Summary•LUTALYSE®(dinoprost tromethamine)SterileSolutioncontainsthenatural prostaglandinF2α(dinoprost)asatromethaminesalt,whereascloprostenolisan analogueofprostaglandinF2α.

•Althoughactiveingredientsandtheirpropertiesdifferbetweenthetwoproducts, bothLUTALYSEandcloprostenolinduceluteolysisbytriggeringacascadeof endogenouseventsthatultimatelyleadtotheregressionofthecorpusluteum(CL).

•Collectively,datainthescientificliteratureindicatestherearenodifferencesin efficacybetweenLUTALYSEandcloprostenol.TheU.S.FoodandDrugAdministration (FDA)confirmedthisconclusionina2010communicationtoIntervet/Schering-Plough.

•ThebenefitsofusingLUTALYSEextendbeyondthecontentsofthevial.LUTALYSEisthemostresearchedprostaglandinintheU.S.andisbackedbytheZoetisFieldForce,thelargestofitskindintheindustry.TheunparalleledsupportthatcustomersofLUTALYSEreceivemakesittheundisputablemarketleaderandtheprostaglandinofchoicetocattleproducers.

LUTALYSE® and cloprostenol:Clearing up misconceptionsFred Moreira, DVM, MS, Ph.D.Zoetis

LUTALYSE® (dinoprost tromethamine) Sterile Solution has been approved for

synchronization of estrus in cattle for more than 30 years. It has been the most widely used prostaglandin product since its launch and is the trusted foundation of breeding programs across the country. Zoetis, the makers of LUTALYSE have invested heavily in research to understand all aspects of the biology and practical use of LUTALYSE under commercial conditions. This has not only furthered understanding of LUTALYSE but also has helped move reproductive management forward within the U.S. dairy industry.

Nonetheless, competitive suppliers have pursued advertising and sales messaging that suggest LUTALYSE is not as efficacious as cloprostenol or does not work under modern conditions. Intervet/Schering-Plough (now known as Merck Animal Health), which markets cloprostenol as Estrumate®

(cloprostenol sodium) in the U.S., was the source of this misleading messaging. FDA issued communication Sept. 16, 2010, ordering Intervet/Schering-Plough to immediately cease and desist claims of biological superiority in comparison with LUTALYSE, as these claims have not been demonstrated by substantial evidence or substantial clinical experience.

Doug Hammon, DVM, Ph.D.Zoetis

LUT13004ZOETIS

TECHNICAL BULLETINMarch 2012

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LUTALYSE® (dinoprost tromethamine) Sterile Solution, cloprostenol and other prostaglandins have been researched in hundreds of published studies. From time to time, any one particular trial may show one prostaglandin product is numerically superior to the other by chance. These differences may even be significant in some cases. Most times, the very same data do not indicate a statistical difference between the two products, just a numerical difference that it is unduly interpreted as relevant. FDA addressed these superiority claims and determined them to be unsubstantiated.

The data in the scientific literature overwhelmingly indicate there are no differences in efficacy between LUTALYSE and cloprostenol. The objective of this technical bulletin is to provide a review of the science and peer-reviewed, published data on LUTALYSE and the other prostaglandins.

Chemical StructuresLUTALYSE contains the naturally occurring prostaglandin F2α (PGF2α; dinoprost) as a tromethamine salt. Its chemical structure is depicted in Figure 2. Each milliliter of LUTALYSE contains dinoprost tromethamine equivalent to 5 mg of dinoprost. Dose titration studies have indicated 25 mg of dinoprost (i.e., 5 mL of LUTALYSE) is the most appropriate dose.

The route of administration is intramuscular, whereas the intravenous administration of LUTALYSE is contraindicated. The subcutaneous route has not been fully examined; it is not an approved route of administration and, therefore, is not recommended.As with all parenteral products, aseptic technique should be used to reduce the possibility of post-injection bacterial infections. Do not administer in pregnant animals unless cessation of pregnancy is desired. Not for intravenous administration. Women of childbearing age and persons with respiratory problems should exercise extreme caution when handling this product.In the U.S., cloprostenol is sold as Estrumate®

and the generic product called estroPLAN®, which contains cloprostenol sodium, a salt form of the synthetic analogue. The original chemical structure of PGF2α (Figure 2) was modified to result in cloprostenol. Each milliliter of Estrumate contains 250 mcg of cloprostenol equivalent. The suggested dose of Estrumate is 2 mL, to be used intramuscularly.Due to these structural modifications, cloprostenol has some different properties when compared with dinoprost. Cloprostenol does have a higher affinity for the PGF2α receptor, and there are indications it may have a slightly longer half-life. However, as indicated below, these attributes do not correlate with a higher efficacy to synchronize estrus in cattle.Also noteworthy is the fact that cloprostenol, as it relates to its optical orientation, is a racemic solution. That means it can be either dextrorotatory (D-) or levorotatory (L-). It was observed that only D-cloprostenol binds to the prostaglandin receptors. In some countries, companies started producing the D- form and selling the concept that this is the reason why “now” cloprostenol works better than dinoprost. Unless recent modifications were introduced, Estrumate remains a racemic solution.

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LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol.Figure 2 – Chemical structures of PGF 2a (dinoprost) and cloprostenol sodium.

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Figure 1 – Number of original research articles since 1994 published in the Journal of Animal Science, Journal of Dairy Science and Theriogenology that reported use of prostaglandins. LUTALYSE was the prostaglandin product cited in 87% (186/214) of the references.

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The Luteolytic ProcessThe complete regression of the CL is the main objective to be achieved after an injection of PGF2α or its analogues. The regression of the CL and the consequent decrease in progesterone concentration allow for the final maturation of the pre-ovulatory follicle and for an increase in the circulating levels of estradiol.The rise in estradiol concentrations stimulate the immune system in the uterus and leads to a surge of luteinizing hormone (LH) release that will induce ovulation. These events ultimately are responsible for the main indications of prostaglandins:• Synchronization of estrus in cattle• Treatment of uterine infections such as pyometra• Induction of abortion in pregnant cattleThe series of illustrations to the right demonstrate the events that occur in the reproductive tract following an injection of PGF2α or its analogues.As described in Figures 3A-3D, the initial injection of PGF2α simply triggers the events that ultimately will lead to the regression of the CL and to the decrease of progesterone concentrations.

