Pharmacia & Upjohn
dinoprost tromethamine injection
Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.
For intramuscular use for estrus
synchronization, treatment of unobserved (silent) estrus and pyometra
(chronic endometritis) in cattle; for abortion of feedlot and other
non-lactating cattle; for parturition induction in swine; and for
controlling the timing of estrus in estrous cycling mares and
clinically anestrous mares that have a corpus luteum.
This product contains the naturally occurring
prostaglandin F2 alpha (dinoprost) as the tromethamine salt. Each mL
contains dinoprost tromethamine equivalent to 5 mg dinoprost: also,
benzyl alcohol, 16.5 mg added as preservative. When necessary, pH was
adjusted with sodium hydroxide and/or hydrochloric acid. Dinoprost
tromethamine is a white or slightly off-white crystalline powder that
is readily soluble in water at room temperature in concentrations to at
least 200 mg/mL.
General Biologic Activity: Prostaglandins
occur in nearly all mammalian tissues. Prostaglandins, especially PGE’s
and PGF’s, have been shown, in certain species, to 1) increase at time
of parturition in amniotic fluid, maternal placenta, myometrium, and
blood, 2) stimulate myometrial activity, and 3) to induce either
abortion or parturition. Prostaglandins, especially 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
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 half-life of minutes.
Dinoprost is a natural prostaglandin. All systems
associated with dinoprost metabolism exist in the body; therefore, no
new metabolic, transport, excretory, binding or other systems need be
established by the body to metabolize injected dinoprost.
INDICATIONS AND USAGE
Cattle: LUTALYSE Sterile Solution is indicated as a luteolytic agent.
LUTALYSE is effective only in those cattle having a
corpus luteum, i.e., those which ovulated at least five days prior to
treatment. Future reproductive performance of animals that are not
cycling will be unaffected by injection of LUTALYSE.
1. For Intramuscular Use for Estrus Synchronization in Beef Cattle and Non-Lactating Dairy Heifers. LUTALYSE is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum.
Inject a dose of 5 mL LUTALYSE (25 mg PGF2α) intramuscularly either once or twice at a 10 to 12 day interval.
With the single injection, cattle should be bred at the usual time relative to estrus.
With the two injections cattle can be bred after the
second injection either at the usual time relative to detected estrus
or at about 80 hours after the second injection of LUTALYSE.
Estrus is expected to occur 1 to 5 days after
injection if a corpus luteum was present. Cattle that do not become
pregnant to breeding at estrus on days 1 to 5 after injection will be
expected to return to estrus in about 18 to 24 days.
2. For Intramuscular Use for Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum.
Inject a dose of 5 mL LUTALYSE (25 mg PGF2α) intramuscularly. Breed
cows as they are detected in estrus. If estrus has not been observed by
80 hours after injection, breed at 80 hours. If the cow returns to
estrus breed at the usual time relative to estrus.
Management Considerations: Many
factors contribute to success and failure of reproduction management,
and these factors are important also when time of breeding is to be
regulated with LUTALYSE Sterile Solution. Some of these factors are:
a. Cattle must be ready to breed - they must have a corpus luteum and be healthy;
b. Nutritional status must be adequate as this has a
direct effect on conception and the initiation of estrus in heifers or
return of estrous cycles in cows following calving;
c. Physical facilities must be adequate to allow cattle handling without being detrimental to the animal;
d. Estrus must be detected accurately if timed AI is not employed;
e. Semen of high fertility must be used;
f. Semen must be inseminated properly.
A successful breeding program can employ LUTALYSE
effectively, but a poorly managed breeding program will continue to be
poor when LUTALYSE is employed unless other management deficiencies are
Cattle expressing estrus following LUTALYSE are
receptive to breeding by a bull. Using bulls to breed large numbers of
cattle in heat following LUTALYSE will require proper management of
bulls and cattle.
3. For Intramuscular Use for Treatment of Pyometra (chronic endometritis) in Cattle.
Inject a dose of 5 mL LUTALYSE (25 mg PGF2α) intramuscularly. In
studies conducted with LUTALYSE, pyometra was defined as presence of a
corpus luteum in the ovary and uterine horns containing fluid but not a
conceptus based on palpation per rectum. Return to normal was defined as evacuation of fluid and return of the uterine horn size to 40mm or less based on palpation per rectum
at 14 and 28 days. Most cattle that recovered in response to LUTALYSE
recovered within 14 days after injection. After 14 days, recovery rate
of treated cattle was no different than that of nontreated cattle.
4. For Intramuscular Use for Abortion of Feedlot and Other Non-Lactating Cattle.
LUTALYSE is indicated for its abortifacient effect in feedlot and other
non-lactating cattle during the first 100 days of gestation. Inject a
dose of 25 mg intramuscularly. Cattle that abort will abort within 35
days of injection.
Commercial cattle were palpated per rectum
for pregnancy in six feedlots. The percent of pregnant cattle in each
feedlot less than 100 days of gestation ranged between 26 and 84; 80%
or more of the pregnant cattle were less than 150 days of gestation.
