dinoprost

Cattle (beef cows, beef heifers, and replacement dairy heifers)

For estrus synchronization in beef cows, beef heifers and replacement dairy heifers.

ProstaMate®

Cattle (lactating dairy cows)

For use with gonadorelin injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows.

ProstaMate®

Cattle (lactating dairy cows)

For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in lactating dairy cows.

ProstaMate®

Cattle (lactating dairy cows)

For unobserved (silent) estrus in lactating dairy cows with a corpus luteum.

ProstaMate®

Cattle (beef cows, dairy cows, beef heifers and replacement dairy heifers)

For treatment of pyometra (chronic endometritis) in cattle.

ProstaMate®

Cattle (beef cows, beef heifers and replacement dairy heifers)

For abortion in beef cows, beef heifers and replacement dairy heifers.

ProstaMate®

Cattle (beef cows, replacement beef and dairy heifers)

For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers.

ProstaMate®

Beef Cows, Beef Heifers and Replacement Dairy Heifers

For estrus synchronization in beef cows, beef heifers and replacement dairy heifers

Lutalyse® Injection

Beef Cows, Beef Heifers and Replacement Dairy Heifers

For abortion in beef cows, beef heifers and replacement dairy heifers

Lutalyse® Injection

Lactating Dairy Cows

For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows

Lutalyse® Injection

Lactating Dairy Cows

For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in lactating dairy cows

Lutalyse® Injection

Lactating Dairy Cows

For unobserved (silent) estrus in lactating dairy cows with a corpus luteum

Lutalyse® Injection

For treatment of pyometra (chronic endometritis) in cattle.

Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Suckled Beef Cows, Replacement Beef and Dairy Heifers)

For use with EAZI-BREED CIDR (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers.

Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday). Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the 7 Day administration period. Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Beef Cows, Beef Heifers, Replacement Dairy Heifers)

For estrus synchronization in beef cows, beef heifers and replacement dairy heifers.

LUTALYSE HighCon Injection is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. 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 HighCon Injection. 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. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Beef Cows, Beef Heifers, Replacement Dairy Heifers)

For abortion in beef cows, beef heifers and replacement dairy heifers.

LUTALYSE HighCon Injection is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Cattle that abort will abort within 35 days of injection. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Lactating Dairy Cows)

For use with FACTREL (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows.

Administer 2 to 4 mL FACTREL Injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework:Administer the first dose of FACTREL Injection (2 – 4 mL) at Day 0Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 6 – 8 days after the first dose of FACTREL Injection.Administer a second dose of FACTREL Injection (2 – 4 mL) 30 to 72 hours after LUTALYSE HighCon InjectionPerform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows on detected estrus using standard herd practices.Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Lactating Dairy Cows)

For use with EAZI-BREED CIDR (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in lactating dairy cows.

Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example, if administered on a Monday remove the following Monday). Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals found in estrus following normal herd practices. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Lactating Dairy Cows)

For unobserved (silent) estrus in lactating dairy cows with a corpus luteum.

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. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Horses (mares)

For controlling the timing of estrus in estrous cycling mares and for difficult-to-breed mares (clinically anestrous mares that have a corpus luteum).

ProstaMate®

Horses (mares)

For its luteolytic effect to control timing of estrus in estrus cycling mares and in clinically anestrous mares that have a corpus luteum.

Not for use in horses intended for food. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Women of child-bearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion and bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water. Use of this product in excess of the approved dose may result in drug residues. Do not administer intravenously; this may potentiate adverse reactions.

Prostin F2 Alpha® Sterile Solution

Horse (mares)

For controlling the timing of estrus in estrous cycling mares. For difficult-to-breed mares (clinically anestrous mares that have a corpus luteum).

Lutalyse® Injection

Swine (gilts and sows)

For parturition induction in swine.

ProstaMate®

Swine (sows and gilts)

For parturition induction in swine

Lutalyse® Injection

LUTALYSE HighCon Injection is indicated as a luteolytic agent. LUTALYSE HighCon Injection is effective only in those cattle having a corpus luteum, i.e., those which ovulated at least five days prior to treatment. • For estrus synchronization in beef cows, beef heifers and replacement dairy heifers • For unobserved (silent) estrus in lactating dairy cows with a corpus luteum • For treatment of pyometra (chronic endometritis) in cattle • For abortion in beef cows, beef heifers and replacement dairy heifers • For use with FACTREL (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows • For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in lactating dairy cows • For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers

