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 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.

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).

TEST METHODOLOGY

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.

Procedure:

1. Venous blood samples should be drawn at -15 minutes and immediately prior to Factrel administration. The LH baseline is obtained by averaging the LH values of the two samples.
2. Administer a bolus of 100 mcg of Factrel subcutaneously or intravenously.
3. Draw venous blood samples at 15, 30, 45, 60, and 120 minutes after administration.
4. Blood samples should be handled as recommended by the laboratory that will determine the LH content. It must be emphasized that the reliability of the test is directly related to the inter-assay and intra-assay reliability of the laboratory performing the assay.

INTERPRETATION OF TEST RESULTS

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.

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.

DIRECTIONS

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.

Manufactured by:
Ayerst Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, PA 19101

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.

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.

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.

No Information Provided.

A.  General

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.

B.  Drug Interactions

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.

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.

Hypersensitivity to gonadorelin hydrochloride or any of the components.

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:

1. LH peak (mIU/mL)
   (highest LH value post-Factrel administration)
2. Maximum LH increase (mIU/mL)
   (peak LH value LH baseline value)
3. LH percent response
   peak LH baseline LH   γ-  100%
          baseline LH
4. Time to peak (minutes)
   (time required to reach LH peak value)

Normal adult subjects were shown to have these LH responses following Factrel administration by subcutaneous or intravenous routes.

1.   MALE ADULTS:
   
   1. Subcutaneous Administration
      The results are based on 18 tests in males between the ages of 18-42 years, inclusive:
      
      1. LH peak: mean 60.3 ± 26.2 mIU/mL
         100% >= 24.0 mIU/mL
           90% >= 32.8 mIU/mL
      2. Maximum LH increase: mean 46.7 ± 20.8 mIU/mL
         100% >= 12.3 mIU/mL
           90% >= 20.9 mIU/mL
      3. LH percent response: mean 437 ± 243% range: 66-1853%
          90% >= 188%
      4. Time to peak: mean 34 ± 13 min
   2. Intravenous Administration
      The results are based on 26 tests in males between the ages of 19-58 years, inclusive:
      
      1. LH peak: mean 63.8 ± 40.3 mIU/mL
         100% >= 12.6 mIU/mL
           90% >= 26.0 mIU/mL
      2. Maximum LH increase: mean 51.3 ± 35.2 mIU/mL
         100% >=  7.4 mIU/mL
           90% >= 14.8 mIU/mL
      3. LH percent response: mean 481 ± 184% range: 67-2139%
          90% >= 142%
      4. 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.
   
   
2.   FEMALE ADULTS:
   
   1. Subcutaneous Administration
      The results are based on 38 tests in females between the ages of 19-36 years, inclusive:
      
      1. LH peak: mean 67.9 ± 27.5 mIU/mL
         100% >= 12.5 mIU/mL
           90% >= 39.0 mIU/mL
      2. Maximum LH increase: mean 52.8 ± 26.4 mIU/mL
         100% >=  7.5 mIU/mL
           90% >= 23.8 mIU/mL
      3. LH percent response: mean 374 ± 221% range: 108-981%
          90% >= 185%
      4. Time to peak: mean 71.5 ± 49.6 min
   2. Intravenous Administration
      The results are based on 31 tests in females between the ages of 20-35 years, inclusive:
      
      1. LH peak: mean 57.6 ± 36.7 mIU/mL
         100% >= 20.0 mIU/mL
           90% >= 24.6 mIU/mL
      2. Maximum LH increase: mean 44.5 ± 31.8 mIU/mL
         100% >=  7.5 mIU/mL
           90% >= 16.2 mIU/mL
      3. LH percent response: mean 356 ± 282% range: 60-1300%
          90% >= 142%
      4. Time to peak: mean 36 ± 24 min

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's syndrome, 16 (84%) had a subnormal response. In the Factrel test in 44 patients with Kallmann's syndrome, 33 (77%) had subnormal LH responses.

No Information Provided.