LUTALYSE® and Cloprostenol: Clearing up Misconceptions Fred Moreira, DVM, MS, Ph.D

LUT12001

March 2012 LUTALYSE® and cloprostenol: Clearing up misconceptions Fred Moreira, DVM, MS, Ph.D. Doug Hammon, DVM, Ph.D. Pfizer Animal Health Pfizer Animal Health

Summary • LUTALYSE® (dinoprost tromethamine) Sterile Solution contains the natural

prostaglandin F2α (dinoprost) as a tromethamine salt, whereas cloprostenol is an analogue of prostaglandin F2α. • Although active ingredients and their properties differ between the two products, both LUTALYSE and cloprostenol induce luteolysis by triggering a cascade of endogenous events that ultimately lead to the regression of the corpus luteum (CL).

• Collectively, data in the scientific literature indicates there are no differences in efficacy between LUTALYSE and cloprostenol. The U.S. Food and Drug Administration (FDA) confirmed this conclusion in a 2010 communication to Intervet/Schering-Plough.

• The benefits of using LUTALYSE extend beyond the contents of the vial. LUTALYSE is the most researched prostaglandin in the U.S. and is backed by the Pfizer Animal Health Field Force, the largest of its kind in the industry. The unparalleled support that customers of LUTALYSE receive makes it the undisputable market leader and the prostaglandin of choice to cattle producers.

UTALYSE® (dinoprost tromethamine) Nonetheless, competitive suppliers have Sterile Solution has been approved for pursued advertising and sales messaging that Lsynchronization of estrus in cattle for more suggest LUTALYSE is not as efficacious than 30 years. It has been the most widely used as cloprostenol or does not work under prostaglandin product since its launch and is the modern conditions. Intervet/Schering-Plough trusted foundation of breeding programs across (now known as Merck Animal Health), the country. Pfizer Animal Health, the makers of which markets cloprostenol as Estrumate® LUTALYSE have invested heavily in research (cloprostenol sodium) in the U.S., was the to understand all aspects of the biology and source of this misleading messaging. FDA practical use of LUTALYSE under commercial issued communication Sept. 16, 2010, ordering conditions. This has not only furthered Intervet/Schering-Plough to immediately cease understanding of LUTALYSE but also has and desist claims of biological superiority in helped move reproductive management forward comparison with LUTALYSE, as these claims within the U.S. dairy industry. have not been demonstrated by substantial evidence or substantial clinical experience. OH Prostaglandin F Cloprostenol sodium 2α OH

COOH COOH

LUTALYSE® (dinoprost tromethamine) Sterile The route of administration is intramuscular, CH3 O Solution, cloprostenol and other prostaglandins whereas the intravenous administration of have been researched in hundreds of published LUTALYSE is contraindicated. The subcutaneous OH OH Cl OH OH studies. From time to time, any one particular route has not been fully examined; it is not an trial may show one prostaglandin product is approved route of administration and, therefore, LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. numerically superior to the other by chance. is not recommended. These differences may even be significant in As with all parenteral products, aseptic technique some cases. Most times, the very same data do should be used to reduce the possibility of post- not indicate a statistical difference between the injection bacterial infections. Do not administer two products, just a numerical difference that it in pregnant animals unless cessation of pregnancy is unduly interpreted as relevant. FDA addressed is desired. Not for intravenous administration. these superiority claims and determined them to Women of childbearing age and persons with be unsubstantiated. respiratory problems should exercise extreme The data in the scientific literature caution when handling this product. overwhelmingly indicate there are no In the U.S., cloprostenol is sold as Estrumate® differences in efficacy between LUTALYSE and the generic product called estroPLAN®, and cloprostenol. The objective of this which contains cloprostenol sodium, a salt technical bulletin is to provide a review of the form of the synthetic analogue. The original science and peer-reviewed, published data on chemical structure of PGF2α (Figure 2) was LUTALYSE and the other prostaglandins. modified to result in cloprostenol. Each milliliter of Estrumate contains 250 mcg of cloprostenol Chemical Structures equivalent. The suggested dose of Estrumate is 2 mL, to be used intramuscularly. LUTALYSE contains the naturally occurring Due to these structural modifications, prostaglandin F2α (PGF2α; dinoprost) as a tromethamine salt. Its chemical structure cloprostenol has some different properties when is depicted in Figure 2. Each milliliter of compared with dinoprost. Cloprostenol does LUTALYSE contains dinoprost tromethamine have a higher affinity for the PGF2α receptor, and equivalent to 5 mg of dinoprost. Dose titration there are indications it may have a slightly longer studies have indicated 25 mg of dinoprost half-life. However, as indicated below, these (i.e., 5 mL of LUTALYSE) is the most attributes do not correlate with a higher efficacy appropriate dose. 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.

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.

OH Prostaglandin F Cloprostenol sodium 2α OH

COOH COOH

CH3 O

OH Cl OH OH OH

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

2 OH Prostaglandin F Cloprostenol sodium 2α OH

COOH COOH

CH3 O

OH Cl OH OH OH

LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol.

