Ovu-Late Injection For luteolysis of functional corpora lutea in cows and mares.

ACTIVE CONSTITUENT

Cloprostenol (as sodium salt) 250 μg/mL

 

DIRECTIONS FOR USE

This product is contraindicated in mares suffering from acute or subacute disorders of the gastrointestinal or respiratory system. This product should not be used in pregnant animals when abortion or induced parturition is not the objective. This product should not be administered intravenously. Following withdrawal of the first dose, use the remainder of the vial within 28 days or discard the unused portion.

Cows: Single or repeat doses of 2 mL by intramuscular injection.

Mares: Less than 400 kg bodyweight: 0.5-1 mL by intramuscular injection. Greater than 400 kg bodyweight: 1-2 mL by intramuscular injection.

WITHHOLDING PERIODS: MEAT: (COWS): DO NOT USE less than 1 day before slaughter for human consumption.

(HORSES): NOT TO BE USED in horses intended for human consumption.

MILK: NIL

TRADE ADVICE: EXPORT SLAUGHTER

INTERVAL (ESI): ESI not established.

FIRST AID: If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 13 11 26; New Zealand 0800 764 766.

Dispose of empty container by wrapping with paper and putting in garbage. Store below 25°C (air conditioning). Protect from light.

PHARMACOLOGY

Prostaglandins (PGs) are 20-carbon unsaturated fatty acids which consist of a cyclopentane ring with two aliphatic side chains. They are synthesised from free arachidonic acid in most major tissues in the body and serve as local hormones, acting on tissues near their site of synthesis.

PGs are structurally classed into nine major groups, A to I, each containing subgroups denoted by the subscripts 1, 2 and 3. In domestic animals the most important PG appears to be PGF2α. Cloprostenol is a functional synthetic analogue of the naturally occurring PGF2α dinoprost.

Actions: In the reproductive system PGs play a role in ovulation, luteolysis, gamete transport, uterine motility, expulsion of foetal membranes, and sperm transport in both the male and female tracts.

PGs are employed in reproductive therapeutics primarily for their potent luteolytic effects. PGF2α causes rapid regression of functional corpora lutea, with resultant rapid decline in progesterone production. Luteolysis is usually followed by ovarian follicular development and a return to oestrus with normal ovulation. In cattle oestrus occurs 2-4 days after luteolysis, and in mares 2-5 days after luteolysis. The early corpus luteum is insensitive to the effects of PG; in cattle and horses this refractory period spans the first 4-5 days post ovulation.

The precise mechanism of PG-induced luteolysis is uncertain but may relate to blood flow changes in the uteoovarian vessels, inhibition of the normal ovarian response to circulating gonadotrophin, or stimulation of catalytic enzymes. PGF2 also has a direct stimulatory effect on uterine smooth muscle causing contraction, and a relaxant effect on the cervix.

Pharmacokinetics: Cloprostenol is rapidly distributed in the body following intramuscular administration. In cattle maximum tissue levels are reached within 30 minutes of dosing. Cloprostenol is eliminated in approximately equal amounts via the kidney and in bile. Excretion in urine is partly as unchanged cloprostenol, and partly as its tetranor acid both in conjugated and unconjugated form.

In cattle cloprostenol has a biological half-life of 1.6 hours. Within 24 hours the concentration of cloprostenol at the injection site falls below the limits of detection. Cloprostenol does not accumulate in the mammary gland, with less than 0.75% of a given dose eliminated in the milk.

CLINICAL APPLICATION

Cows: Cloprostenol induces luteolysis of functional corpora lutea, with return to oestrus in most cows in 2-4 days. The corpus luteum is refractory to the effects of PG in the first 4-5 days post ovulation. Conception rates at the induced and subsequent oestrus periods are normal, and there are no detrimental effects on calves conceived during PG treatment.

This product can be used in the following clinical situations: Synchronisation of the oestrous cycle for controlled breeding.

This product can be used in a number of treatment regimes to synchronise the oestrus cycle of groups of cows. Some of these are described below.

Double Prostaglandin Program: Two injections of this product 14 days apart. Artificial insemination or natural mating at the induced oestrus which should be detected 2-4 days after the second injection.

Why-Wait Program: Heat detection during the first 5-7 days of the mating period and artificial insemination or natural joining of cows observed in oestrus. Injection of cows not observed in oestrus with this product at the end of the 5-7 day period and artificial or natural mating at the induced oestrus which should be detected 2-4 days after the injection.

Modified Why-Wait Program: Heat detection during the 6 days prior to the start of mating. Cows not observed in oestrus are given a single injection of this product on day 5 of the mating period. In both groups artificial or natural mating at the induced oestrus which should b e detected 2-4 after the injection.