Lutalyse® HighCon

For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers

Lutalyse® Injection

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 PGF2α, 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 PGF2α has been reported to cause increase in blood pressure, bronchoconstriction, and smooth muscle stimulation in certain species. 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 distributed 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 thework 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. Relative Bioavailability Study: The requirement for substantial evidence of effectiveness was fulfilled by a pharmacokinetic study comparing the relative bioavailability of the subcutaneous (SC) administration of 25 mg of LUTALYSE HighCon Injection (12.5 mg dinoprost/mL) to the approved intramuscular (IM) administration of 25 mg of LUTALYSE Injection (5 mg dinoprost/mL). The effectiveness data for LUTALYSE Injection at doses of 25 and 35 mg IM were used to support an adjusted Test/Reference (T/R) ratio of 1.4 and 90% Confidence Intervals of 80 - 164% for Cmax and AUC to demonstrate therapeutic equivalence. The pivotal relative bioavailability study was a randomized, non-replicated, three treatment, three period, six sequence crossover study in 24 cows (4 cows per sequence). Each cow received a single dose of 25 mg dinoprost administered as 5 mL of LUTALYSE Injection IM, 5 mL of LUTALYSE Injection SC, or 2 mL of LUTALYSE HighCon SC, with a washout period of 48 hours between doses. Plasma samples were collected at 60 and 10 minutes prior to dose administration, and at 5, 10, 15, 20, 30, 75 minutes, and at 2, 3, 4.5, 6, 7.5, and 12 hours after each dose. Samples were analyzed by UPLC-MS/MS for PGF2α (dinoprost) and PGFm (metabolite) concentrations. PGFm was chosen as the analyte of interest because its concentrations are reflective of exogenously administered dinoprost (after subtraction of endogenous concentrations), and it has a longer half-life and therefore less blood level fluctuations than PGF2α. The results of the relative bioavailability study are summarized in Table 1. The Cmax and AUClast of LUTALYSE HighCon were within the adjusted 90% Confidence Intervals. Therefore, the SC administration of 25 mg of LUTALYSE HighCon was equivalent to the IM administration of 25 mg LUTALYSE Injection. Table 1: Relative Bioavailability Results for LUTALYSE HighCon Injection Parameter Product/ Route LSMean Ratio T/ R† Lower 90% CI Upper 90% CI Cmax (ng/mL) LUTALYSE Injection (IM)* 41.26 LUTALYSE Injection (SC)* 50.80 1.23 110.99 136.60 LUTALYSE HighCon Injection (SC) 55.12 1.34 120.42 148.20 AUClast) (hr*ng/mL) LUTALYSE Injection (IM)* 66.85 LUTALYSE Injection (SC) 67.25 1.00 96.26 105.12 LUTALYSE HighCon Injection (SC) 65.81 0.98 94.20 102.87 Cmax - maximum plasma concentration AUClast - the area under the plasma concentration vs. time curve from time of injection to the limit of quantification of the assay * Reference product and route of administration † Geometric means

Lutalyse® HighCon

CLINICAL PHARMACOLOGY 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 PGF2α, 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 PGF2α has been reported to cause increase in blood pressure, bronchoconstriction, and smooth muscle stimulation in certain species. 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 distributed 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 halflife 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.

ProstaMate™(dinoprost tromethamine)Sterile Solution

WARNINGS AND PRECAUTIONS User Safety: Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water. Contact Information: To report adverse reactions call Bimeda, Inc. at 1-888-524-6332. Residue Warnings: 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. Do not use in horses intended for human consumption. Animal Safety Warnings: Severe localized clostridial infections associated with injection of ProstaMate have been reported. In rare instances, such infections have resulted in death. Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site whether localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse reactions. Non-steroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not be administered concurrently. Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestin would be expected to have a reduced response to ProstaMate. 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. In mares, ProstaMate is ineffective when administered prior to day-5 after ovulation. Mare pregnancy status should be determined prior to treatment since dinoprost tromethamine injection 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.

ProstaMate™(dinoprost tromethamine)Sterile Solution

User Safety: Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water. Residue Warnings: 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. Do not use in horses intended for human consumption. Animal Safety Warnings: Severe localized clostridial infections associated with injection of LUTALYSE Injection have been reported. In rare instances, such infections have resulted in death. Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site whether localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse reactions. Non-steroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not be administered concurrently. Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestin would be expected to have a reduced response to LUTALYSE Injection. 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. In mares, LUTALYSE Injection is ineffective when administered prior to day-5 after ovulation. Mare pregnancy status should be determined prior to treatment since LUTALYSE Injection 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.

Lutalyse® Injection

User Safety: Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water. Residue Warnings: No milk discard or preslaughter drug withdrawal period is required for labeled uses in cattle. Use of this product in excess of the approved dose may result in drug residues. Animal Safety Warnings: Severe localized clostridial infections associated with injection of LUTALYSE Injection have been reported. In rare instances, such infections have resulted in death. Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site whether localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse reactions. Nonsteroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not be administered concurrently. Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestin would be expected to have a reduced response to LUTALYSE Injection.

