Prescription Drugs

CLINICAL PHARMACOLOGY Factrel (gonadorelin) has been shown to have gonadotropin-releasing effects upon the anterior pituitary. The range for normal baseline LH levels, as determined from the literature, is 5-25 mIU/mL in postpubertal males, and postpubertal and premenopausal females. The standard used is the Second International Reference Preparation HMC. This range may not correspond in each laboratory performing the assay since the concentration of LH in normal individuals varies with different assay methods. The normal responses to Factrel (gonadorelin) analyzed from the results of clinical studies included: LH peak (mIU/mL) (highest LH value post-Factrel (gonadorelin) administration) Maximum LH increase (mIU/mL) (peak LH value LH baseline value) LH percent response peak LH baseline LH γ- 100% baseline LH Time to peak (minutes) (time required to reach LH peak value) Normal adult subjects were shown to have these LH responses following Factrel (gonadorelin) administration by subcutaneous or intravenous routes. MALE ADULTS: Subcutaneous Administration The results are based on 18 tests in males between the ages of 18-42 years, inclusive: LH peak: mean 60.3 ± 26.2 mIU/mL 100% >= 24.0 mIU/mL 90% >= 32.8 mIU/mL Maximum LH increase: mean 46.7 ± 20.8 mIU/mL 100% >= 12.3 mIU/mL 90% >= 20.9 mIU/mL LH percent response: mean 437 ± 243% range: 66-1853% 90% >= 188% Time to peak: mean 34 ± 13 min Intravenous Administration The results are based on 26 tests in males between the ages of 19-58 years, inclusive: LH peak: mean 63.8 ± 40.3 mIU/mL 100% >= 12.6 mIU/mL 90% >= 26.0 mIU/mL Maximum LH increase: mean 51.3 ± 35.2 mIU/mL 100% >= 7.4 mIU/mL 90% >= 14.8 mIU/mL LH percent response: mean 481 ± 184% range: 67-2139% 90% >= 142% Time to peak: mean 27 ± 14 min In males older than 50 years, the LH baseline and peak levels tend to be higher; however, the maximum LH increases do not differ in regard to age. FEMALE ADULTS: Subcutaneous Administration The results are based on 38 tests in females between the ages of 19-36 years, inclusive: LH peak: mean 67.9 ± 27.5 mIU/mL 100% >= 12.5 mIU/mL 90% >= 39.0 mIU/mL Maximum LH increase: mean 52.8 ± 26.4 mIU/mL 100% >= 7.5 mIU/mL 90% >= 23.8 mIU/mL LH percent response: mean 374 ± 221% range: 108-981% 90% >= 185% Time to peak: mean 71.5 ± 49.6 min Intravenous Administration The results are based on 31 tests in females between the ages of 20-35 years, inclusive: LH peak: mean 57.6 ± 36.7 mIU/mL 100% >= 20.0 mIU/mL 90% >= 24.6 mIU/mL Maximum LH increase: mean 44.5 ± 31.8 mIU/mL 100% >= 7.5 mIU/mL 90% >= 16.2 mIU/mL LH percent response: mean 356 ± 282% range: 60-1300% 90% >= 142% Time to peak: mean 36 ± 24 min The Factrel (gonadorelin) tests on which the normal female responses are based were performed in the early follicular phase of the menstrual cycle (Days 1-7). In menopausal and postmenopausal females, the baseline LH levels are elevated and the maximum LH increases are exaggerated when compared with the premenopausal levels. Patients with clinically diagnosed or suspected pituitary and/or hypothalamic dysfunction were often shown to have subnormal or no LH responses following Factrel (gonadorelin) administration. For example, in clinical tests of 6 patients with known postpubertal panhypopituitarism, and 11 patients with Prader-Willi syndrome, 100% showed subnormal responses or no rise in LH. Subnormal responses to the Factrel (gonadorelin) test also were observed in 21 (95%) of 22 patients with prepubertal panhypopituitarism. In 19 patients with Sheehan's syndrome, 16 (84%) had a subnormal response. In the Factrel (gonadorelin) test in 44 patients with Kallmann's syndrome, 33 (77%) had subnormal LH responses.