PGF2α + GnRH Programs: Injection of this product in combination with Gonadotrophin Releasing Hormone (GnRH) followed by fixed time insemination, which may be summarised as follows:

Day 0: GnRH administration
Day 7: PGF2α administration
Day 9: GnRH administration (48 hours after PGF2α)

Insemination 8-24 hours after 2nd GnRH.

Insemination is performed at a fixed time 8 to 24 hours after the 2nd GnRH dose, regardless of the presence or absence of visible oestrus.

Synchronisation of ovulation achieved by the above protocol is of a degree of precision that allows fixed-time insemination, which provides numerous management and economic benefits, particularly in situations where the level of oestrus detection is low. Large groups of cows may be inseminated together, the need for oestrus detection in the first round is eliminated, the calving to conception interval is reduced and a tighter calving pattern is achieved. Protocols such as described above have measured favourably against standard prostaglandin programs in terms of reproductive parameters such as pregnancy rate and calving to conception interval.

GnRH/PGF2α oestrus synchronisation protocols are intended for lactating dairy cattle. Variable results are reported in the literature for the application of GnRH/PGF2α in heifers.

Routine use in the early postpartum period to improve reproductive performance: Routine treatment with cloprostenol in the early postpartum period can reduce the calving to conception interval in dairy herds. A number of factors are thought to be involved in this response: the myometrial stimulatory effect of PG resulting in more rapid uterine involution; a sparing effect on uterine infection; and the luteal effect providing more prompt treatment of cows with sub or silent oestrus or prolonged luteal phases. One or two treatments can be given between 12 and 40 days post partum.

Unobserved oestrus in cows with normal corpora lutea: Cows may be cycling normally but either fail to display behavioural oestrus or display only very subtle signs. This condition occurs most commonly in high yielding dairy cows at peak lactation. Normal ovarian cyclical activity should be determined by rectal palpation of a corpus luteum prior to administration.

Oestrus should commence 2-4 days following treatment, with artificial insemination or joining at the detected heat. Failure of oestrus induction may result if the treatment is given during the refractory period of the corpus luteum and will necessitate a further injection 14 days after the first.

Termination of unwanted normal pregnancies (e.g. following mismating): Pregnancy can be terminated by treatment with this product from days 7-150 following conception. Between days 7 and 100 abortion is rapidly and reliably induced within 3-5 days of treatment. Between days 100-150 results may be less reliable due to the decreasing role of luteal progesterone and increasing role of placental progesterone in the maintenance of pregnancy. If abortion has not occurred by the eighth day following treatment, a repeat injection should be given.

Treated animals should be closely observed until expulsion of foetus and placental membranes is complete. Abortion should not be induced with this product alone after day 150 of gestation.

Termination of abnormal pregnancy (e.g. expulsion of mummified foetuses): Foetal death may result in the mummification of the foetus in utero. Treatment with this product at any stage of gestation will result in luteolysis and expulsion of the mummified foetus from the uterus. Occasionally manual removal of the foetus from the vagina is necessary.

Pathological accumulation of placental fluids (hydramnios or hydrallantois) can be a life threatening condition, and is rarely resolved by surgical drainage. Termination of pregnancy by this product is often the preferred treatment option.

Induction of parturition: Parturition may be induced using this product alone but to optimise calf viability should be carried out as close to the predicted calving date as possible and should not be attempted prior to day 270 of gestation. Parturition usually occurs between 36 and 48 hours following treatment with this product. All cows so induced should be closely supervised. As with all other methods used to induce parturition there may be a higher than usual incidence of retained foetal membranes. Any reduction in survival rates of calves born as a result of parturition induction is considered to be a result of prematurity rather than an effect attributable to PG treatment.

Retained foetal membranes, pyometra or chronic endometritis: Cloprostenol has a stimulatory effect on the myometrium, causing uterine contraction. This action can aid in the expulsion of retained foetal membranes. In the absence of septicaemia this product may aid in the treatment of post-partum uterine infections via regression of the corpus luteum and stimulation of myometrial contractions. The rapid decline in progesterone and increase in oestrogen which occur as a result of luteolysis stimulate uterine defence mechanisms and further aid in resolution of infection.

Luteal cysts: Cystic ovaries may be associated with persistent luteal tissue, and treatment with this product may effectively resolve such conditions and allow a return to normal cyclical activity.

Mares: Cloprostenol causes regression of the corpus luteum in mares except during the refractory period spanning the first 4-5 days after ovulation.

Oestrus commences 2-5 days following administration of this product, with normal ovulation occurring 8-12 days after treatment. Conception rates at the induced oestrus are normal, and there are no deleterious effects on foals born as a result of cycle manipulation. This product may be of clinical value in the following situations:

Unobserved or undetected oestrus (“silent heat”) in mares which are cycling normally: Mares which are cycling normally may not display full behavioural oestrus or other physiological changes commonly associated with oestrus (e.g. oedema and relaxation of the cervix), resulting in failure to observe optimal covering times. This condition has a higher incidence in maiden mares early in the breeding season.