The Luteolytic Process Figure 3A – This depicts the reproductive tract with the uterine The complete regression of the CL is the main body, uterine horns, oviducts, and objective to be achieved after an injection of right and left ovaries are in blue. A corpus luteum (CL; in orange) is PGF2α or its analogues. The regression of the depicted on the right ovary, and a CL and the consequent decrease in progesterone dominant follicle is shown (in red) concentration allow for the final maturation of on the left ovary. The CL in the right ovary is actively producing the pre-ovulatory follicle and for an increase in progesterone. Secretion of the circulating levels of estradiol. estradiol by the dominant follicle is low, due to the high The rise in estradiol concentrations stimulate concentrations of progesterone the immune system in the uterus and leads to a secreted by the CL. surge of luteinizing hormone (LH) release that Figure 3B – The events that will induce ovulation. These events ultimately follow an injection of PGF2a: the are responsible for the main indications of injected PGF2a reaches the CL (1) and functions as a “trigger” prostaglandins: that induces the secretion of • Synchronization of estrus in cattle oxytocin from the CL (2). Oxytocin secreted by the CL reaches the • Treatment of uterine infections such uterus and stimulates the release as pyometra of endogenous PGF2a (3). The • Induction of abortion in pregnant cattle endogenous PGF2a goes back to the CL and induces the release of The series of illustrations to the right demonstrate more oxytocin. the events that occur in the reproductive tract Figure 3C – The continuous following an injection of PGF2α or its analogues. PGF2a- oxytocin cycle is triggered by the initial injection of PGF2a. As described in Figures 3A-3D, the initial The oxytocin produced by the injection of PGF2α simply triggers the events CL continues to stimulate the that ultimately will lead to the regression of secretion of endogenous PGF2a by the uterus, which further the CL and to the decrease of progesterone stimulates the secretion of concentrations. oxytocin by the CL in a classic feedback mechanism. As the CL regresses, concentrations Effects on Progesterone of progesterone decrease. This Concentration cycle continues until the CL is completely regressed. The decrease in progesterone concentration is Figure 3D – In Figure 2D, at the signal for the increase in estradiol, which will the end of the feedback cycle, induce estrous behavior. Thus, when comparing the the CL is completely regressed ® and, in its place, there only efficacy of LUTALYSE (dinoprost tromethamine) remains a scar (corpus albicans). Sterile Solution and cloprostenol, researchers Since progesterone is not being measured the ability of each prostaglandin to produced, secretion of estradiol decrease progesterone concentrations. from the dominant follicle is increased. Estradiol will reach Seguin, et al. (1985), injected nonlactating behavioral centers in the brain dairy cows with either LUTALYSE (n=62) and stimulate estrous behavior. Estradiol will also induce a surge or cloprostenol (n=62) and measured plasma of luteinizing hormone (LH) that progesterone concentrations at 0, 2, 4, 8, 12, leads to ovulation. 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.

3 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 OH Prostaglandin F Cloprostenol sodium the rate of progesterone decline after treatments 2α OH with either LUTALYSE or cloprostenol. In his

COOH 1984 study, Johnson also reported no differences COOH in the decline of milk progesterone concentrations at 48 hours following injections of LUTALYSE

CH3 OH Prostaglandin F2α Cloprostenol sodium *ND = values below assay detection limits. or cloprostenol in lactating dairy cows. However, OH O Stevenson, et al. (2010), reported that a higher OH Cl (P<0.01) proportion of cows with blood OH COOH OH OH Table 2 – Proportion of cows undergoing luteal regression by 72 hours after treatment and percent pregnant COOH following AI in cows treated with Lutalyse or cloprostenol as part of a timed-AI protocol. progesterone concentrations ≥1 ng/mL prior to LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. Reference Herds (n) N Luteal regression1 Pregnancy rate treatment had low (<1 ng/mL) blood progesterone OH Prostaglandin F2α Cloprostenol sodium CH3 OH at 72h (%) 2 (%) 72 hours after treatment when treated with O LUTALYSE Cloprostenol P LUTALYSE Cloprostenol P LUTALYSE compared with cloprostenol. COOH Stevenson, et al., 2010 6 1,264 91.3 86.6 P<0.05 37.8 36.7 NS OH CClOOH OH OH OH Experiment 1 In a 1988 study, Guay, et al., measured both serum Stevenson, et al., 2010 1 427 78.5 69.1 P<0.05 32.8 31.3 NS progesterone and estradiol concentrations at 0 LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. Experiment 2 CH3 and 24 hours after LUTALYSEor cloprostenol O treatment in Holstein heifers that had been OH Cl submitted to a superovulation treatment. Results OH OH OH (Table 3) also indicate there is no difference in the LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol. 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

*NS = differences were not significant. of LUTALYSE or cloprostenol.

1 Percentage of animals detected in estrus relative to the total number of animals within each group. 6 NS = differences were not statistically significant. 2 Percentage of animals that conceived relative to the number of animals inseminated. 7 Includes only cows injected with LUTALYSE and cloprostenol intramuscularly. 3 Percentage of animals that conceived relative to the total number of animals within each group. 8 Includes both intramuscular and intravenous route of administration for LUTALYSE and 4 Type of cattle used in the study (LDC=lactating dairy cows; NLDC=nonlactating dairy cows; cloprostenol. BC=beef cows; BH=beef heifers; DH=dairy heifers). 5 Number of animals included in the experiment.

4 OH Prostaglandin F Cloprostenol sodium 2α OH

COOH COOH

CH3 O

OH Cl OH OH OH

LUTALYSE® (dinoprost tromethamine) Sterile Solution or cloprostenol.