Effects on Progesterone ConcentrationThe decrease in progesterone concentration is the signal for the increase in estradiol, which will induce estrous behavior. Thus, when comparing the efficacy of LUTALYSE® (dinoprost tromethamine) Sterile Solution and cloprostenol, researchers measured the ability of each prostaglandin to decrease progesterone concentrations. Seguin, et al. (1985), injected nonlactating dairy cows with either LUTALYSE (n=62) or cloprostenol (n=62) and measured plasma progesterone concentrations at 0, 2, 4, 8, 12, 24 and 48 hours after treatments (see Table 1, Page 4). In a recent study in lactating dairy cows (n=1264, Experiment 1; n=427, Experiment 2), Stevenson, et al. (2010), measured progesterone in cows receiving either LUTALYSE or cloprostenol and measured progesterone concentrations at 0, 48 and 72 hours after treatment. In Experiment 1, LUTALYSE increased luteal regression, based on blood progesterone concentrations, from 86.6 percent to 91.3 percent (P<0.05) compared with cloprostenol.

Figure 3A – This depicts the reproductive tract with the uterine body, uterine horns, oviducts, and right and left ovaries are in blue. A corpus luteum (CL; in orange) is depicted on the right ovary, and a dominant follicle is shown (in red) on the left ovary. The CL in the right ovary is actively producing progesterone. Secretion of estradiol by the dominant follicle is low, due to the high concentrations of progesterone secreted by the CL.

Figure 3B – The events that follow an injection of PGF2a: the injected PGF2a reaches the CL (1) and functions as a “trigger” that induces the secretion of oxytocin from the CL (2). Oxytocin secreted by the CL reaches the uterus and stimulates the release of endogenous PGF2a (3). The endogenous PGF2a goes back to the CL and induces the release of more oxytocin.

Figure 3C – The continuous PGF2a- oxytocin cycle is triggered by the initial injection of PGF2a. The oxytocin produced by the CL continues to stimulate the secretion of endogenous PGF2a by the uterus, which further stimulates the secretion of oxytocin by the CL in a classic feedback mechanism. As the CL regresses, concentrations of progesterone decrease. This cycle continues until the CL is completely regressed.

Figure 3D – In Figure 2D, at the end of the feedback cycle, the CL is completely regressed and, in its place, there only remains a scar (corpus albicans). Since progesterone is not being produced, secretion of estradiol from the dominant follicle is increased. Estradiol will reach behavioral centers in the brain and stimulate estrous behavior. Estradiol will also induce a surge of luteinizing hormone (LH) that leads to ovulation.

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In Experiment 2, LUTALYSE® (dinoprost tromethamine) Sterile Solution increased luteal regression from 69.1 percent to 75.8 percent (P<0.05) compared with cloprostenol in cows with one or more CL, regardless of the number of CL present (Table 2).Data in Table 1 indicate there is no difference in the rate of progesterone decline after treatments with either LUTALYSE or cloprostenol. In his 1984 study, Johnson also reported no differences in the decline of milk progesterone concentrations at 48 hours following injections of LUTALYSE or cloprostenol in lactating dairy cows. However, Stevenson, et al. (2010), reported that a higher (P<0.01) proportion of cows with blood progesterone concentrations ≥1 ng/mL prior to treatment had low (<1 ng/mL) blood progesterone 72 hours after treatment when treated with LUTALYSE compared with cloprostenol.In a 1988 study, Guay, et al., measured both serum progesterone and estradiol concentrations at 0 and 24 hours after LUTALYSE or cloprostenol treatment in Holstein heifers that had been submitted to a superovulation treatment. Results (Table 3) also indicate there is no difference in the ability of LUTALYSE and cloprostenol to induce CL regression.Concentration of estradiol — which induces onset of estrous behavior — also did not differ between treatments. Thus, there is no defensible physiological reason for the intensity or duration of estrous behavior to differ following injections of LUTALYSE or cloprostenol.

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*ND=valuesbelowassaydetectionlimits.

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1Percentageofanimalsdetectedinestrusrelativetothetotalnumberofanimalswithineachgroup.2Percentageofanimalsthatconceivedrelativetothenumberofanimalsinseminated.3Percentageofanimalsthatconceivedrelativetothetotalnumberofanimalswithineachgroup.4Typeofcattleusedinthestudy(LDC=lactatingdairycows;NLDC=nonlactatingdairycows;BC=beefcows;BH=beefheifers;DH=dairyheifers).

5Numberofanimalsincludedintheexperiment.

6NS=differenceswerenotstatisticallysignificant.7IncludesonlycowsinjectedwithLUTALYSEandcloprostenolintramuscularly.8IncludesbothintramuscularandintravenousrouteofadministrationforLUTALYSEandcloprostenol.

Table 2 – Proportion of cows undergoing luteal regression by 72 hours after treatment and percent pregnant following AI in cows treated with Lutalyse or cloprostenol as part of a timed-AI protocol.

Reference Herds (n) N Luteal regression1 Pregnancy rate at 72h (%) 2 (%)

LUTALYSE Cloprostenol P LUTALYSE Cloprostenol P

Stevenson, et al., 2010 6 1,264 91.3 86.6 P<0.05 37.8 36.7 NSExperiment 1

Stevenson, et al., 2010 1 427 78.5 69.1 P<0.05 32.8 31.3 NSExperiment 2

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*NS=differenceswerenotsignificant.

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Fertility of Cattle Treated with LUTALYSE or CloprostenolPeer-reviewed studies that compared the efficacy of LUTALYSE® with cloprostenol to synchronize estrus in cattle are summarized in Table 4 (on page 4).Results from every study and the overall interpretation from the collective data point to the same conclusion: There are no differences in the efficacy between LUTALYSE® (dinoprost tromethamine) Sterile Solution and cloprostenol to synchronize estrus in cattle.