Rectal palpation or ultrasound aid in the diagnosis of normal cyclical activity. Treatment with this product enables prediction of the time of onset of oestrus, allowing optimal utilisation of teasing and stallion resources.

Prolonged dioestrus: Prolonged dioestrus due to the presence of persistent corpora lutea occurs in up to 20% of mares, and responds to a single injection of this product.

Early foetal death followed by resorption: Early foetal death (in the first 100 days) occurs in up to 8-10% of mares, and may be followed by foetal resorption and a failure to return to cyclical activity due to the presence of persistent corpora lutea. Administration of this product may be useful in the treatment of this condition.

Pseudopregnancy: Mares with a persistent corpus luteum may display signs of pregnancy but be found to be non-pregnant on examination. Treatment with this product should induce luteolysis and a return to normal cyclical activity.

Lactation-induced anoestrus: Lactational anoestrus occurs relatively commonly, particularly in mares which foal early in the breeding season. Affected mares may or may not ovulate at the “foal heat” but thereafter fail to return to oestrus, often for several months. This product may be effective in inducing a return to normal cyclical activity, although results are variable.

Induction of abortion prior to day 45 (e.g. following mismating): Abortion may be induced by treatment with a single injection of this product prior to day 35 following conception. Following the formation of the endometrial cups at day 35 treatment with a single injection of PG may fail to induce abortion, and this product must be administered at daily intervals for 4 days to induce abortion in such mares. Mares in which abortion is induced after day 35 do not return to oestrus until the endometrial cups cease functioning.

Nomination of time of service: Treatment with this product may be employed to bring mares into oestrus at nominated times, for the optimal management of high-demand stallions during the breeding season.

Synchronisation of oestrus cycles: Treatment with this product may be employed to synchronise the cycles of a group of mares, for example donor and recipient mares used in embryo transfer programmes.

DIRECTIONS FOR USE

This product is contraindicated in mares suffering from acute or subacute disorders of the gastrointestinal or respiratory system. This product should not be used in pregnant animals when abortion or induced parturition is not the objective. This product should not be administered intravenously. Following withdrawal of the first dose, use the remainder of the vial within 28 days or discard the unused portion.

Cows: Single or repeat doses of 2 mL (500 µg Cloprostenol) by intramuscular injection
Oestrus Synchronisation Protocol: Day 0: Injection of 1 mL Cattle-Mate Injection 100 µg/mL
Day 7: 2 mL Ovu-Late Injection
Day 9: Injection of 1 mL Cattle-Mate Injection 100 µg/mL
Insemination: 8-24 hours after 2nd injection of Cattle-Mate Injection.
Mares: Less than 400 kg bodyweight: 0.5-1 mL (125-250 µg cloprostenol) by intramuscular injection.
Greater than 400 kg bodyweight: 1-2 mL (250-500 µg cloprostenol) by intramuscular injection.

WITHHOLDING PERIODS

MEAT WITHHOLDING PERIOD: (COWS): DO NOT USE less than 1 day before slaughter for human consumption.

(HORSES): NOT TO BE USED in horses intended for human consumption.

MILK WITHHOLDING PERIOD: NIL

TRADE ADVICE: EXPORT SLAUGHTER INTERVAL (ESI): This product does not have an ESI established. For advice on the ESI, contact the manufacturer before using this product.

CAUTION: Women of child-bearing age, asthmatics or other people with bronchial disease should use extreme caution when handling cloprostenol as the drug may induce abortion or acute bronchoconstriction. Gloves should be worn when administering the drug.

Cloprostenol is readily absorbed through the skin: any cloprostenol contacting skin must be washed off immediately using soap and water.

ADVERSE EFFECTS: Occasional side effects have been observed following intramuscular administration of PG. Such effects are generally transient and have little detrimental effect on the animal.

In cows, increased body temperature and salivary secretion have been reported, usually associated with the administration of 5-10 times the recommended dose. Experimental administration of 50-100 times the recommended dose to cattle resulted in signs of uneasiness, salivation and milk let-down, but no other adverse effects.

In mares, sweating, increased respiratory and heart rates, ataxia, watery diarrhoea and signs of mild abdominal pain have been observed. Such reactions have usually resulted from doses in excess of that recommended, and are generally mild and transient.

FIRST AID: If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 13 11 26; New Zealand 0800 764 766.

STORAGE & DISPOSAL: Store below 25°C (air conditioning). Protect from light. Following withdrawal of the first dose, use the remainder of the vial within 28 days or discard the unused portion. Dispose of empty container by wrapping with paper and putting garbage.

REGISTRATION

ACVM No. A10159 (New Zealand)

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