The abortion rates following injection of LUTALYSE increased with
increasing doses up to about 25 mg. As examples, the abortion rates,
over 7 feedlots on the dose titration study, were 22%, 50%, 71%, 90%
and 78% for cattle up to 100 days of gestation when injected IM with
LUTALYSE doses of 0, 1 (5 mg), 2 (10 mg), 4 (20 mg) and 8 (40 mg) mL,
respectively. The statistical predicted relative abortion rate based on
the dose titration data, was about 93% for the 5 mL (25 mg) LUTALYSE
dose for cattle injected up to 100 days of gestation.
Swine: For intramuscular use for
parturition induction in swine. LUTALYSE Sterile Solution is indicated
for 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 (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
Management Considerations: Several
factors must be considered for the successful use of LUTALYSE Sterile
Solution for parturition induction in swine. The product must be
administered at a relatively specific time (treatment earlier than 3
days prior to normal predicted farrowing may result in increased piglet
mortality). It is important that adequate records be maintained on (1)
the average length of gestation period for the animals on a specific
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.
Mares: LUTALYSE Sterile Solution
is indicated for its luteolytic effect in mares. This luteolytic effect
can be utilized to control the timing of estrus in estrous cycling and
clinically anestrous mares that have a corpus luteum in the following
1. Controlling Time of Estrus of Estrous Cycling Mares:
Mares treated with LUTALYSE during diestrus (4 or more days after
ovulation) will return to estrus within 2 to 4 days in most cases and
ovulate 8 to 12 days after treatment. This procedure may be utilized as
an aid to scheduling the use of stallions.
2. Difficult-to-Breed Mares: In
extended diestrus there is failure to exhibit regular estrous cycles
which is different from true anestrus. Many mares described as anestrus
during the breeding season have serum progesterone levels consistent
with the presence of a functional corpus luteum.
A proportion of “barren”, maiden, and lactating
mares do not exhibit regular estrous cycles and may be in extended
diestrus. Following abortion, early fetal death and resorption, or as a
result of “pseudopregnancy”, there may be serum progesterone levels
consistent with a functional corpus luteum.
Treatment of such mares with LUTALYSE usually
results in regression of the corpus luteum followed by estrus and/or
ovulation. In one study with 122 Standardbred and Thoroughbred mares in
clinical anestrus for an average of 58 days and treated during the
breeding season, behavioral estrus was detected in 81 percent at an
average time of 3.7 days after injection with 5 mg LUTALYSE; ovulation
occurred an average of 7.0 days after treatment. Of those mares bred,
59% were pregnant following an average of 1.4 services during that
Treatment of “anestrous” mares which abort
subsequent to 36 days of pregnancy may not result in return to estrus
due to presence of functional endometrial cups.
User Safety: Not for human use.
Women of childbearing age, asthmatics, and persons with bronchial and
other respiratory problems should exercise extreme caution
when handling this product. In the early stages, women may be unaware
of their pregnancies. Dinoprost tromethamine is readily absorbed
through the skin and can cause abortion. Accidental spillage on the
skin should be washed off immediately with soap and water.
Residue 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
Animal Safety Warnings: Severe
localized clostridial infections associated with injection of LUTALYSE
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 (I.V.) as this route might potentiate adverse reactions.
- No vial stopper should be entered more than 20 times.
For this reason, the 100 mL bottle should only be used for cattle. The
30 mL bottle may be used for cattle, swine, or mares.
- As with all parenteral products careful aseptic
techniques should be used to decrease the possibility of post-injection
bacterial infections. The vial stopper should be cleaned and
disinfected prior to needle entry. Only sterile needles should be used
and the same needle should not be used more than once.
- Nonsteroidal anti-inflammatory drugs may inhibit
prostaglandin synthesis; therefore this class of drugs should not be
Cattle: Do not administer to
pregnant cattle, unless abortion is desired. Cattle administered a
progestin would be expected to have a reduced response to LUTALYSE
Swine: Do not administer to sows
and/or gilts prior to 3 days of normal predicted farrowing, as an
increased number of stillbirths and postnatal mortality may result.
Mares: LUTALYSE Sterile
Solution is ineffective when administered prior to day-5 after
ovulation. Pregnancy status should be determined prior to treatment
since LUTALYSE has been reported to induce abortion and parturition
when sufficient doses were administered. Mares should not be treated if
they suffer from either acute or subacute disorders of the vascular
system, gastrointestinal tract, respiratory system, or reproductive
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, 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 Sterile Solution was reported but was not confirmed.
To report adverse reactions call Pfizer Animal Health at 1-800-366-5288.
DOSAGE AND ADMINISTRATION
As with any multi-dose vial, practice aseptic
techniques in withdrawing each dose. Adequately clean and disinfect the
vial stopper prior to entry with a sterile needle and syringe. No vial
closure should be entered more than 20 times.
Cattle: LUTALYSE Sterile Solution
is supplied at a concentration of 5 mg dinoprost per mL. LUTALYSE is
luteolytic in cattle at 25 mg (5 mL) administered intramuscularly.