LUTALYSE and Cloprostenol Effects on Synchrony of EstrusThere are no differences in the tightness of estrous synchronization following injections of LUTALYSE or cloprostenol. This was the common interpretation of data reported by research groups that compared both products (see Figure 4).Data depicted in Figure 4 indicate the lack of difference in efficacy of LUTALYSE and cloprostenol to induce estrus in beef heifers according to the 2002 study by Salverson, et al. This is an important observation because this was a multilocation study (n=5) that included a relatively large number of heifers (n=1002). Authors concluded that LUTALYSE and cloprostenol were equally efficacious for synchronous induction of a fertile estrus. Similarly, in nonlactating Holstein cows, in the 1985 study by Seguin, et al., and in Angus cows and heifers in the 1987 study by Turner, et al., researchers did not observe any differences in tightness of estrous synchronization between LUTALYSE and cloprostenol. The interval from prostaglandin treatment to estrus during superovulation treatments of dairy heifers did not differ between LUTALYSE (50.46 + 2.3 hours) and cloprostenol (45.33 + 1.65 hours) according to the 1990 study by Desaulniers, et al. The latter research group also did not observe differences in the interval from treatment with LUTALYSE or cloprostenol treatment to estrus (7.4 + 0.34 day and 7.58 + 0.35 day, respectively) in previously superovulated heifers that had multiple corpora lutea. Suggestions that cloprostenol induces a tighter synchronized estrus or that cloprostenol-treated cattle exhibit estrous behavior quicker than when injected with LUTALYSE are inaccurate.

Frequently Asked Questions on the Effects of LUTALYSE Versus CloprostenolBecause the overall interpretation of published data is that LUTALYSE® (dinoprost tromethamine) Sterile Suspension and cloprostenol have the same level of efficacy to synchronize estrus in cattle, questions have been raised about differences under very specific circumstances. Some of those are addressed below.

1. Does cloprostenol induce a “stronger” heat than LUTALYSE?

There is no physiological reason for such an effect. Prostaglandins do not induce estrus directly as discussed above. Rather, prostaglandins induce estrus by inducing luteolysis and decreasing progesterone concentrations in the blood. The reduction in progesterone concentrations allows the pre-ovulatory follicle to increase its production of estradiol, which will induce estrous behavior. As indicated above in the 1988 study, Guay, et al., reported no differences in estradiol concentrations at 24 hours after injections of LUTALYSE or cloprostenol.It has been reported that concentrations of estradiol at estrus are reduced in lactating dairy cows, especially cows with high milk production. This reduction of estradiol concentrations was associated with increased steroid metabolism in the liver, resulting in dairy cows expressing estrus with less intensity and duration. Such an

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Figure 4 – Distribution of estrus in virgin beef heifers (n=1002) injected with LUTALYSE or cloprostenol. Adapted from Salverson, et al., 2002.

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observation has not been reported in dairy heifers or in beef cattle. This situation in dairy cows is not associated with the efficacy of LUTALYSE® (dinoprost tromethamine) Sterile Solution, cloprostenol or any other prostaglandin product. Suggestions that switching from LUTALYSE to cloprostenol would correct the current situation in dairy cows because cloprostenol induces a “stronger” heat are unsubstantiated.In addition, messages suggesting Estrumate produces a stronger heat because of prolonged half-life are unsubstantiated. This conclusion was drawn from research conducted in swine. Estrumate is approved for use in cattle only and thus any conclusions drawn from research in other species are irrelevant. FDA called use of these half-life values as not relevant and serving only to exaggerate the differences between Estrumate and LUTALYSE.

2. Does the dose of LUTALYSE need to be increased for large-framed cattle?

Questions regarding dose or opinions that a higher dose is necessary are typically associated with poor results in reproductive performance without an apparent explanation. Frustrated producers and veterinarians may be inclined to shift the blame to product efficacy. Despite this, there are no conclusive data that support the recommendation for a higher dose of LUTALYSE in large-framed cattle. A recent study by Stevenson, et al. (2010), reinforced this conclusion. Rates of luteolysis or pregnancy in 1,264 lactating dairy cows from multiple dairy operations were evaluated after either LUTALYSE or cloprostenol was injected as part of a timed-insemination program. This study reported that LUTALYSE increased (P< 0.05) the proportion of cows with luteal regression compared with cloprostenol. The percent of cows pregnant after the first artificial insemination (AI) service was not different.

Dose titration studies conducted in both heifers and adult cows have indicated the label dose (25 mg; 5 mL) is the most effective one. In the 1985 study, Seguin, et al., categorized cows according to weight (from less than 1,000 pounds to more than 1,500 pounds) and concluded there was no evidence that larger cows had more response problems or that there were differences in efficacy of LUTALYSE and cloprostenol according to cow weight. One 2003 study in Europe by Répási, et al., compared the efficacy of the label dose of dinoprost (25 mg; n=20) versus a higher dose (35 mg; n=19) in adult lactating dairy cows. Cows were more than 40 days postpartum and were diagnosed to have a CL by ultrasound. Researchers detected no significant differences between the two doses, their effects on CL regression (area of luteal tissue measured by ultrasound) or on rate of decrease of progesterone concentrations. Differences between the 25 mg and the 35 mg dose also were not observed in estrous-detection rates (95 percent and 84.2 percent, respectively) and conception rates (31.6 percent and 31.2 percent, respectively).

3. Do I need to inject a higher dose of LUTALYSE® (dinoprost tromethamine) Sterile Solution in timed-artificial-insemination (AI) programs?

It was observed that between 5 percent and 19 percent of cattle submitted to timed-AI programs such as Ovsynch® may fail to regress their CL following injection of prostaglandins. Such failure was associated with reduced pregnancy rates to timed insemination. Because the initial injection to induce an LH surge in an Ovsynch program causes more cows to have two corpora lutea when they receive prostaglandin treatment seven days later, researchers initially believed there might be a need to increase the dose of LUTALYSE to reduce the frequency of CL regression failures.

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*Nodifferencesinpregnancyrateswereobserved.