Fertility of Cattle Treated with LUTALYSE or Cloprostenol Peer-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. Figure 4 – Distribution of estrus in virgin beef heifers (n=1002) injected with LUTALYSE or LUTALYSE and Cloprostenol cloprostenol. Adapted from Salverson, et al., 2002. Effects on Synchrony of Estrus There are no differences in the tightness of estrous synchronization following injections of LUTALYSE or cloprostenol. This was the common interpretation of data reported by Frequently Asked Questions on research groups that compared both products the Effects of LUTALYSE Versus (see Figure 4). Cloprostenol Data depicted in Figure 4 indicate the lack Because the overall interpretation of published of difference in efficacy of LUTALYSE and data is that LUTALYSE® (dinoprost tromethamine) cloprostenol to induce estrus in beef heifers Sterile Suspension and cloprostenol have the same according to the 2002 study by Salverson, level of efficacy to synchronize estrus in cattle, et al. This is an important observation because questions have been raised about differences under this was a multilocation study (n=5) that very specific circumstances. Some of those are included a relatively large number of heifers addressed below. (n=1002). Authors concluded that LUTALYSE and cloprostenol were equally efficacious for 1. Does cloprostenol induce a “stronger” heat synchronous induction of a fertile estrus. than LUTALYSE? Similarly, in nonlactating Holstein cows, in the There is no physiological reason for such an 1985 study by Seguin, et al., and in Angus cows effect. Prostaglandins do not induce estrus directly and heifers in the 1987 study by Turner, et al., as discussed above. Rather, prostaglandins induce researchers did not observe any differences in estrus by inducing luteolysis and decreasing tightness of estrous synchronization between progesterone concentrations in the blood. LUTALYSE and cloprostenol. The interval The reduction in progesterone concentrations from prostaglandin treatment to estrus during allows the pre-ovulatory follicle to increase its superovulation treatments of dairy heifers did not production of estradiol, which will induce estrous differ between LUTALYSE (50.46 + 2.3 hours) behavior. As indicated above in the 1988 study, and cloprostenol (45.33 + 1.65 hours) according Guay, et al., reported no differences in estradiol to the 1990 study by Desaulniers, et al. The latter concentrations at 24 hours after injections of research group also did not observe differences in LUTALYSE or cloprostenol. the interval from treatment with LUTALYSE or It has been reported that concentrations of cloprostenol treatment to estrus (7.4 + 0.34 day estradiol at estrus are reduced in lactating dairy and 7.58 + 0.35 day, respectively) in previously cows, especially cows with high milk production. superovulated heifers that had multiple corpora This reduction of estradiol concentrations was lutea. Suggestions that cloprostenol induces a associated with increased steroid metabolism tighter synchronized estrus or that cloprostenol- in the liver, resulting in dairy cows expressing treated cattle exhibit estrous behavior quicker than estrus with less intensity and duration. Such an when injected with LUTALYSE are inaccurate.

5 OH Prostaglandin F Cloprostenol sodium 2α OH observation has not been reported in dairy heifers Dose titration studies conducted in both heifers COOH COOH or in beef cattle. This situation in dairy cows is and adult cows have indicated the label dose not associated with the efficacy of LUTALYSE® (25 mg; 5 mL) is the most effective one. In the

CH3 (dinoprost tromethamine) Sterile Solution, 1985 study, Seguin, et al., categorized cows O cloprostenol or any other prostaglandin product. according to weight (from less than 1,000 OH Cl Suggestions that switching from LUTALYSE to pounds to more than 1,500 pounds) and OH OH OH cloprostenol would correct the current situation concluded there was no evidence that larger LUTALYSE® (dinoprinost dairy tromethamine) cows because Sterile Solution cloprostenol or cloprostenol. induces a cows had more response problems or that there “stronger” heat are unsubstantiated. were differences in efficacy of LUTALYSE and In addition, messages suggesting Estrumate cloprostenol according to cow weight. produces a stronger heat because of prolonged One 2003 study in Europe by Répási, et al., half-life are unsubstantiated. This conclusion compared the efficacy of the label dose of was drawn from research conducted in swine. dinoprost (25 mg; n=20) versus a higher dose Estrumate is approved for use in cattle only and (35 mg; n=19) in adult lactating dairy cows. thus any conclusions drawn from research in Cows were more than 40 days postpartum and other species are irrelevant. FDA called use of were diagnosed to have a CL by ultrasound. these half-life values as not relevant and serving Researchers detected no significant differences only to exaggerate the differences between between the two doses, their effects on CL Estrumate and LUTALYSE. regression (area of luteal tissue measured by ultrasound) or on rate of decrease of progesterone 2. Does the dose of LUTALYSE need to be concentrations. Differences between the 25 mg increased for large-framed cattle? and the 35 mg dose also were not observed in Questions regarding dose or opinions that a estrous-detection rates (95 percent and higher dose is necessary are typically associated 84.2 percent, respectively) and conception rates with poor results in reproductive performance (31.6 percent and 31.2 percent, respectively). without an apparent explanation. Frustrated 3. Do I need to inject a higher dose of producers and veterinarians may be inclined LUTALYSE® (dinoprost tromethamine) to shift the blame to product efficacy. Despite this, there are no conclusive data that support Sterile Solution in timed-artificial-insemination the recommendation for a higher dose of (AI) programs? LUTALYSE in large-framed cattle. A recent It was observed that between 5 percent and study by Stevenson, et al. (2010), reinforced 19 percent of cattle submitted to timed-AI programs this conclusion. Rates of luteolysis or pregnancy such as Ovsynch® may fail to regress their CL in 1,264 lactating dairy cows from multiple following injection of prostaglandins. Such failure dairy operations were evaluated after either was associated with reduced pregnancy rates to LUTALYSE or cloprostenol was injected as part timed insemination. Because the initial injection to of a timed-insemination program. This study induce an LH surge in an Ovsynch program causes reported that LUTALYSE increased (P< 0.05) more cows to have two corpora lutea when they the proportion of cows with luteal regression receive prostaglandin treatment seven days later, compared with cloprostenol. The percent of cows researchers initially believed there might be a need pregnant after the first artificial insemination (AI) to increase the dose of LUTALYSE to reduce the service was not different. frequency of CL regression failures.

