Cattle

LUTALYSE Injection is indicated as a luteolytic agent. LUTALYSE Injection is effective only in those cattle having a corpus luteum, i.e., those which ovulated at least five days prior to treatment.

Future reproductive performance of animals that are not cycling will be unaffected by injection of LUTALYSE Injection.

• 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-BREEDTM CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in lactating dairy cows

• For use with EAZI-BREEDTM 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

Swine

• For parturition induction in swine

Mares

• For controlling the timing of estrus in estrous cycling mares

• For difficult-to-breed mares (clinically anestrous mares that have a corpus luteum)

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 Injection. Some of these factors are:

    a. Cattle must be ready to breed—they must have a corpus luteum and be healthy;

    b. Nutritional status must be adequate as this has a direct effect on conception and the initiation of estrus in heifers or return of estrous               cycles in cows following calving;

    c. Physical facilities must be adequate to allow cattle handling without being detrimental to the animal;

    d. Estrus must be detected accurately if timed Al is not employed;

    e. Semen of high fertility must be used;

    f. Semen must be inseminated properly.

A successful breeding program can employ LUTALYSE Injection effectively, but a poorly managed breeding program will continue to be poor when LUTALYSE Injection is employed unless other management deficiencies are remedied first. Cattle expressing estrus following LUTALYSE Injection are receptive to breeding by a bull. Using bulls to breed large numbers of cattle in heat following LUTALYSE Injection will require proper management of bulls and cattle.

Cattle

1. For Estrus Synchronization in 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.

2. For Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum. 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.

3. For Treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) intramuscularly.

4. For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE 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 25 mg dinoprost (5 mL) intramuscularly. 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 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.

Below are three examples of treatment regimens for FTAI that fit within the dosage regimen framework described immediately above:

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 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.

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).

• Inject 5 mL LUTALYSE Injection (equivalent to 5 mg/mL dinoprost) 1 day prior to EAZIBREED 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.

Swine

For Parturition Induction in Swine: For intramuscular use for parturition induction in swine. LUTALYSE Injection 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 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.

Management Considerations: Several factors must be considered for the successful use of LUTALYSE Injection for parturition induction in swine. The product must be administered at a relatively specific time (treatment earlier than 3 days prior to normal predicted farrowing may result in increased piglet mortality). It is important that adequate records be maintained on (1) the average length of gestation period for the animals on a specific location, and (2) the breeding and projected farrowing dates for each animal. This information is essential to determine the appropriate time for administration of LUTALYSE Injection.

Mares

LUTALYSE Injection is indicated for its luteolytic effect in 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 in the following circumstances:

    1. Controlling Time of Estrus of Estrous Cycling     

         Mares: Mares treated with LUTALYSE Injection during diestrus (4 or more days after ovulation) will return to estrus within 2 to 4                    days  in most cases and ovulate 8 to 12 days after treatment. This procedure may be utilized as an aid to scheduling the use of                         stallions.

    2. Difficult-to-Breed

         Mares: In extended diestrus there is failure to exhibit regular estrous cycles which is different from true anestrus.  Many mares                         described as anestrus during the breeding season have serum progesterone levels consistent with the presence of a                                        functional corpus luteum. A proportion of “barren”, maiden, and lactating mares do not exhibit regular estrous cycles and may be in               extended diestrus. Following abortion, early fetal death and resorption, or as a result of “pseudopregnancy”, there may be serum                    progesterone levels consistent with a functional corpus luteum. Treatment of such mares with LUTALYSE Injection usually results in               regression of the corpus luteum followed by estrus and/or ovulation. Treatment of “anestrous” mares which abort subsequent to 36               days of pregnancy may not result in return to estrus due to presence of functional endometrial cups.

LABORATORY ANIMALS

Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and 20.0 mg dinoprost/kg/day from day 6th-15th of gestation or when administered subcutaneously at 0.5 and 1.0 mg/ kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered either subcutaneously at doses of 0.5 and 1.0 mg dinoprost/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14 or 15, 16 and 17 or orally at doses of 0.01, 0.1 and 1.0 mg dinoprost/ kg/day on days 6-18 or 5.0 mg/kg/day on days 8-18 of gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg dinoprost/kg/ day respectively. This was due to the expected luteolytic properties of the drug.

A 14-day continuous intravenous infusion study in rats at 20 mg PGF2α per kg body weight indicated prostaglandins of the F series could induce bone deposition. However, such bone changes were not observed in monkeys similarly administered LUTALYSE Injection at 15 mg dinoprost per kg body weight for 14 days.