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Although studies with higher doses of LUTALYSE were conducted, no trials directly compared the efficacy of label versus higher doses on timed-insemination success. Comparisons of results from different studies are not appropriate due to the many other factors that impact product performance. However, the use of higher doses of LUTALYSE did not seem to induce significant increases in pregnancy rates to timed insemination. As a result, the same research groups that initially started using higher doses of LUTALYSE chose to use the label-recommended dose in more recent studies.Most likely, the use of higher doses of LUTALYSE — or cloprostenol — in timed-insemination programs either does not result in increased pregnancy rates or the magnitude of the benefit is so small it would be too difficult to detect. Thus, the current recommendation is the label dose of LUTALYSE (25 mg) is the most appropriate for timed-AI programs. Furthermore, Stevenson, et al. (2010), showed LUTALYSE administered at the label dose is effective in inducing CL regression when used in timed-AI protocols across multiple dairy operations, and the proportion of cows pregnant following first AI was not different for LUTALYSE versus cloprostenol.

4. Which product works better for timed-AI programs?

For the reasons cited in the answer above, failure of complete CL regression was judged to be associated with reduced efficacy of LUTALYSE. These opinions indicated either the dose of LUTALYSE® (dinoprost tromethamine) Sterile Solution needed to be increased or cloprostenol was more effective in timed-AI programs.This specific question was addressed by the 2003 study by Hiers, et al. Nonlactating beef cows

(mostly Bos indicus x Bos taurus) were treated with the CoSynch program with concurrent heat suppression. All cows received an injection to induce an LH surge on Day 0, then heat was suppressed on Days 1 to 7, and at Day 7 cows received either an injection of LUTALYSE, an injection of cloprostenol or a half-dose of LUTALYSE at Day 7 and another half-dose at Day 8 (split-dose). All cows received a second injection to induce an LH surge and were timed- inseminated at Day 9 (approximately 72 to 80 hours after heat suppression). Results are depicted in Table 5. No differences in pregnancy rates were observed for the treatment groups. This is in agreement with work by Stevenson, et al. (2010), who showed the proportion of cows pregnant following timed AI across multiple herds was not different for LUTALYSE versus cloprostenol.

5. Does cloprostenol work better than LUTALYSE in Bos indicus cattle?

Data do not support any claims of improved performance of cloprostenol in Bos indicus cattle. There is some evidence that Bos indicus breeds and their crosses are more refractory to prostaglandin treatments in general. Cows close to Days 5 and 6 of the estrous cycle are said to be a greater problem for Bos indicus. The opinion is cloprostenol would be more effective at that specific stage of the cycle. The data above in the 2003 study by Hiers, et al., indicated no differences in efficacy between LUTALYSE and cloprostenol in Bos indicus crosses. Authors went further and indicated that in a preliminary study with Bos indicus crosses, results suggested there were no differences in the ability to induce luteolysis as measured by the decrease in progesterone concentrations after injections of LUTALYSE or cloprostenol. Once more, there is no indication that cloprostenol would have greater efficacy than LUTALYSE.

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If efficacy is the same, why choose LUTALYSE?Efficacy is not the only consideration in product choice among producers and veterinarians. It is important to recognize the benefits to using LUTALYSE® (dinoprost tromethamine) Sterile Solution extend beyond the product itself. Consider below the reasons that LUTALYSE is the undisputable market leader:1) Product support: Zoetis provides expertise on capturing the most value from a dairy producer’s investment. The team of technical experts supporting Zoetis products work with customers and their veterinarians to effectively incorporate each solution into the dairy’s reproductive protocols. This ensures producers are protecting reproductive efficiency and capturing an effective return on investment. And more important, this ensures the reproductive program is designed to get cows bred and protect the growing fetus from reproductive disease.2) Research backing: LUTALYSE is the most researched and studied prostaglandin in the marketplace. A review of scientific publications conducted in the U.S. in the past 10 years clearly shows the depth of research of LUTALYSE as compared with other brands. The vast majority of those scientific studies were conducted with Zoetis support, demonstrating the company’s commitment to the understanding of all aspects of the biology and practical use of LUTALYSE under commercial conditions.What does that mean to customers? That means through research and practical experience, Zoetis personnel know better than any of our competitors how to make LUTALYSE work for our customers’ operations. This means we have the answers producers and veterinarians are looking for, and those answers are rooted in solid scientific data. Zoetis is committed to support research and will continue to provide the most current information to customers.3) Reproductive solution: Prostaglandins are an integral part of any reproductive program, but there is more to reproductive programs than prostaglandins. Backed by years of proven success, Zoetis products are the leading choice of dairy producers across the country and can help improve the efficiency of a reproductive program. In addition to LUTALYSE, Zoetis has a complete line of reproductive solutions, including FACTREL® (gonadorelin hydrochloride) Sterile Solution and Eazi-Breed™ CIDR® Cattle Insert.

LUTALYSE is the only prostaglandin product approved for use in synchronization protocols with Eazi-Breed CIDR Cattle Insert. A synchronization program, including leading products from Zoetis, can improve the efficiency and success of breeding programs.

ConclusionData in the scientific literature conclusively indicate there is no difference in efficacy or product performance between LUTALYSE and cloprostenol. As discussed, there are a large number of peer-reviewed, published articles by many respected researchers that continue to demonstrate this point, with research published as recently as 2010. Other messages indicating differently are a misinterpretation of the science. FDA has shown it will not tolerate any misinterpretation or misuse of science to draw unsubstantiated conclusions.Ultimately, the backbone of a successful reproduction program is much broader than just the prostaglandin used. Zoetis technical experts are among the most respected in the dairy industry and are consistently sought-after speakers. When choosing products from Zoetis, producers are not only choosing innovative and market-leading formulas but also our commitment to providing solutions necessary for a dairy operation to survive.Zoetis is committed to providing veterinarians with products that carry the most robust label claims that science can validate. Our promise is that science will validate every claim for every one of our products. We are committed to continued research on the physiological activity of LUTALYSE as well as supporting ongoing scientific research that veterinarians and producers need to make appropriate decisions about the use of prostaglandins in their herds. As we learn more about the science behind LUTALYSE® (dinoprost tromethamine) Sterile Solution, we will continue to pursue new approved label indications for its use.