*No differences in pregnancy rates were observed.

6 Although studies with higher doses of (mostly Bos indicus x Bos taurus) were treated LUTALYSE were conducted, no trials with the CoSynch program with concurrent heat directly compared the efficacy of label versus suppression. All cows received an injection to higher doses on timed-insemination success. induce an LH surge on Day 0, then heat was Comparisons of results from different studies are suppressed on Days 1 to 7, and at Day 7 cows not appropriate due to the many other factors that received either an injection of LUTALYSE, impact product performance. However, the use an injection of cloprostenol or a half-dose of of higher doses of LUTALYSE did not seem to LUTALYSE at Day 7 and another half-dose at induce significant increases in pregnancy rates Day 8 (split-dose). All cows received a second to timed insemination. As a result, the same injection to induce an LH surge and were timed- research groups that initially started using higher inseminated at Day 9 (approximately 72 to 80 doses of LUTALYSE chose to use the label- hours after heat suppression). Results are depicted recommended dose in more recent studies. in Table 5. No differences in pregnancy rates Most likely, the use of higher doses of were observed for the treatment groups. This is in LUTALYSE — or cloprostenol — in timed- agreement with work by Stevenson, et al. (2010), insemination programs either does not result in who showed the proportion of cows pregnant increased pregnancy rates or the magnitude of following timed AI across multiple herds was not the benefit is so small it would be too difficult to different for LUTALYSE versus cloprostenol. detect. Thus, the current recommendation is the 5. Does cloprostenol work better than label dose of LUTALYSE (25 mg) is the most LUTALYSE in Bos indicus cattle? appropriate for timed-AI programs. Furthermore, Stevenson, et al. (2010), showed LUTALYSE Data do not support any claims of improved administered at the label dose is effective in performance of cloprostenol in Bos indicus inducing CL regression when used in timed-AI cattle. There is some evidence that Bos indicus protocols across multiple dairy operations, and breeds and their crosses are more refractory to the proportion of cows pregnant following first prostaglandin treatments in general. Cows close AI was not different for LUTALYSE versus to Days 5 and 6 of the estrous cycle are said cloprostenol. to be a greater problem for Bos indicus. The opinion is cloprostenol would be more effective 4. Which product works better for timed-AI at that specific stage of the cycle. The data above programs? in the 2003 study by Hiers, et al., indicated no For the reasons cited in the answer above, failure differences in efficacy between LUTALYSE of complete CL regression was judged to be and cloprostenol in Bos indicus crosses. Authors associated with reduced efficacy of LUTALYSE. went further and indicated that in a preliminary These opinions indicated either the dose of study with Bos indicus crosses, results suggested LUTALYSE® (dinoprost tromethamine) Sterile there were no differences in the ability to Solution needed to be increased or cloprostenol induce luteolysis as measured by the decrease in was more effective in timed-AI programs. progesterone concentrations after injections of LUTALYSE or cloprostenol. Once more, there This specific question was addressed by the 2003 is no indication that cloprostenol would have study by Hiers, et al. Nonlactating beef cows greater efficacy than LUTALYSE.

