Caution: Federal law prohibits dispensing without prescription.
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 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, 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.
Factrel 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 analyzed from the results of clinical studies included:
Normal adult subjects were shown to have these LH responses following Factrel administration by subcutaneous or intravenous routes.
The Factrel 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 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 test also were observed in 21 (95%) of 22 patients with prepubertal panhypopituitarism. In 19 patients with Sheehan' syndrome, 16 (84%) had a subnormal response. In the Factrel test in 44 patients with Kallmann' syndrome, 33 (77%) had subnormal LH responses.
Factrel as a single injection is indicated for evaluating the functional capacity and response of the gonadotropes of the anterior pituitary. This single-injection test does not measure pituitary gonadotropic reserve, for which more prolonged or repeated administration may be required. The LH response is useful in testing patients with suspected gonadotropin deficiency, whether due to the hypothalamus alone or in combination with anterior pituitary failure. Factrel is also indicated for evaluating residual gonadotropic function of the pituitary following removal of a pituitary tumor by surgery and/or irradiation. In clinical studies to date, however, the single-injection test has not been useful in differentiating pituitary disorders from hypothalamic disorders. The Factrel test can be performed concomitantly with other post-treatment evaluations. The results of the Factrel test complement the clinical examination and other laboratory tests used to confirm or substantiate hypogonadotropic hypogonadism.
In cases where there is a normal response, it indicates the presence of functional pituitary gonadotropes. The single-injection test does not measure pituitary gonadotropic reserve.
Hypersensitivity to gonadorelin hydrochloride or any of the components.
Although allergic and hypersensitivity reactions have been observed with other polypeptide hormones, and rarely with multiple doses of Factrel, to date no such reactions have been reported following the administration of a single 100 mcg dose of Factrel.
Antibody formation has been reported rarely after chronic administration of large doses of Factrel.
The Factrel 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 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 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. 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 is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Systemic effects have been reported rarely following administration of 100 mcg of Factrel.
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.
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.
Factrel 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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Adults: 100 mcg dose, subcutaneously or intravenously. In females for whom the phase of the menstrual cycle can be established, the test should be performed in the early follicular phase (Days 1-7).
To determine the status of the gonadotropin secretory capacity of the anterior pituitary, a test procedure requiring seven venous blood samples for LH is recommended.
Interpretation of the LH response to Factrel requires an understanding of the hypothalamic-pituitary physiology, knowledge of the clinical status of the individual patient, and familiarity with the normal ranges and the standards used in the laboratory performing the LH assays.
Figures 1 through 4 represent the LH response curves after Factrel administration in normal subjects. The normal LH response curves were established between the 10th percentile (B line) and 90th percentile (A line) of all LH responses in normal subjects analyzed from the results of clinical studies. LH values are reported in units of mIU/mL and time is displayed in minutes. Individual patient responses should be plotted on the appropriate curve. A subnormal response in patients is defined as three or more LH values which fall below the B line of the normal LH response curve.
In cases where there is a blunted or borderline response, the Factrel test should be repeated.
The Factrel test complements the clinical assessment of patients with a variety of endocrine disorders involving the hypothalamic-pituitary axis. In cases where there is a normal response, it indicates the presence of functional pituitary gonadotropes. The single-injection test does not determine the pathophysiological cause for the subnormal response and does not measure pituitary gonadotropic reserve.
Lyophilized Powder--in single-dose Secule® vials containing 100 mcg (NDC 0046-0507-05) and 500 mcg (NDC 0046-0509-05) gonadorelin as the hydrochloride with 100 mg lactose, USP. Each Secule vial is accompanied by one ampul containing 2 mL sterile diluent of 2% benzyl alcohol in sterile water.
Reconstitute 100 mcg Secule® vial with 1.0 mL of the accompanying sterile diluent.
Reconstitute 500 mcg Secule® vial with 2.0 mL of the accompanying sterile diluent.
Prepare solution immediately before use. After reconstitution, store at room temperature and use within 1 day.
Discard unused reconstituted solution and diluent.
Secule®--Registered trademark to designate a vial containing an injectable preparation in dry form.
Ayerst Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, PA 19101
CI 4992-1 Issued July 25, 1997