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ReferencesDesaulniers DM, Guay P, Vaillancourt D. Estrus induction with prostaglandin F2α, cloprostenol or fenprostalene during the normal estrous cycle, superovulation and after embryo collection. Theriogenology 1990;34(4):667-682.

Guay P, Rieger D, Roberge S. Superovulatory and endocrine responses in Holstein heifers treated with either prostaglandin F2α, cloprostenol or fenprostalene. Theriogenology 1988;29(5):1193-1199.

Hiers EA, Barthle CR, Dahms MKV, Portillo GE, Bridges GA, Rae DO, et al. Synchronization of Bos indicus x Bos taurus cows for timed artificial insemination using gonadotropin-releasing hormone plus prostaglandin F22α in combination with melengestrol acetate. J Anim Sci 2003;81(4):830-835.

Johnson AP. Response to prostaglandin therapy by lactating dairy cows with unobserved estrus. Veterinary Medicine 1984;4:555-557.

Martineau R. Dinoprost versus cloprostenol: Does route of injection modulate their efficacy in dairy cattle? Bovine Practitioner 2003;37:10-19.

Répási A, Beckers JF, Sulon J, Perényi Z, Reiczigel J, Szenci O. Effect of different doses of prostaglandin on the area of corpus luteum, the largest follicle and progesterone concentration in the dairy cow. Reprod Do Anim 2003;38(6):423-428.

Salverson RR, DeJarnette JM, Marshall CE, Wallace RA. Synchronization of estrus in virgin beef heifers using melengestrol acetate and PGF2α: an efficacy comparison of cloprostenol and dinoprost tromethamine. Theriogenology 2002;57(2):853-858.

Seguin B, Momont H, Baumann L. Cloprostenol and dinoprost tromethamine in experimental and field trials treating unobserved estrus in dairy cows. Bovine Practitioner 1985;20:85-90.

Stevenson JS, Phatak AP. Rates of luteolysis and pregnancy in dairy cows after treatment with cloprostenol or dinoprost. Theriogenology 2010;73(8):1127-1138.

Turner TB, Peterson GA, Davis ME, Wilson GR, Irvin KM, Forry JT. Synchronization of estrus in beef cows and heifers with fenprostalene, cloprostenol sodium, and prostaglandin F2α. Theriogenology 1987;28(1):15-24.

U.S. Food and Drug Administration, Department of Health and Human Services. RE: NADA 113-645 Estrumate® (cloprostenol sodium) Injectable Solution, September 16, 2010. Retrieved October 22, 2010, from www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/ComplianceEnforcement/cucm226544.htm.

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LutaLyse®

brand of dinoprost tromethamine sterile solutionCaution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

For intramuscular use for estrus synchronization, treatment of unobserved (silent) estrus and pyometra (chronic endometritis) in cattle; for abortion of feedlot and other non-lactating cattle; for parturition induction in swine; and for controlling the timing of estrus in estrous cycling mares and clinically anestrous mares that have a corpus luteum.

DesCRIPtION This product contains the naturally occurring prostaglandin F2 alpha (dinoprost) as the tromethamine salt. Each mL contains dinoprost tromethamine equivalent to 5 mg dinoprost: also, benzyl alcohol, 16.5 mg added as preserva-tive. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. Dinoprost tromethamine is a white or slightly off-white crystalline powder that is readily soluble in water at room temperature in concentrations to at least 200 mg/mL.General Biologic activity: Prostaglandins occur in nearly all mammalian tissues. Prostaglandins, especially PGE’s and PGF’s, have been shown, in certain species, to 1) increase at time of parturition in amniotic fluid, maternal placenta, myometrium, and blood, 2) stimulate myometrial activity, and 3) to induce either abortion or parturition. Prostaglandins, especially PGF2a, have been shown to 1) increase in the uterus and blood to levels similar to levels achieved by exogenous administration which elicited luteolysis, 2) be capable of crossing from the uterine vein to the ovarian artery (sheep), 3) be related to IUD induced luteal regression (sheep), and 4) be capable of regressing the corpus luteum of most mammalian species studied to date. Prostaglandins have been reported to result in release of pituitary tropic hormones. Data suggest prostaglandins, especially PGE’s and PGF’s, may be involved in the process of ovulation and gamete transport. Also PGF2a has been reported to cause increase in blood pressure, bronchocon-striction, and smooth muscle stimulation in certain species.