7 If efficacy is the same, why FACTREL® (gonadorelin hydrochloride) Sterile Solution and Eazi-Breed™ CIDR® Cattle Insert. choose LUTALYSE? LUTALYSE is the only prostaglandin product Efficacy is not the only consideration in product approved for use in synchronization protocols choice among producers and veterinarians. It with Eazi-Breed CIDR Cattle Insert. A is important to recognize the benefits to using synchronization program, including leading LUTALYSE® (dinoprost tromethamine) Sterile products from Pfizer Animal Health, can improve Solution extend beyond the product itself. the efficiency and success of breeding programs. Consider below the reasons that LUTALYSE is the undisputable market leader: Conclusion 1) Product support: Pfizer Animal Health Data in the scientific literature conclusively provides expertise on capturing the most value indicate there is no difference in efficacy or from a dairy producer’s investment. The team product performance between LUTALYSE and of technical experts supporting Pfizer Animal cloprostenol. As discussed, there are a large Health products work with customers and number of peer-reviewed, published articles their veterinarians to effectively incorporate by many respected researchers that continue to each solution into the dairy’s reproductive demonstrate this point, with research published protocols. This ensures producers are protecting as recently as 2010. Other messages indicating reproductive efficiency and capturing an effective differently are a misinterpretation of the return on investment. And more important, this science. FDA has shown it will not tolerate any ensures the reproductive program is designed to misinterpretation or misuse of science to draw get cows bred and protect the growing fetus from unsubstantiated conclusions. reproductive disease. Ultimately, the backbone of a successful 2) Research backing: LUTALYSE is the most reproduction program is much broader than just researched and studied prostaglandin in the the prostaglandin used. Pfizer Animal Health marketplace. A review of scientific publications technical experts are among the most respected conducted in the U.S. in the past 10 years clearly in the dairy industry and are consistently sought- shows the depth of research of LUTALYSE as after speakers. When choosing products from compared with other brands. The vast majority Pfizer Animal Health, producers are not only of those scientific studies were conducted with choosing innovative and market-leading formulas Pfizer Animal Health support, demonstrating the but also our commitment to providing solutions company’s commitment to the understanding necessary for a dairy operation to survive. of all aspects of the biology and practical use of LUTALYSE under commercial conditions. Pfizer Animal Health is committed to providing veterinarians with products that carry the most What does that mean to customers? That means robust label claims that science can validate. Our through research and practical experience, promise is that science will validate every claim Pfizer Animal Health personnel know better than for every one of our products. We are committed any of our competitors how to make LUTALYSE to continued research on the physiological work for our customers’ operations. This means activity of LUTALYSE as well as supporting we have the answers producers and veterinarians ongoing scientific research that veterinarians and are looking for, and those answers are rooted producers need to make appropriate decisions in solid scientific data. Pfizer Animal Health is about the use of prostaglandins in their herds. committed to support research and will continue to As we learn more about the science behind provide the most current information to customers. LUTALYSE® (dinoprost tromethamine) Sterile 3) Reproductive solution: Prostaglandins are Solution, we will continue to pursue new an integral part of any reproductive program, approved label indications for its use. but there is more to reproductive programs than prostaglandins. Backed by years of proven success, Pfizer Animal Health 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, Pfizer Animal Health has a complete line of reproductive solutions, including

