle population where anthelmintic resistant parasites had been observed the previous year [abstract]. Am Assoc Vet Para Pro. 2005:63. 13 Rehbein S, Barth D, Cramer LG, Soll MD. Efficacy of the IVOMEC SR Bolus against macrocyclic lactone resistant Cooperia spp. in cattle. Proceedings of 20th World Buiatrics Congress. 1998;769:1-2. 14 Yazwinski T, Edmonds J, Edmonds M, Tucker C, Johnson E. Treatment of subclinical nematodiasis in Idaho stocker cattle with CYDECTIN long-acting injectable or IVOMEC injectable. Intern J Appl Res Vet Med. 2006;4:3. 15 Yazwinski T, Tucker C, PhD, Johnson Z, Powell J. Field trial evaluation of the effectiveness and benefit of CYDECTIN long-acting injectable and IVOMEC injectable as used one time in grazing stocker cattle. Vet Ther. 2006;7:1. 16 Dobson RJ, Lejambre L, Gill J. Management of anthelmintic resistance: inheritance of resistance and selection with persistent drugs. Int J Parasitol. 1996;26(8/9):993-1000. 17 Toutain PL, Upson DW, Terhune TN, McKenzie ME. Comparative pharmacokinetics of doramectin and ivermectin in cattle. Vet Parasitol. 1997;72:3-8. IVOMEC, EPRINEX and The CATTLE HEAD LOGO are registered trademarks, and TM and THERAPHASE are trademarks, of Merial Limited. All other marks are the property of their respective owners. 2012 Merial Limited, Duluth, GA. All rights reserved. RUMIELR1244 (12/12) 43 44 8