saFety aND tOXICItyLaboratory animals: Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and 20.0 mg/kg/day from day 6th-15th of gestation or when administered subcutaneously at 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered either subcutaneously at doses of 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14 or 15, 16 and 17 or orally at doses of 0.01, 0.1 and 1.0 mg/kg/day on days 6-18 or 5.0 mg/kg/day on days 8-18 of gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg/kg/day, respectively. This was due to the expected luteolytic properties of the drug. A 14-day continuous intravenous infusion study in rats at 20 mg PGF2a per kg body weight indicated prosta-glandins of the F series could induce bone deposition. However, such bone changes were not observed in monkeys similarly administered LUTALYSE Sterile Solution at 15 mg PGF2a per kg body weight for 14 days.Cattle: In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, urinalysis, organ weights, and gross plus microscopic measurements following treatment with various doses up to 250 mg dinoprost administered twice intramuscularly at a 10 day interval or doses of 25 mg administered daily for 10 days. There was no unequivocal effect of dinoprost on the hematology or clinical chemistry parameters measured. Clinically, a slight transitory increase in heart rate was detected. Rectal temperature was elevated about 1.5° F through the 6th hour after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No dinoprost associated gross lesions were detected. There was no evidence of toxicological effects. Thus, dinoprost had a safety factor of at least 10X on injection (25 mg luteolytic dose vs. 250 mg safe dose), based on studies conducted with cattle. At luteo-lytic doses, dinoprost had no effect on progeny. If given to a pregnant cow, it may cause abortion; the dose required for abortion varies considerably with the stage of gestation. Induction of abortion in feedlot cattle at stages of gestation up to 100 days of gestation did not result in dystocia, retained placenta or death of heifers in the field studies. The smallness of the fetus at this early stage of gestation should not lead to complications at abortion. However, induction of parturition or abortion with any exogenous com-pound may precipitate dystocia, fetal death, retained placenta and/or metritis, especially at latter stages of gestation.swine: In pigs, evaluation was made of clinical observations, food consumption, clinical pathologic determinations, body weight changes, urinalysis, organ weights, and gross and microscopic observations following treatment with single doses of 10, 30, 50 and 100 mg dinoprost administered intramuscularly. The results indicated no treatment related effects from dinoprost treatment that were deleterious to the health of the animals or to their offspring.Mares: Dinoprost tromethamine was administered to adult mares (weighing 320 to 485 kg; 2 to 20 years old), at the rates of 0, 100, 200, 400, and 800 mg per mare per day for 8 days. Route of administration for each dose group was both intramuscularly (2 mares) and subcutaneously (2 mares). Changes were detected in all treated groups for clinical (reduced sensitivity to pain; locomotor incoordination; hypergastromotility; sweating; hyperthermia; labored respiration), blood chemistry (elevated cholesterol, total bilirubin, LDH, and glucose), and hematology (decreased eosinophils; increased hemoglobin, hematocrit, and erythrocytes) measurements. The effects in the 100 mg dose, and to a lesser extent, the 200 mg dose groups were transient in nature, lasting for a few minutes to several hours. Mares did not appear to sustain adverse effects following termination of the side effects. Mares treated with either 400 mg or 800 mg exhibited more profound symptoms. The excessive hyperstimulation of the gastrointestinal tract caused a protracted diarrhea, slight electrolyte imbalance (decreased sodium and potassium), dehydration, gastrointestinal irritation, and slight liver malfunction (elevated SGOT, SGPT at 800 mg only). Heart rate was increased but pH of the urine was decreased. Other measurements evaluated in the study remained within normal limits. No mortality occurred in any of the groups. No apparent differences were observed between the intra-muscular and subcutaneous routes of administration. Luteolytic doses of dinoprost tromethamine are on the order of 5 to 10 mg administered on one day, therefore, LUTALYSE was demonstrated to have a wide margin of safety. Thus, the 100 mg dose gave a safety margin of 10 to 20X for a single injection or 80 to 160X for the 8 daily injections. Additional studies investigated the effects in the mare of single intramuscular doses of 0, 0.25, 1.0, 2.5, 3.0, 5.0, and 10.0 mg dinoprost tromethamine. Heart rate, respiration rate, rectal temperature, and sweating were measured at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6.0 hr. after injection. Neither heart rate nor respiration rates were significantly altered (P > 0.05) when compared to contemporary control values. Sweating was observed for 0 of 9, 2 of 9, 7 of 9, 9 of 9, and 8 of 9 mares injected with 0.25, 1.0, 2.5, 3.0, 5.0, or 10.0 mg dinoprost tromethamine, respectively. Sweating was temporary in all cases and was mild for doses of 3.0 mg or less but was extensive (beads of sweat over the entire body and dripping) for the 10 mg dose. Sweating after the 5.0 mg dose was intermediate between that seen for mares treated with 3.0 and 10.0 mg. Sweating began within 15 minutes after injection and ceased by 45 to 60 minutes after injection. Rectal temperature was decreased during the interval 0.5 until 1.0, 3 to 4, or 5 hours after injection for 0.25 and 1.0 mg, 2.5 and 3.0, or 5.0 and 10.0 mg dose groups, respectively. Average rectal temperature during the periods of decreased temperature was on the order of 97.5 to 99.6, with the greatest decreases observed in the 10 mg dose group.

MetaBOLIsM A number of metabolism studies have been done in laboratory animals. The metabolism of tritium labeled dinoprost (3H PGF2 alpha) in the rat and in the monkey was similar. Although quantitative differences were observed, qualitatively similar metabolites were produced. A study demonstrated that equimolar doses of 3H PGF2 alpha Tham and 3H PGF2 alpha free acid administered intravenously to rats demonstrated no significant differences in blood concentration of dinoprost. An interesting observation in the above study was that the radioactive dose of 3H PGF2 alpha rapidly dis-tributed in tissues and dissipated in tissues with almost the same curve as it did in the serum. The half-life of dinoprost in bovine blood has been reported to be on the order of minutes. A complete study on the distribution of decline of 3H PGF2 alpha Tham in the tissue of rats was well correlated with the work done in the cow. Cattle serum collected during 24 hours after doses of 0 to 250 mg dinoprost have been assayed by RIA for dinoprost and the 15-keto metabolites. These data support previous reports that dinoprost has a half-life of minutes. Dinoprost is a natural prostaglandin. All systems associated with dinoprost metabolism exist in the body; therefore, no new metabolic, transport, excretory, binding or other systems need be established by the body to metabolize injected dinoprost.

INDICatIONs aND INstRuCtIONs FOR useCattle: LUTALYSE Sterile Solution is indicated as a luteolytic agent. LUTALYSE is effective only in those cattle having a corpus luteum; i.e., those which ovulated at least five days prior to treatment. Future reproductive performance of animals that are not cycling will be unaffected by injection of LUTALYSE. 1. For Intramuscular use for estrus synchronization in Beef Cattle and Non-Lactating Dairy Heifers. LUTALYSE is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. Inject a dose of 5 mL LUTALYSE (25 mg PGF2a) intramuscularly either once or twice at a 10 to 12 day interval. With the single injection, cattle should be bred at the usual time relative to estrus. With the two injections cattle can be bred after the second injection either at the usual time relative to detected estrus or at about 80 hours after the second injection of LUTALYSE. Estrus is expected to occur 1 to 5 days after injection if a corpus luteum was present. Cattle that do not become pregnant to breeding at estrus on days 1 to 5 after injection will be expected to return to estrus in about 18 to 24 days. 2. For Intramuscular use for unobserved (silent) estrus in Lactating Dairy Cows with a Corpus Luteum. Inject a dose of 5 mL LUTALYSE (25 mg PGF2a) intramuscularly. Breed cows as they are detected in estrus. If estrus has not been observed by 80 hours after injection, breed at 80 hours. If the cow returns to estrus breed at the usual time relative to estrus. Management Considerations: Many factors contribute to success and failure of reproduction management, and these factors are important also when time of breeding is to be regulated with LUTALYSE Sterile Solution. Some of these factors are: a. Cattle must be ready to breed— they must have a corpus luteum and be healthy; b. Nutritional status must be adequate as this has a direct effect on conception and the initiation of estrus in heifers or return of estrous cycles in cows following calving; c. Physical facilities must be adequate to allow cattle handling without being detrimental to the animal; d. Estrus must be detected accurately if timed Al is not employed; e. Semen of high fertility must be used; f. Semen must be inseminated properly. A successful breeding program can employ LUTALYSE effectively, but a poorly managed breeding program