8 References Desaulniers 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.

9 ® will continue to be poor when LUTALYSE is employed unless other management deficiencies are remedied first. LutaLyse 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. brand of dinoprost tromethamine sterile solution 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 Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian. 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 For intramuscular use for estrus synchronization, treatment of unobserved (silent) estrus and pyometra 40 mm or less based on palpation per rectum at 14 and 28 days. Most cattle that recovered in response to (chronic endometritis) in cattle; for abortion of feedlot and other non-lactating cattle; for parturition induction LUTALYSE recovered within 14 days after injection. After 14 days, recovery rate of treated cattle was no different in swine; and for controlling the timing of estrus in estrous cycling mares and clinically anestrous mares that than that of nontreated cattle. have a corpus luteum. 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 DesCRIPtION a dose of 25 mg intramuscularly. Cattle that abort will abort within 35 days of injection. This product contains the naturally occurring prostaglandin F2 alpha (dinoprost) as the tromethamine salt. Each Commercial cattle were palpated per rectum for pregnancy in six feedlots. The percent of pregnant cattle mL contains dinoprost tromethamine equivalent to 5 mg dinoprost: also, benzyl alcohol, 16.5 mg added as preserva- in each feedlot less than 100 days of gestation ranged between 26 and 84; 80% or more of the pregnant cattle tive. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. Dinoprost tromethamine is a were less than 150 days of gestation. The abortion rates following injection of LUTALYSE increased with white or slightly off-white crystalline powder that is readily soluble in water at room temperature in concentrations to increasing doses up to about 25 mg. As examples, the abortion rates, over 7 feedlots on the dose titration at least 200 mg/mL. study, were 22%, 50%, 71%, 90% and 78% for cattle up to 100 days of gestation when injected IM with General Biologic activity: Prostaglandins occur in nearly all mammalian tissues. Prostaglandins, especially PGE’s LUTALYSE doses of 0,1 (5 mg), 2 (10 mg), 4 (20 mg) and 8 (40 mg) mL, respectively. The statistical predicted and PGF’s, have been shown, in certain species, to 1) increase at time of parturition in amniotic fluid, maternal relative abortion rate based on the dose titration data, was about 93% for the 5 mL (25 mg) LUTALYSE dose placenta, myometrium, and blood, 2) stimulate myometrial activity, and 3) to induce either abortion or parturition. for cattle injected up to 100 days of gestation. Prostaglandins, especially PGF2a, have been shown to 1) increase in the uterus and blood to levels similar to levels swine: For intramuscular use for parturition induction in swine. LUTALYSE Sterile Solution is indicated for parturi- achieved by exogenous administration which elicited luteolysis, 2) be capable of crossing from the uterine vein to the tion induction in swine when injected within 3 days of normal predicted farrowing. ovarian artery (sheep), 3) be related to IUD induced luteal regression (sheep), and 4) be capable of regressing the The response to treatment varies by individual animals with a mean interval from administration of 2 mL corpus luteum of most mammalian species studied to date. Prostaglandins have been reported to result in release of LUTALYSE (10 mg dinoprost) to parturition of approximately 30 hours. This can be employed to control the time pituitary tropic hormones. Data suggest prostaglandins, especially PGE’s and PGF’s, may be involved in the process of farrowing in sows and gilts in late gestation. of ovulation and gamete transport. Also PGF2a has been reported to cause increase in blood pressure, bronchocon- Management Considerations: Several factors must be considered for the successful use of LUTALYSE Sterile striction, and smooth muscle stimulation in certain species. 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 saFety aND tOXICIty adequate records be maintained on (1) the average length of gestation period for the animals on a specific loca- Laboratory animals: Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and 20.0 mg/ tion, and (2) the breeding and projected farrowing dates for each animal. This information is essential to determine kg/day from day 6th-15th of gestation or when administered subcutaneously at 0.5 and 1.0 mg/kg/day on gestation the appropriate time for administration of LUTALYSE. days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered Mares: LUTALYSE Sterile Solution is indicated for its luteolytic effect in mares. This luteolytic effect can be utilized 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 to control the timing of estrus in estrous cycling and clinically anestrous mares that have a corpus luteum in the 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 following circumstances: gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg/kg/day, respectively. 1. Controlling time of estrus of estrous Cycling Mares: Mares treated with LUTALYSE during diestrus (4 or This was due to the expected luteolytic properties of the drug. more days after ovulation) will return to estrus within 2 to 4 days in most cases and ovulate 8 to 12 days after A 14-day continuous intravenous infusion study in rats at 20 mg PGF2a per kg body weight indicated prosta- treatment. This procedure may be utilized as an aid to scheduling the use of stallions. glandins of the F series could induce bone deposition. However, such bone changes were not observed in monkeys 2. Difficult-to-Breed Mares: In extended diestrus there is failure to exhibit regular estrous cycles which is similarly administered LUTALYSE Sterile Solution at 15 mg PGF2a per kg body weight for 14 days. different from true anestrus. Many mares described as anestrus during the breeding season have serum Cattle: In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, urinalysis, organ progesterone levels consistent with the presence of a functional corpus luteum. weights, and gross plus microscopic measurements following treatment with various doses up to 250 mg dinoprost A proportion of “barren”, maiden, and lactating mares do not exhibit regular estrous cycles and may be administered twice intramuscularly at a 10 day interval or doses of 25 mg administered daily for 10 days. There was in extended diestrus. Following abortion, early fetal death and resorption, or as a result of “pseudopregnancy”, no unequivocal effect of dinoprost on the hematology or clinical chemistry parameters measured. Clinically, a slight there may be serum progesterone levels consistent with a functional corpus luteum. transitory increase in heart rate was detected. Rectal temperature was elevated about 1.5° F through the 6th hour Treatment of such mares with LUTALYSE usually results in regression of the corpus luteum followed after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No dinoprost associated by estrus and/or ovulation. In one study with 122 Standardbred and Thoroughbred mares in clinical anestrus gross lesions were detected. There was no evidence of toxicological effects. Thus, dinoprost had a safety factor of at for an average of 58 days and treated during the breeding season, behavioral estrus was detected in 81 least 10X on injection (25 mg luteolytic dose vs. 250 mg safe dose), based on studies conducted with cattle. At luteo- percent at an average time of 3.7 days after injection with 5 mg LUTALYSE; ovulation occurred an average of lytic doses, dinoprost had no effect on progeny. If given to a pregnant cow, it may cause abortion; the dose required 7.0 days after treatment. Of those mares bred, 59% were pregnant following an average of 1.4 services during for abortion varies considerably with the stage of gestation. that estrus. Induction of abortion in feedlot cattle at stages of gestation up to 100 days of gestation did not result in dystocia, Treatment of “anestrous” mares which abort subsequent to 36 days of pregnancy may not result in return retained placenta or death of heifers in the field studies. The smallness of the fetus at this early stage of gestation to estrus due to presence of functional endometrial cups. 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. useR saFety (HuMaN WaRNINGs) swine: In pigs, evaluation was made of clinical observations, food consumption, clinical pathologic determinations, Not for human use. Women of childbearing age, asthmatics, and persons with bronchial and other respiratory body weight changes, urinalysis, organ weights, and gross and microscopic observations following treatment with problems should exercise extreme caution when handling this product. In the early stages, women may be unaware single doses of 10, 30, 50 and 100 mg dinoprost administered intramuscularly. The results indicated no treatment of their pregnancies. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion. Accidental related effects from dinoprost treatment that were deleterious to the health of the animals or to their offspring. spillage on the skin should be washed off immediately with soap and water. 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 ResIDue INFORMatION was both intramuscularly (2 mares) and subcutaneously (2 mares). Changes were detected in all treated groups for No milk discard or preslaughter drug withdrawal period is required for labeled uses in cattle. No preslaughter drug clinical (reduced sensitivity to pain; locomotor incoordination; hypergastromotility; sweating; hyperthermia; labored withdrawal period is required for labeled uses in swine. Use of this product in excess of the approved dose may result respiration), blood chemistry (elevated cholesterol, total bilirubin, LDH, and glucose), and hematology (decreased in drug residues. Not for horses intended for human consumption. 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. aNIMaL saFety (WaRNINGs) Mares did not appear to sustain adverse effects following termination of the side effects. Severe localized clostridial infections associated with injection of LUTALYSE have been reported. In rare instanc- Mares treated with either 400 mg or 800 mg exhibited more profound symptoms. The excessive hyperstimulation of es, such infections have resulted in death. Aggressive antibiotic therapy should be employed at the first sign of infec- the gastrointestinal tract caused a protracted diarrhea, slight electrolyte imbalance (decreased sodium and potassium), tion at the injection site whether localized or diffuse. 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 PReCautIONs normal limits. No mortality occurred in any of the groups. No apparent differences were observed between the intra- • Do not administer intravenously (I.V.) as this route may potentiate adverse reactions. muscular and subcutaneous routes of administration. Luteolytic doses of dinoprost tromethamine are on the order of 5 • No vial stopper should be entered more than 20 times. For this reason, the 100 mL bottle should only be used for to 10 mg administered on one day, therefore, LUTALYSE was demonstrated to have a wide margin of safety. Thus, the cattle. The 30 mL bottle may be used for cattle, swine, or mares. 100 mg dose gave a safety margin of 10 to 20X for a single injection or 80 to 160X for the 8 daily injections. • As with all parenteral products careful aseptic techniques should be used to decrease the possibility of post- Additional studies investigated the effects in the mare of single intramuscular doses of 0, 0.25, 1.0, 2.5, 3.0, 5.0, injection bacterial infections. The vial stopper should be cleaned and disinfected prior to needle entry. Only sterile and 10.0 mg dinoprost tromethamine. Heart rate, respiration rate, rectal temperature, and sweating were measured needles should be used and the same needle should not be used more than once. 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 • Nonsteroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not were significantly altered P( > 0.05) when compared to contemporary control values. Sweating was observed for 0 be administered concurrently. 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, Cattle: Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestogen would be respectively. Sweating was temporary in all cases and was mild for doses of 3.0 mg or less but was extensive (beads expected to have a reduced response to LUTALYSE Sterile Solution. of sweat over the entire body and dripping) for the 10 mg dose. Sweating after the 5.0 mg dose was intermediate swine: Do not administer to sows and/or gilts prior to 3 days of normal predicted farrowing as an increased number between that seen for mares treated with 3.0 and 10.0 mg. Sweating began within 15 minutes after injection and of stillbirths and postnatal mortality may result. ceased by 45 to 60 minutes after injection. Rectal temperature was decreased during the interval 0.5 until 1.0, 3 to Mares: LUTALYSE Sterile Solution is ineffective when administered prior to day-5 after ovulation. Pregnancy status 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 should be determined prior to treatment since LUTALYSE has been reported to induce abortion and parturition when rectal temperature during the periods of decreased temperature was on the order of 97.5 to 99.6, with the greatest sufficient doses were administered. Mares should not be treated if they suffer from either acute or subacute disorders decreases observed in the 10 mg dose group. of the vascular system, gastrointestinal tract, respiratory system, or reproductive tract.