Lutalyse® HighCon

ADVERSE REACTIONS Cattle: 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 vocalization, salivation, and at the 100 mg (10x) dose only, possible vomiting. These side effects are transitory, lasting from 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 dinoprost tromethamine injection was reported but was not confirmed. CONTACT INFORMATIONTo report suspected adverse events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS) contact Bimeda, Inc. at 1-888-524-3222. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at www.fda.gov/reportanimalae.

ProstaMate™(dinoprost tromethamine)Sterile Solution

Cattle: 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 vocalization, salivation, and at the 100 mg (10x) dose only, possible vomiting. These side effects are transitory, lasting from 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 Injection was reported but was not confirmed. CONTACT INFORMATION For a copy of the Safety Data Sheet or to report adverse reactions, call Zoetis Inc. at 1-888-963-8471. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or www.fda.gov/reportanimalae.

Lutalyse® Injection

Cattle (beef cows, beef heifers, and replacement dairy heifers)

ProstaMate 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 ProstaMate (25 mg dinoprost) 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 ProstaMate. 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.

Intramuscular

ProstaMate®

Cattle (lactating dairy cows)

Administer 2 to 4 mL gonadorelin injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework: Administer the first dose of gonadorelin injection (2-4 mL) at Day 0 Administer ProstaMate® (25 mg dinoprost, as dinoprost tromethamine) by intramuscular injection 6-8 days after the first dose of gonadorelin injection. Administer a second dose of gonadorelin injection (2-4 mL) 30 to 72 hours after the ProstaMate® injection. Perform FTAI 0 to 24 hours after the second dose of gonadorelin injection, or inseminate cows on detected estrus using standard herd practices.

Intramuscular

ProstaMate®

Cattle (lactating dairy cows)

Administer one EAZI-BREED™ CIDR® Cattle Insert per animal and remove 7 days later (for example if administered on a Monday remove the following Monday). Administer 5 mL ProstaMate® at the time of removal of the EAZI-BREED™ CIDR® Cattle Insert. Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED™ CIDR® Cattle Insert and inseminate animals found in estrus following normal herd practices.

Intramuscular

ProstaMate®

Cattle (lactating dairy cows)

Inject a dose of 5 mL ProstaMate (25 mg dinoprost) 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.

Intramuscular

ProstaMate®

Cattle (beef cows, dairy cows, beef heifers and replacement dairy heifers)

Inject a dose of 5 mL ProstaMate (25 mg dinoprost) intramuscularly.

Intramuscular

ProstaMate®

Cattle (beef cows, beef heifers and replacement dairy heifers)

ProstaMate® is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Inject a dose of 25 mg dinoprost (5 mL) intramuscularly. Cattle that abort will abort within 35 days of injection.

Intramuscular

ProstaMate®

Cattle (beef cows, replacement beef and dairy heifers)

Administer one EAZI-BREED™ CIDR® Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday). Inject 5 mL ProstaMate (equivalent to 5 mg/mL dinoprost) 1 day prior to EAZI-BREED™ CIDR® Cattle Insert removal, on Day 6 of the 7 day administration period. Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED™ CIDR® Cattle Insert and inseminate animals about 12 hours after onset of estrus.

Intramuscular

ProstaMate®

Beef Cows, Beef Heifers and Replacement Dairy Heifers

LUTALYSE Injection 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 Injection (25 mg dinoprost) 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 Injection. 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.

Intramuscular

Lutalyse® Injection

Beef Cows, Beef Heifers and Replacement Dairy Heifers

Inject a dose of 25 mg dinoprost (5 mL) intramuscularly during the first 100 days of gestation. Cattle that abort will abort within 35 days of injection.

Intramuscular

Lutalyse® Injection

Lactating Dairy Cows

Administer 2 to 4 mL FACTREL Injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework: Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 Administer LUTALYSE (25 mg dinoprost, as dinoprost tromethamine) Injection by intramuscular injection 6-8 days after the first dose of FACTREL Injection. Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE injection. Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows on detected estrus using standard herd practices.

Intramuscular

Lutalyse® Injection

Lactating Dairy Cows

Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example if administered on a Monday remove the following Monday). Administer 5 mL LUTALYSE Injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals found in estrus following normal herd practices.

Intramuscular

Lutalyse® Injection

Lactating Dairy Cows

Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) 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.

Intramuscular

Lutalyse® Injection

Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection.

Intramuscular, Subcutaneous

Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) intramuscularly.

Intramuscular

Lutalyse® Injection

Cattle (Suckled Beef Cows, Replacement Beef and Dairy Heifers)

Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection.

Intramuscular, Subcutaneous

Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday). Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the 7 Day administration period. Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Beef Cows, Beef Heifers, Replacement Dairy Heifers)

Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) intramuscularly or subcutaneously either once or twice at a 10 to 12 day interval.