will continue to be poor when LUTALYSE is employed unless other management deficiencies are remedied first. Cattle expressing estrus following LUTALYSE are receptive to breeding by a bull. Using bulls to breed large numbers of cattle in heat following LUTALYSE will require proper management of bulls and cattle. 3. For Intramuscular use for treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 5 mL LUTALYSE (25 mg PGF2a) intramuscularly. In studies conducted with LUTALYSE, pyometra was defined as presence of a corpus luteum in the ovary and uterine horns containing fluid but not a conceptus based on palpation per rectum. Return to normal was defined as evacuation of fluid and return of the uterine horn size to 40 mm or less based on palpation per rectum at 14 and 28 days. Most cattle that recovered in response to LUTALYSE recovered within 14 days after injection. After 14 days, recovery rate of treated cattle was no different than that of nontreated cattle. 4. For Intramuscular use for abortion of Feedlot and Other Non-Lactating Cattle. LUTALYSE is indicated for its abortifacient effect in feedlot and other non-lactating cattle during the first 100 days of gestation. Inject a dose of 25 mg intramuscularly. Cattle that abort will abort within 35 days of injection. Commercial cattle were palpated per rectum for pregnancy in six feedlots. The percent of pregnant cattle in each feedlot less than 100 days of gestation ranged between 26 and 84; 80% or more of the pregnant cattle were less than 150 days of gestation. The abortion rates following injection of LUTALYSE increased with increasing doses up to about 25 mg. As examples, the abortion rates, over 7 feedlots on the dose titration study, were 22%, 50%, 71%, 90% and 78% for cattle up to 100 days of gestation when injected IM with LUTALYSE doses of 0,1 (5 mg), 2 (10 mg), 4 (20 mg) and 8 (40 mg) mL, respectively. The statistical predicted relative abortion rate based on the dose titration data, was about 93% for the 5 mL (25 mg) LUTALYSE dose for cattle injected up to 100 days of gestation. swine: For intramuscular use for parturition induction in swine. LUTALYSE Sterile Solution is indicated for parturi- tion induction in swine when injected within 3 days of normal predicted farrowing. The response to treatment varies by individual animals with a mean interval from administration of 2 mL LUTALYSE (10 mg dinoprost) to parturition of approximately 30 hours. This can be employed to control the time of farrowing in sows and gilts in late gestation. Management Considerations: Several factors must be considered for the successful use of LUTALYSE Sterile Solution for parturition induction in swine. The product must be administered at a relatively specific time (treatment earlier than 3 days prior to normal predicted farrowing may result in increased piglet mortality). It is important that adequate records be maintained on (1) the average length of gestation period for the animals on a specific loca- tion, and (2) the breeding and projected farrowing dates for each animal. This information is essential to determine the appropriate time for administration of LUTALYSE. Mares: LUTALYSE Sterile Solution is indicated for its luteolytic effect in mares. This luteolytic effect can be utilized to control the timing of estrus in estrous cycling and clinically anestrous mares that have a corpus luteum in the following circumstances: 1. Controlling time of estrus of estrous Cycling Mares: Mares treated with LUTALYSE during diestrus (4 or more days after ovulation) will return to estrus within 2 to 4 days in most cases and ovulate 8 to 12 days after treatment. This procedure may be utilized as an aid to scheduling the use of stallions. 2. Difficult-to-Breed Mares: In extended diestrus there is failure to exhibit regular estrous cycles which is different from true anestrus. Many mares described as anestrus during the breeding season have serum progesterone levels consistent with the presence of a functional corpus luteum. A proportion of “barren”, maiden, and lactating mares do not exhibit regular estrous cycles and may be in extended diestrus. Following abortion, early fetal death and resorption, or as a result of “pseudopregnancy”, there may be serum progesterone levels consistent with a functional corpus luteum. Treatment of such mares with LUTALYSE usually results in regression of the corpus luteum followed by estrus and/or ovulation. In one study with 122 Standardbred and Thoroughbred mares in clinical anestrus for an average of 58 days and treated during the breeding season, behavioral estrus was detected in 81 percent at an average time of 3.7 days after injection with 5 mg LUTALYSE; ovulation occurred an average of 7.0 days after treatment. Of those mares bred, 59% were pregnant following an average of 1.4 services during that estrus. Treatment of “anestrous” mares which abort subsequent to 36 days of pregnancy may not result in return to estrus due to presence of functional endometrial cups.

useR saFety (HuMaN WaRNINGs) Not for human use. Women of childbearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. In the early stages, women may be unaware of their pregnancies. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion. Accidental spillage on the skin should be washed off immediately with soap and water.

ResIDue INFORMatION No milk discard or preslaughter drug withdrawal period is required for labeled uses in cattle. No preslaughter drug withdrawal period is required for labeled uses in swine. Use of this product in excess of the approved dose may result in drug residues. Not for horses intended for human consumption.

aNIMaL saFety (WaRNINGs) Severe localized clostridial infections associated with injection of LUTALYSE have been reported. In rare instanc-es, such infections have resulted in death. Aggressive antibiotic therapy should be employed at the first sign of infec-tion at the injection site whether localized or diffuse.