MetaBOLIsM aDVeRse ReaCtIONs A number of metabolism studies have been done in laboratory animals. The metabolism of tritium labeled dinoprost Cattle: Limited salivation has been reported in some instances. 3 ( H PGF2 alpha) in the rat and in the monkey was similar. Although quantitative differences were observed, qualitatively swine: The most frequently observed side effects were erythema and pruritus, slight incoordination, nesting behavior, 3 3 similar metabolites were produced. A study demonstrated that equimolar doses of H PGF2 alpha Tham and H PGF2 itching, urination, defecation, abdominal muscle spasms, tail movements, hyperpnea or dyspnea, increased vocaliza- alpha free acid administered intravenously to rats demonstrated no significant differences in blood concentration of tion, salivation, and at the 100 mg (10X) dose only, possible vomiting. These side effects are transitory, lasting 3 dinoprost. An interesting observation in the above study was that the radioactive dose of H PGF2 alpha rapidly dis- from 10 minutes to 3 hours, and were not detrimental to the health of the animal. tributed in tissues and dissipated in tissues with almost the same curve as it did in the serum. The half-life of dinoprost Mares: The most frequently observed side effects are sweating and decreased rectal temperature. However, these in bovine blood has been reported to be on the order of minutes. A complete study on the distribution of decline of 3H have been transient in all cases observed and have not been detrimental to the animal. Other reactions seen have PGF2 alpha Tham in the tissue of rats was well correlated with the work done in the cow. Cattle serum collected during been increase in heart rate, increase in respiration rate, some abdominal discomfort, locomotor incoordination, and 24 hours after doses of 0 to 250 mg dinoprost have been assayed by RIA for dinoprost and the 15-keto metabolites. lying down. These effects are usually seen within 15 minutes of injection and disappear within one hour. Mares usually These data support previous reports that dinoprost has a half-life of minutes. continue to eat during the period of expression of side effects. One anaphylactic reaction of several hundred mares Dinoprost is a natural prostaglandin. All systems associated with dinoprost metabolism exist in the body; therefore, treated with LUTALYSE Sterile Solution was reported but was not confirmed. no new metabolic, transport, excretory, binding or other systems need be established by the body to metabolize injected dinoprost. DOsaGe aND aDMINIstRatION As with any multi-dose vial, practice aseptic techniques in withdrawing each dose. Adequately clean and disinfect INDICatIONs aND INstRuCtIONs FOR use 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 indicated as a luteolytic agent. Cattle: LUTALYSE Sterile Solution is supplied at a concentration of 5 mg dinoprost per mL. LUTALYSE is luteolytic LUTALYSE is effective only in those cattle having a corpus luteum; i.e., those which ovulated at least five days in cattle at 25 mg (5 mL) administered intramuscularly. prior to treatment. Future reproductive performance of animals that are not cycling will be unaffected by injection of swine: LUTALYSE Sterile Solution will induce parturition in swine at 10 mg (2 mL) when injected intramuscularly. LUTALYSE. Mares: 1. Evaluate the reproductive status of the mare. 1. For Intramuscular use for estrus synchronization in Beef Cattle and Non-Lactating Dairy Heifers. 2. Administer a single intramuscular injection of 1 mg per 100 lbs (45.5 kg) body weight which is usually 1 mL LUTALYSE is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. to 2 mL LUTALYSE Sterile Solution. Inject a dose of 5 mL LUTALYSE (25 mg PGF2a) intramuscularly either once or twice at a 10 to 12 day interval. 3. Observe for signs of estrus by means of daily teasing with a stallion, and evaluate follicular changes on With the single injection, cattle should be bred at the usual time relative to estrus. the ovary by palpation of the ovary per rectum. With the two injections cattle can be bred after the second injection either at the usual time relative to 4. Some clinically anestrous mares will not express estrus but will develop a follicle which will ovulate. These detected estrus or at about 80 hours after the second injection of LUTALYSE. mares may become pregnant if inseminated at the appropriate time relative to rupture of the follicle. Estrus is expected to occur 1 to 5 days after injection if a corpus luteum was present. Cattle that do not 5. Breed mares in estrus in a manner consistent with normal management. 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. HOW suPPLIeD 2. For Intramuscular use for unobserved (silent) estrus in Lactating Dairy Cows with a Corpus Luteum. LUTALYSE Sterile Solution is available in 30 and 100 mL vials. 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 stORaGe CONDItIONs at the usual time relative to estrus. Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. Protect the 100 mL vial from freezing. 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 Restricted Drug (California), Use Only As Directed of these factors are: a. Cattle must be ready to breed— they must have a corpus luteum and be healthy; NADA #108-901, Approved by FDA b. Nutritional status must be adequate as this has a direct effect on conception and the initiation of estrus in U.S. Patent No. 6,187,818 heifers or return of estrous cycles in cows following calving; Distributed by: Pharmacia and Upjohn Company LLC c. Physical facilities must be adequate to allow cattle handling without being detrimental to the animal; Division of Pfizer Inc. d. Estrus must be detected accurately if timed Al is not employed; New York, NY 10017 e. Semen of high fertility must be used; 810 470 417 f. Semen must be inseminated properly. 693741 A successful breeding program can employ LUTALYSE effectively, but a poorly managed breeding program Revised June 2004 327-33