Intramuscular, Subcutaneous

LUTALYSE HighCon Injection is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. 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 HighCon Injection. 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. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Beef Cows, Beef Heifers, Replacement Dairy Heifers)

Inject a dose of 25 mg (2 mL) by intramuscular or subcutaneous injection.

Intramuscular, Subcutaneous

LUTALYSE HighCon Injection is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Cattle that abort will abort within 35 days of injection. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Cattle (Lactating Dairy Cows)

Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection.

Intramuscular, Subcutaneous

Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example, if administered on a Monday remove the following Monday). Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals found in estrus following normal herd practices. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, or 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 and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

LUTALYSE® HighCon Injection

Horses (mares)

Administer a single intramuscular injection of 1 mg per 100 lbs (45.5 kg) body weight which is usually 1 mL to 2 mL ProstaMate.

Intramuscular

ProstaMate®

Horses (mares)

Equivalent of 1 milligram of dinoprost per 100 pounds of body weight. For use once as a single intramuscular injection.

Intramuscular

Not for use in horses intended for food. Federal law restricts this drug to use by or on the order of a licensed veterinarian. Women of child-bearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion and bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water. Use of this product in excess of the approved dose may result in drug residues. Do not administer intravenously; this may potentiate adverse reactions.

Prostin F2 Alpha® Sterile Solution

Horse (mares)

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 Injection. This luteolytic effect can be utilized to control the timing of estrus in estrous cycling and clinically anestrous mares that have a corpus luteum

Intramuscular

Lutalyse® Injection

Swine (gilts and sows)

For intramuscular use for parturition induction in swine. ProstaMate is indicated for parturition 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 ProstaMate (10 mg dinoprost) to parturition of approximately 30 hours. This can be employed to control the time of arrowing in sows and gilts in late gestation.

Intramuscular

ProstaMate®

Swine (sows and gilts)

Inject intramuscularly 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 Injection (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. Do not administer to sows and/or gilts prior to 3 day of normal predicted farrowing as an increased number of stillbirths and postnatal mortality may result.

Intramuscular

Lutalyse® Injection

As with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the possibility of post- injection bacterial infections. Adequately clean and disinfect the vial stopper prior to entry with a sterile needle and syringe. Use only sterile needles, and use each needle only once. No vial stopper should be entered more than 20 times. 1. For Estrus Synchronization in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE HighCon Injection is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) intramuscularly or subcutaneously 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 HighCon Injection. 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 Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. 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 breed at the usual time relative to estrus. 3. For Treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. 4. For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE HighCon Injection is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. Cattle that abort will abort within 35 days of injection. 5. For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: Administer 2 to 4 mL FACTREL Injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework: • Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 6-8 days after the first dose of FACTREL Injection. • Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE HighCon Injection. • Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows on detected estrus using standard herd practices. Below are three examples of treatment regimens for the dosage regimen framework described immediately above: Example 1 Example 2 Example 3 Day 0 (Monday) 1st Factrel 1st Factrel 1st Factrel Day 7 (the following Monday) LUTALYSE HighCon LUTALYSE HighCon LUTALYSE HighCon Day 9 (Wednesday) 2nd Factrel + FTAI at 48 hours after LUTALYSE HighCon 2nd Factrel at 48 hours after LUTALYSE HighCon 2nd Factrel at 56 hours after LUTALYSE HighCon Day 10 (Thursday) FTAI 24 hours after 2nd FACTREL FTAI 18 hours after 2nd FACTREL 6. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for Synchronization of Estrus in Lactating Dairy Cows: • Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example if administered on a Monday remove the following Monday). • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular subcutaneous injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. • Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals found in estrus following normal herd practices. 7. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers: • Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday). • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the 7 day administration period. • Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus.

INTRAMUSCULAR

Lutalyse® HighCon

DOSAGE AND ADMINISTRATION As with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the possibility of post-injection bacterial infections. Adequately clean and disinfect the vial stopper prior to entry with a sterile needle and syringe. Use only sterile needles, and use each needle only once. Use within 3 months of first puncture and puncture a maximum of 20 times with a needle or 5 times with a dosage delivery device. When using a draw-off spike or needle with bore diameter larger than 4.90 mm, discard any product remaining in the vial immediately after use.

INTRAMUSCULAR

ProstaMate™(dinoprost tromethamine)Sterile Solution

As with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the possibility of post-injection bacterial infections. Adequately clean and disinfect the vial stopper prior to entry with a sterile needle and syringe. Use only sterile needles, and use each needle only once. 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.

INTRAMUSCULAR

Lutalyse® Injection

Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday). Inject 5 mL LUTALYSE Injection (equivalent to 5 mg/mL dinoprost) 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the 7 day administration period. Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus.

Intramuscular

Lutalyse® Injection