Swine: LUTALYSE Sterile Solution will induce parturition in swine at 10 mg (2 mL) when injected intramuscularly.
1. Evaluate the reproductive status of the mare.
2. Administer a single intramuscular injection of 1 mg
per 100 lbs (45.5 kg) body weight which is usually 1 mL to 2 mL
LUTALYSE Sterile Solution.
3. Observe for signs of estrus by means of daily
teasing with a stallion, and evaluate follicular changes on the ovary
by palpation of the ovary per rectum.
4. Some clinically anestrous mares will not express
estrus but will develop a follicle which will ovulate. These mares may
become pregnant if inseminated at the appropriate time relative to
rupture of the follicle.
5. Breed mares in estrus in a manner consistent with normal management.
SAFETY AND TOXITY
Laboratory Animals: Dinoprost was
non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and
20.0 mg/kg/day from day 6th-15th of gestation or when administered
subcutaneously at 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or
9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the
rabbit when administered either subcutaneously at doses of 0.5 and 1.0
mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14
or 15, 16 and 17 or orally at doses of 0.01, 0.1 and 1.0 mg/kg/day on
days 6-18 or 5.0 mg/kg/day on days 8-18 of gestation. A slight and
marked embryo lethal effect was observed in dams given 1.0 and 5.0
mg/kg/day respectively. This was due to the expected luteolytic
properties of the drug.
A 14-day continuous intravenous infusion study in rats
at 20 mg 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 Sterile
Solution at 15 mg PGF2α 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
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
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
Mares: Dinoprost tromethamine was
administered to adult mares (weighing 320 to 485 kg; 2 to 20 years
old), at the rates of 0, 100, 200, 400, and 800 mg per mare per day for
8 days. Route of administration for each dose group was both
intramuscularly (2 mares) and subcutaneously (2 mares). Changes were
detected in all treated groups for clinical (reduced sensitivity to
pain; locomotor incoordination; hypergastromotility; sweating;
hyperthermia; labored respiration), blood chemistry (elevated
cholesterol, total bilirubin, LDH, and glucose), and hematology
(decreased eosinophils; increased hemoglobin, hematocrit, and
erythrocytes) measurements. The effects in the 100 mg dose, and to a
lesser extent, the 200 mg dose groups were transient in nature, lasting
for a few minutes to several hours. Mares did not appear to sustain
adverse effects following termination of the side effects.
Mares treated with either 400 mg or 800 mg exhibited
more profound symptoms. The excessive hyperstimulation of the
gastrointestinal tract caused a protracted diarrhea, slight electrolyte
imbalance (decreased sodium and potassium), dehydration,
gastrointestinal irritation, and slight liver malfunction (elevated
SGOT, SGPT at 800 mg only). Heart rate was increased but pH of the
urine was decreased. Other measurements evaluated in the study remained
within normal limits. No mortality occurred in any of the groups. No
apparent differences were observed between the 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 was demonstrated to have a wide margin of safety.
Thus, the 100 mg dose gave a safety margin of 10 to 20X for a single
injection or 80 to 160X for the 8 daily injections.
Additional studies investigated the effects in the mare
of single intramuscular doses of 0, 0.25, 1.0, 2.5, 3.0, 5.0, and 10.0
mg dinoprost tromethamine. Heart rate, respiration rate, rectal
temperature, and sweating were measured at 0, 0.25, 0.50, 0.75, 1.0,
1.5, 2.0, 3.0, 4.0, 5.0, and 6.0 hr. after injection. Neither heart
rate nor respiration rates were significantly altered (P > 0.05)
when compared to contemporary control values. Sweating was observed for
0 of 9, 2 of 9, 7 of 9, 9 of 9, and 8 of 9 mares injected with 0.25,
1.0, 2.5, 3.0, 5.0, or 10.0 mg dinoprost tromethamine, respectively.
Sweating was temporary in all cases and was mild for doses of 3.0 mg or
less but was extensive (beads of sweat over the entire body and
dripping) for the 10 mg dose. Sweating after the 5.0 mg dose was
intermediate between that seen for mares treated with 3.0 and 10.0 mg.
Sweating began within 15 minutes after injection and ceased by 45 to 60
minutes after injection. Rectal temperature was decreased during the
interval 0.5 until 1.0, 3 to 4, or 5 hours after injection for 0.25 and
1.0 mg, 2.5 and 3.0, or 5.0 and 10.0 mg dose groups, respectively.
Average rectal temperature during the periods of decreased temperature
was on the order of 97.5 to 99.6, with the greatest decreases observed
in the 10 mg dose group.
LUTALYSE Sterile Solution is available in 30 and 100 mL vials.
Store at controlled room temperature 20° to 25° C (68° to 77° F). Protect from freezing
NADA #108-901, Approved by FDA
U.S. Patent No. 6,187,818
Distributed by: Pharmacia & Upjohn Company, Division of Pfizer Inc, NY, NY 10017
Revised March 2007
810 470 418
NAC No.: 10490302