PReCautIONs• Do not administer intravenously (I.V.) as this route may potentiate adverse reactions.• No vial stopper should be entered more than 20 times. For this reason, the 100 mL bottle should only be used for cattle. The 30 mL bottle may be used for cattle, swine, or mares.• As with all parenteral products careful aseptic techniques should be used to decrease the possibility of post- injection bacterial infections. The vial stopper should be cleaned and disinfected prior to needle entry. Only sterile needles should be used and the same needle should not be used more than once.• Nonsteroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not be administered concurrently.Cattle: Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestogen would be expected to have a reduced response to LUTALYSE Sterile Solution.swine: Do not administer to sows and/or gilts prior to 3 days of normal predicted farrowing as an increased number of stillbirths and postnatal mortality may result.Mares: LUTALYSE Sterile Solution is ineffective when administered prior to day-5 after ovulation. Pregnancy status should be determined prior to treatment since LUTALYSE has been reported to induce abortion and parturition when sufficient doses were administered. Mares should not be treated if they suffer from either acute or subacute disorders of the vascular system, gastrointestinal tract, respiratory system, or reproductive tract.

aDVeRse ReaCtIONsCattle: Limited salivation has been reported in some instances.swine: The most frequently observed side effects were erythema and pruritus, slight incoordination, nesting behavior, itching, urination, defecation, abdominal muscle spasms, tail movements, hyperpnea or dyspnea, increased vocaliza-tion, salivation, and at the 100 mg (10X) dose only, possible vomiting. These side effects are transitory, lastingfrom 10 minutes to 3 hours, and were not detrimental to the health of the animal.Mares: The most frequently observed side effects are sweating and decreased rectal temperature. However, these have been transient in all cases observed and have not been detrimental to the animal. Other reactions seen have been increase in heart rate, increase in respiration rate, some abdominal discomfort, locomotor incoordination, and lying down. These effects are usually seen within 15 minutes of injection and disappear within one hour. Mares usually continue to eat during the period of expression of side effects. One anaphylactic reaction of several hundred mares treated with LUTALYSE Sterile Solution was reported but was not confirmed.

DOsaGe aND aDMINIstRatION As with any multi-dose vial, practice aseptic techniques in withdrawing each dose. Adequately clean and disinfect the vial stopper prior to entry with a sterile needle and syringe. No vial closure should be entered more than 20 times. Cattle: LUTALYSE Sterile Solution is supplied at a concentration of 5 mg dinoprost per mL. LUTALYSE is luteolytic in cattle at 25 mg (5 mL) administered intramuscularly. swine: LUTALYSE Sterile Solution will induce parturition in swine at 10 mg (2 mL) when injected intramuscularly. Mares: 1. Evaluate the reproductive status of the mare. 2. Administer a single intramuscular injection of 1 mg per 100 lbs (45.5 kg) body weight which is usually 1 mL to 2 mL LUTALYSE Sterile Solution. 3. Observe for signs of estrus by means of daily teasing with a stallion, and evaluate follicular changes on the ovary by palpation of the ovary per rectum. 4. Some clinically anestrous mares will not express estrus but will develop a follicle which will ovulate. These mares may become pregnant if inseminated at the appropriate time relative to rupture of the follicle. 5. Breed mares in estrus in a manner consistent with normal management.

HOW suPPLIeDLUTALYSE Sterile Solution is available in 30 and 100 mL vials.

stORaGe CONDItIONsStore at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. Protect the 100 mL vial from freezing.

Restricted Drug (California), Use Only As Directed

NADA #108-901, Approved by FDAU.S. Patent No. 6,187,818

Distributed by: Pharmacia and Upjohn Company LLC Division of Pfizer Inc. New York, NY 10017 810 470 417 693741Revised June 2004 327-33

11

NADA 139-237, Approved by FDA

Factrel®

GONADORELINHYDROCHLORIDE

For InjectionFor the treatment of cystic ovaries in cattle.

CAUTIONFederal law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION FACTREL (gonadorelin hydrochloride) is a sterile solution containing 50 micrograms of synthetic gonadorelin (as hydrochloride) per mL in aqueous formulation containing 0.6% sodium chloride and 2% benzyl alcohol (as a preservative). Gonadorelin is the gonadotropin releasing hormone (GnRH) which is produced by the hypothalamus and causes the release of the gonadotropin luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. FACTREL (gonadorelin hydrochloride) has the identical amino acid sequence as endogenous gonadorelin; 5-oxo Pro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 with identical physiological activities. The molecular weight of gonadorelin is 1182 with a molecular formula of C55H75N17O13. The corresponding values for gonadorelin hydrochloride are 1219 (1 HCI) expressed as C55H75N17O13HCI, or 1255 (2 HCI) expressed as C55H75N17O13 2HCI.

MECHANISM OF ACTIONFollicular cysts are enlarged non-ovulatory follicles resulting from a malfunction of the neuroendocrine mechanism controlling follicular maturation and ovulation. Exogenous administration of agents possessing luteinizing hormone (LH) activity, such as pituitary extracts or human chorionic gonadotropin, often causes ovulation or regression of follicular cysts. FACTREL induces release of endogenous luteinizing hormone (LH) to produce this same effect. No significant differences have been demonstrated in days from treatment to conception, frequency of cows conceiving at first or subsequent heats, or conception rates among treated or non-treated control animals.

INDICATIONSFACTREL (gonadorelin hydrochloride) is indicated for the treatment of ovarian follicular cysts in cattle. The treatment effect of FACTREL when used in cattle with ovarian follicular cysts is a reduction in the number of days to first estrus.

DOSAGEThe recommended dosage of FACTREL is 100 mcg/cow intramuscularly.

RESIDUE WARNINGBecause FACTREL is identical to endogenous GnRH such that both are rapidly metabolized without detectable levels in milk or tissue, no withdrawal period is required.

STORAGE CONDITIONSStore at refrigerator temperature 2° to 8°C (36° to 46°F).

SAFETY AND TOXICITYIn cows the intramuscular administration of up to 25 times recommended dosage (2,500 mcg/day) of FACTREL for 3 days did not affect any physiological or clinical parameter. Likewise, single intramuscular doses of 5 times recommended dosage (500 mcg) did not interfere with pregnancy. No evidence of irritation at injection site was found in any animal.

HOW SUPPLIEDFACTREL (gonadorelin hydrochloride) solution 50 mcg/mL is available in 20 mL multidose vials (box of one). NDC 0856-4311-02 – 20 mL – box of 1

Fort Dodge Animal HealthFort Dodge, Iowa 50501 USA

01203 Rev. Apr. 2003 4310H

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