DESCRIPTION An agent for use in evaluating hypothalamic-pituitary gonadotropic function. Factrel (gonadorelin hydrochloride) injectable is available as a sterile lyophilized powder for reconstitution and administration by subcutaneous or intravenous routes. Chemical Name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl -L- tyrosyl-glycyl -L- leucyl-L-arginyl-L-prolyl glycinamide hydrochloride Factrel (gonadorelin) is C 55 H 75 N 17 O 13 HCl, as the mono- or dihydrochloride, or their mixture. The gonadorelin base has a molecular weight of 1182.33. It is a white powder, soluble in alcohol and water, hygroscopic and moisture-sensitive, and stable at room temperature. The synthetic decapeptide, Factrel (gonadorelin) , has a chemical composition and structure identical to the natural hormone, identified from porcine or ovine hypothalami. Each Secule® vial of Factrel contains 100 or 500 mcg gonadorelin as the hydrochloride, with 100 mg lactose, USP. Each ampul of sterile diluent contains 2% benzyl alcohol in sterile water.

PATIENT INFORMATION No Information Provided.

OVERDOSE Factrel (gonadorelin) has been administered parenterally in doses up to 3 mg b.i.d. for 28 days without any signs or symptoms of overdosage. In case of overdosage or idiosyncrasy, symptomatic treatment should be administered as required. CONTRAINDICATIONS Hypersensitivity to gonadorelin hydrochloride or any of the components.

SIDE EFFECTS Systemic effects have been reported rarely following administration of 100 mcg of Factrel (gonadorelin) . CNS: headache, light-headedness. GI: nausea, abdominal discomfort. Dermatologic: local swelling, occasionally with pain and pruritis, at the injection site may occur following subcutaneous administration; local and generalized skin rash have been noted after chronic subcutaneous administration. Cardiovascular: flushing. Rare instances of hypersensitivity reaction (bronchospasm, tachycardia, flushing, urticaria, induration at injection site) and anaphylactic reactions have been reported following multiple-dose administration. There has been a report of pituitary apoplexy and sudden blindness following gonadotropin-releasing hormone administration to a patient with a gonadotropin-secreting adenoma. > DRUG INTERACTIONS The Factrel (gonadorelin) test should be conducted in the absence of other drugs which directly affect the pituitary secretion of the gonadotropins. These would include a variety of preparations which contain androgens, estrogens, progestins, or glucocorticoids. The gonadotropin levels may be transiently elevated by spironolactone, minimally elevated by levodopa, and suppressed by oral contraceptives and digoxin. The response to Factrel (gonadorelin) may be blunted by phenothiazines and dopamine antagonists which cause a rise in prolactin.

WARNINGS No Information Provided. PRECAUTIONS A. General Although allergic and hypersensitivity reactions have been observed with other polypeptide hormones, and rarely with multiple doses of Factrel (gonadorelin) , to date no such reactions have been reported following the administration of a single 100 mcg dose of Factrel (gonadorelin) . Antibody formation has been reported rarely after chronic administration of large doses of Factrel (gonadorelin) . B. Drug Interactions The Factrel (gonadorelin) test should be conducted in the absence of other drugs which directly affect the pituitary secretion of the gonadotropins. These would include a variety of preparations which contain androgens, estrogens, progestins, or glucocorticoids. The gonadotropin levels may be transiently elevated by spironolactone, minimally elevated by levodopa, and suppressed by oral contraceptives and digoxin. The response to Factrel (gonadorelin) may be blunted by phenothiazines and dopamine antagonists which cause a rise in prolactin. C. Carcinogenesis, Mutagenesis, Impairment of Fertility Repetitive, high doses of Factrel (gonadorelin) may cause luteolysis and inhibition of spermatogenesis. No long-term animal studies have been done to evaluate carcinogenic potential. D. Pregnancy Category B Reproduction studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose, and have revealed no evidence of harm to the fetus due to Factrel (gonadorelin) . There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Appropriate precautions should be taken because the effects of LH-RH on the fetus and developing offspring have not been adequately evaluated. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Factrel (gonadorelin) is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established.