Humegon (Human Gonadotropin)

HUMEGON®

Organon

Human Gonadotropin

Human Gonadotropins

Action And Clinical Pharmacology: Humegon (human gonadotropin) is a purified preparation of gonadotropins extracted from the urine of post menopausal and pregnant women. It contains follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are necessary for the normal gamete maturation (follicle ripening in the female and spermatogenesis in the male) and for gonadal steroid production. Unlike menotropins, human gonadotropin is standardized with hCG. Human gonadotropin is used to stimulate these processes in selected cases of disturbed gonadal function. It is generally used in combination with a gonadotropin with LH activity, such as human chorionic gonadotropin (hCG). The combined treatment may be either sequential (in the case of ovulation induction) or concomitant (in the case of Leydig cell stimulation). tag_IndicationsIndications

Indications And Clinical Uses: Women: Human gonadotropin and human chorionic gonadotropin (hCG) given sequentially are indicated for the induction of ovulation and pregnancy in females infertile due to anovulation where the cause of anovulation is functional and not due to primary ovarian failure.

Men: Human gonadotropin and concomitant hCG is indicated for the stimulation of spermatogenesis in males with primary or secondary hypogonadotropic hypogonadism.

Contra-Indications: Women: Ovarian tumors. In patients whose blood levels of gonadotropins and/or prolactin are above normal. A high level of urinary gonadotropins – indicating primary ovarian failure. In the presence of overt thyroid and adrenal dysfunction. An organic intracranial lesion such as a pituitary tumor. The presence of any cause of infertility other than anovulation as stated in the indications. In women with abnormal vaginal bleeding of undetermined origin.

Men: Testicular and pituitary tumors. In patients whose blood levels of gonadotropins and/or prolactin are above normal. Normal urinary gonadotropin levels indicating normal pituitary function. Infertility disorders other than hypogonadotropic hypogonadism.

Manufacturers’ Warnings In Clinical States: Because human gonadotropin is a potent gonadotropic agent that is capable of causing severe adverse effects in women, it should be used only by physicians who are experienced in the management of fertility disorders and only when facilities for appropriate clinical and endocrinologic evaluations are available.

Overstimulation of the Ovary During Human Gonadotropin Therapy: To minimize the risk associated with abnormal ovarian enlargement in women receiving human gonadotropin and chorionic gonadotropin therapy for induction of ovulation and pregnancy, the drugs should be administered at the lowest possible effective dosage. Since human gonadotropin may cause ovarian enlargement and/or hyperstimulation, patients should be examined at least every other day for signs of excessive ovarian stimulation during menotropins/human chorionic gonadotropin (hCG) therapy and for a 2 week post treatment period. Careful monitoring of ovarian response can minimize the risk of overstimulation.

Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain occurs in approximately 20% of patients treated with human gonadotropin/menotropins and hCG, and generally regresses without treatment within 2 to 3 weeks.

Ovarian hyperstimulation syndrome is characterized by sudden ovarian enlargement accompanied by ascites with or without pain and/or pleural effusion.

If hyperstimulation occurs, treatment should be stopped and the patient hospitalized. Hyperstimulation syndrome develops rapidly within 3 to 4 days and generally during the 2 week period following treatment.

Hemoconcentration associated with fluid loss into the abdominal cavity has been observed to occur and should be thoroughly assessed as follows: 1) fluid intake and output; 2) weight; 3) hematocrit; 4) serum and urinary electrolytes; and 5) urine specific gravity. These determinations should be performed daily or more often if needed. Treatment consists of primarily bed rest, fluid and electrolyte replacement, and analgesics as needed. Generally, the ascitic fluid should not be removed because of the potential for damage to the ovary.

Hemoperitoneum may occur from ruptured ovarian cysts. This is usually the result of pelvic examination. Should this occur accompanied by bleeding to the extent that surgery is required, partial resection of the enlarged ovary or ovaries is generally adequate.

Intercourse should be prohibited in those patients in whom significant ovarian enlargement occurs after ovulation due to the risk of hemoperitoneum resulting from ruptured ovarian cysts.