10 NADA 139-237, Approved by FDA

Factrel® GONADORELIN HYDROCHLORIDE For Injection

For the treatment of cystic ovaries in cattle. DOSAGE The recommended dosage of FACTREL is 100 mcg/cow intramuscularly. CAUTION Federal law restricts this drug to use by or on the order of a licensed veterinarian. RESIDUE WARNING Because FACTREL is identical to endogenous GnRH such that both are rapidly DESCRIPTION metabolized without detectable levels in milk or tissue, no withdrawal period is required. FACTREL (gonadorelin hydrochloride) is a sterile solution containing 50 micrograms of synthetic gonadorelin (as hydrochloride) per mL in aqueous formulation containing STORAGE CONDITIONS 0.6% sodium chloride and 2% benzyl alcohol (as a preservative). Gonadorelin is the Store at refrigerator temperature 2° to 8°C (36° to 46°F). gonadotropin releasing hormone (GnRH) which is produced by the hypothalamus and causes the release of the gonadotropin luteinizing hormone (LH) and SAFETY AND TOXICITY follicle-stimulating hormone (FSH) from the anterior pituitary. FACTREL (gonadorelin In cows the intramuscular administration of up to 25 times recommended dosage hydrochloride) has the identical amino acid sequence as endogenous gonadorelin; (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 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 (500 mcg) did not interfere with pregnancy. No evidence of irritation at injection site was found in any animal. C55H75N17O13. The corresponding values for gonadorelin hydrochloride are 1219 (1 HCI) expressed as C55H75N17O13HCI, or 1255 (2 HCI) expressed as C55H75N17O13 2HCI. HOW SUPPLIED MECHANISM OF ACTION FACTREL (gonadorelin hydrochloride) solution 50 mcg/mL is available in 20 mL Follicular cysts are enlarged non-ovulatory follicles resulting from a malfunction of the multidose vials (box of one). NDC 0856-4311-02 – 20 mL – box of 1 neuroendocrine mechanism controlling follicular maturation and ovulation. Exogenous administration of agents possessing luteinizing hormone (LH) activity, such as pituitary Fort Dodge Animal Health extracts or human chorionic gonadotropin, often causes ovulation or regression of Fort Dodge, Iowa 50501 USA follicular cysts. FACTREL induces release of endogenous luteinizing hormone (LH) to produce this same effect. No significant differences have been demonstrated in days 01203 Rev. Apr. 2003 4310H from treatment to conception, frequency of cows conceiving at first or subsequent heats, or conception rates among treated or non-treated control animals.

INDICATIONS FACTREL (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.