CATTLE

In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, urinalysis,organ weights, and gross plus microscopic measurements following treatment with various doses up to 250 mg dinoprost administered twice intramuscularly at a 10 day interval or doses of 25 mg administered daily for 10 days. There was no unequivocal effect of dinoprost on the hematology or clinical chemistry parameters measured. Clinically, a slight transitory increase in heart rate was detected. Rectal temperature was elevated about 1.5˚ F through the 6th hour after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No dinoprost associated gross lesions were detected. There was no evidence of toxicological effects. Thus, dinoprost had a safety factor of at least 10X on injection (25 mg luteolytic dose vs. 250 mg safe dose), based on studies conducted with cattle. At luteolytic doses, dinoprost had no effect on progeny. If given to a pregnant cow, it may cause abortion; the dose  required for abortion varies considerably with the stage of gestation. Induction of abortion in feedlot cattle at stages of gestation up to 100 days of gestation did not result in dystocia, retained placenta or death of heifers in the field studies. The smallness of the fetus at this early stage of gestation should not lead to complications at abortion. However, induction of parturition or abortion with any exogenous compound may precipitate dystocia, fetal death, retained placenta and/or metritis, especially at latter stages of gestation.

SWINE

In pigs, evaluation was made of clinical observations, food consumption, clinical pathologic determinations, body weight changes, urinalysis, organ weights, and gross and microscopic observations following treatment with single doses of 10, 30, 50 and 100 mg dinoprost administered intramuscularly. The results indicated no treatment related effects from dinoprost treatment that were deleterious to the health of the animals or to their offspring.

MARES

Dinoprost tromethamine was administered to adult mares (weighing 320 to 485 kg; 2 to 20 yearsold), at the rates of 0, 100, 200, 400, and 800 mg per mare per day for 8 days. Route of administration for each dose group was both intramuscularly (2 mares) and subcutaneously (2 mares). Changes were detected in all treated groups for clinical (reduced sensitivity to pain; locomotor incoordination; hypergastromotility; sweating; hyperthermia; labored respiration), blood chemistry (elevated cholesterol, total bilirubin, LDH, and glucose), and hematology (decreased eosinophils; increased hemoglobin, hematocrit, and erythrocytes) measurements. The effects in the 100 mg dose, and to a lesser extent, the 200 mg dose groups were transient in nature, lasting for a few minutes to several hours. Mares did not appear to sustain adverse effects following termination of the side effects.

Mares treated with either 400 mg or 800 mg exhibited more profound symptoms. The excessive hyperstimulation of the gastrointestinal tract caused a protracted diarrhea, slight electrolyte imbalance (decreased sodium and potassium), dehydration, gastrointestinal irritation, and slight liver malfunction (elevated SGOT, SGPT at 800 mg only). Heart rate was increased but pH of the urine was decreased. Other measurements evaluated in the study remained within normal limits. No mortality occurred in any of the groups. No apparent differences were observed between the intramuscular and subcutaneous routes of administration. Luteolytic doses of dinoprost tromethamine are on the order of 5 to 10 mg administered on one day, therefore, LUTALYSE Injection was demonstrated to have a wide margin of safety. Thus, the 100 mg dose gave a safety margin of 10 to 20X for a single injection or 80 to 160X for the 8 daily injections. Additional studies investigated the effects in the mare of single intramuscular doses of 0, 0.25, 1.0, 2.5, 3.0, 5.0, and 10.0 mg dinoprost tromethamine. Heart rate, respiration rate, rectal temperature, and sweating were measured at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6.0 hr. after injection. Neither heart rate nor respiration rates were significantly altered (P > 0.05) when compared to contemporary control values. Sweating was observed for 0 of 9, 2 of 9, 7 of 9, 9 of 9, and 8 of 9 mares injected with 0.25, 1.0, 2.5, 3.0, 5.0, or 10.0 mg dinoprost tromethamine, respectively. Sweating was temporary in all cases and was mild for doses of 3.0 mg or less but was extensive (beads of sweat over the entire body and dripping) for the 10 mg dose. Sweating after the 5.0 mg dose was intermediate between that seen for mares treated with 3.0 and 10.0 mg. Sweating began within 15 minutes after injection and ceased by 45 to 60 minutes after injection. Rectal temperature was decreased during the interval 0.5 until 1.0, 3 to 4, or 5 hours after injection for 0.25 and 1.0 mg, 2.5 and 3.0, or 5.0 and 10.0 mg dose groups, respectively. Average rectal temperature during the periods of decreased temperature was on the orderof 97.5 to 99.6, with the greatest decreases observed in the 10 mg dose group.

STORAGE CONDITIONS

Store at controlled room temperature 20° to 25°C (68° to 77°F).

Use contents within 12 weeks of first vial puncture.

Protect from freezing.