Factrel (Canada)

Manufacturer: Wyeth Animal Health

Gonadorelin Hydrochloride Injection

Sterile

DIN 00573760

Veterinary Use Only

Description

FACTREL (gonadorelin hydrochloride injection) is a sterile solution of synthetic luteinizing hormone/releasing hormone (LRH) intended for intramuscular administration.

Active Ingredient: Each mL of sterile solution contains gonadorelin (as hydrochloride salt), 50 µg.

Preservative: Benzyl alcohol 2% w/v.

FACTREL's (gonadorelin hydrochloride) chemical name is 5-oxo-L-propyl-L-histidyl- L-tryptophyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride.

Its molecular formula is C₅₅H₇₅H₁₇O₁₃ X HCl (X = 1 ~ 2), and it has a molecular weight of 1219 to 1255 depending on its hydrochloric acid content. It is structurally identical to the natural Luteinizing Hormone/Releasing Hormone (LRH) isolated from porcine or ovine hypothalami. The hydrochloride salt of gonadorelin used in FACTREL is a water-soluble white powder. It is synthesized by the classical solution method, and is virtually free of extraneous peptides or amino acids.

Actions

Gonadorelin (GnRH) induces ovulation when administered subcutaneously on the day of proestrus. It acts by augmenting anterior pituitary secretion of the gonadotropins, Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH).

Gonadorelin's capacity to cause the secretion of LH was found to be equal to that of LH/FSH-RH of natural origin.

In the treatment of cystic ovaries, FACTREL was demonstrated to be safe and effective at a clinical dose of 100 µg. Clinically it has been demonstrated that breeder cows treated with GnRH, at their third or greater services, showed a 51.1% conception rate, as opposed to a 43.2% conception rate for the control group.

Factrel Indications

As an aid in the treatment of cystic ovaries in the bovine. For use in repeat breeder dairy cows on or at the time of their third or greater service.

Warning

Treated animals must not be slaughtered for use in food for at least 7 days after the latest treatment with this drug. Milk taken from treated animals during treatment and within 12 hours after the latest treatment must not be used as food.

Toxicology

Gonadorelin did not elicit any signs of toxicity and was not lethal after intravenous administration of single doses of 100 mg/kg in mice and of single doses of 150 mg/kg in rats.

Following 28 consecutive days i.v. administration in mature rats at doses of 5, 25 and 50 µg/kg/day secondary pharmacology or hormonal changes were observed in treated males. These changes included decreased seminal vesicle weight (all doses), decreased body weight and prostatic weight (25 µg/kg or greater). These organ and body weight changes are regarded as secondary effects resulting from gonadotrophin release and the feed-back mechanism to high circulating levels of LH. There were no drug-related histopathologic alternations of seminal vesicle or prostate. In treated females, body and organ weights were comparable to the controls and there were no drug-related histopathologic alterations.

In monkeys receiving daily doses of 500 µg of gonadorelin for 28 days and in monkeys receiving either 4, 20 or 100 µg/kg/day from day 8 to day 15 of each animal's cycle, survival body weight, food consumption, clinical laboratory parameters, organ weights, gross and microscopic observations were not affected. No biologically significant changes in clinical chemistry parameters were observed.

Teratology

Teratology studies were carried out in pregnant mice, rats (two strains) and rabbits. Daily doses of gonadorelin up to 100 µg/kg were administered subcutaneously on days 6 through 15 of pregnancy in mice and rats, and on days 6 through 18 of gestation in rabbits. The administration of the compound, at doses of 100 µg/kg or less, did not produce any toxic effects in the dams or fetuses of the species tested.

Factrel Dosage And Administration

Cystic Ovaries

2 mL (100 µg) intramuscularly.

Repeat Breeders

2 mL (100 µg) to be administered intramuscularly on or at the time of cow's third or greater service.

Storage

Refrigerate, store at 2º to 7°C (35º to 45°F).

Availability

Available in 20 and 50 mL vial sizes

Bibliography

1. Banik, U.K. and C. Revesz: Biological activities of synthetic LH-RH (AY-24,031) in rats. Ayerst Research Laboratories, Pharmacology Department Research Report 24,031-04.

2. Revesz, C. and U.K. Banik: Biological testing of AY-24,031, synthetic LH-RH in hamsters. Ayerst Research Laboratories, Pharmacology Department Research Report 24,031-01.

3. Revesz, C. and J. Smyth: Reversal of the persistent estrus syndrome in rats by AY24,031, the synthetic LH-releasing Factor. Ayerst Research Laboratories, Pharmacology Department Research Report 24, 031-06.

4. Schally, A.V., A.J. Kastin and A. Arimura: The hypothalamus and reproduction. Am. J. Obstet. Gynecol. 114:423-442, 1972.

5. Schally, A.V., A. Arimura, W.H. Carter and TW. Redding: Luteinizing hormone-releasing hormone (LH-RH) activity of some synthetic polypeptides. I. Fragments shorter than decapeptide. Biochem. Biophys. Res. Comm. 48:366, 1972.

6. Hirsch, M.A.: Introduction of luteinizing hormone (LH) secretion by AY-24,031 in estrogen-progesterone-treated ovariectomized rats. Ayerst Research Laboratories, Department of Endocrinology and Immunochemistry Research Report AY-24,031-16.

7. Vavra, I. and M.P. Charest: General and cardiovascular acute tolerance studies on AY-24,031. Ayerst Research Laboratories, Pharmacology Department Research Report 24,031-02.

8. Hemm, R.D., L. Arslanoglou and L. Authier: AY-24,031: Twenty-eight day intravenous toxicity study in the rat. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-03.

9. Martini, L., M. Matta and F. Faschini: The Hypothalamus Academic Press Inc., New York (1970).

10. Hemm, R.D. and L. Authier: AY-24,031: Twenty-eight day subcutaneous toxicity study in the monkey. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-13.

11. Hemm, R.D. and L. Authier: AY-24,031: One cycle subcutaneous toxicity study in the monkey. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-05.

12. Hemm, R.D. and L. Authier: AY-24,031: Three cycle subcutaneous toxicity study in the female monkey. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-14.

13. Hemm, R.D. and L. Arslanoglou: AY-24,031: Evaluation of embryotoxic and teratologic potential in the mouse, Segment II of the “FDA Guidelines for Reproductive Studies”. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-07.

14. Hemm, R.D. and L. Arslanoglou: AY-24,031: Evaluation of embryotoxic and teratogenic potential in the Long Evans rat, Segment II of the “FDA Guidelines for Reproductive Studies”. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-10.

15. Hemm, R.D. and L. Arslanoglou: AY-24,031: Evaluation of embryotoxic and teratogenic potential in the Charles River rat, Segment II of the “FDA Guidelines for Reproductive Studies”. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-08.

16. Hemm, R.D. and L. Arslanoglou: AY-24,031: Evaluation of embryotoxic and teratogenic potential in the rabbit, Segment II of the “FDA Guidelines for Reproductive Studies”. Ayerst Research Laboratories, Animal Health Division Research Report 24,031-09.

17. Ayerst clinical report: Evaluation of clinical efficacy of GnRH as treatment for ovarian cysts in dairy cattle (protocols BW-83-1, BA-83-3). Data on file, Ayerst Laboratories.

18. Leslie, K.E. and Kelton, D.F: A study of the relationship of Gonadotrophin releasing hormone administered at breeding to herd, reproductive performance. Data on file, Ayerst Laboratories.

Trademarks used under license

Wyeth Animal Health, Division of Wyeth Canada, Guelph, Ontario, Canada

91459

C4310B

Nac No.

11570513