Arterial Thromboembolism: Arterial thromboembolism has been reported in patients who have received human gonadotropin/menotropins and hCG, both in association with and separate from ovarian hyperstimulation syndrome. Complications resulting from thromboembolism have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, stroke, arterial occlusion necessitating limb amputation, and (rarely) death.

Pregnancy: Multiple ovulations with resulting multiple births occur (mostly twins) frequently (20% of pregnancies) following treatment with human gonadotropin/menotropins and hCG. Prior to human gonadotropin and hCG therapy, the patient and her male sexual partner should be informed of the possibility and potential risks associated with multiple births.

Spontaneous abortion rates have been reported from 10 to 25% of all patients following gonadotropin treatment. Increased abortion rates are more common in women over 35 years of age and are more common in the infertile couple. The increased frequency of multiple pregnancy is also associated with an increased rate of abortion.

Precautions: Prior to treating patients for inadequate endogenous stimulation of the gonads, a physical examination should be performed to exclude anatomical abnormalities of the genital organs or non-gonadal endocrinopathies (e.g. thyroid or adrenal disorders, diabetes).

In pregnancies occurring after induction of ovulation with gonadotropic preparations, there is an increased risk of miscarriages and multiplets.

Adverse Reactions: Women (see Warnings for further details): Arterial thromboembolism. Serious respiratory complications. Serious respiratory complications including atelectasis and acute respiratory distress syndrome have occurred with human gonadotropins/menotropins therapy. These events are rare but death has resulted. Hyperstimulation syndrome (2%). Hemoperitoneum. Abnormal ovarian enlargement (20%). Ectopic pregnancy (3%). Sensitivity to human gonadotropin. Fever has been reported rarely in patients receiving human gonadotropins/menotropins; however, it is not clear if this is a pyrogenic response or a possible allergic reaction. Pain, rash, swelling and/or irritation at the site of injection. Defects at birth. Congenital abnormalities including imperforate anus, aplasia of the sigmoid colon, hypospadias, cecovesical fistula, bifid scrotum, meningocele, bilateral internal tibial torsion, right metatarsus adductus, cardiac lesions, supernumerary digit, exstrophy of the bladder, and Down’s syndrome have been reported in infants conceived following human gonadotropin/menotropins and human chorionic gonadotropin (hCG) therapy; however, these effects have not been directly attributed to gonadotropin therapy.

Men: Gynecomastia may occur occasionally during human gonadotropin and hCG therapy. This effect is known to occur in patients receiving hCG alone. Erythrocytosis has been reported in one patient.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The acute toxicity of human gonadotropin has been shown to be very low. However, too high a dosage for more than 1 day may lead to hyperstimulation of the ovaries (see Warnings).

Dosage And Administration: Selection of Patients: Women: A thorough gynecologic and endocrinologic evaluation must be performed prior to treatment with human gonadotropin. The evaluation may include hysterosalpingography to detect uterine and tubal pathology. Anovulation should be confirmed by observation of the basal body temperature pattern, examination of serial vaginal smears and cervical mucus, determination of urinary pregnanediol excretion, and endometrial biopsy. Tumors of the thyroid, adrenals, pituitary, and ovary may cause anovulation and patients with such tumors should be excluded from human gonadotropin therapy.

Determination of urinary gonadotropin concentrations should be obtained to rule out primary ovarian failure.

The presence of early pregnancy should be ruled out by thorough examination and biochemical pregnancy test.

Cervical dilation and curettage should be performed prior to starting human gonadotropin treatment in the following patients: a) in late reproductive life in order to diagnose endometrial carcinoma and anovulatory disorders; b) with abnormal uterine bleeding.

Evaluation of the fertility of the male sexual partner should also be performed.

Men: The presence of functional reproductive organs, absence of mechanical causes for sperm defects, the absence of interfering endocrinopathies and the documented lack of pituitary function should be the criteria for patient selection. Prior to treatment, patients with pituitary insufficiency will have low serum testosterone concentrations and low or absent serum gonadotropin levels. Those patients with primary hypogonadotropic hypogonadism will exhibit a less than normal development of masculinization and patients with secondary hypogonadotropic hypogonadism will have decreased masculinization.

Women: The dosage of human gonadotropin required to produce follicular maturation must be individualized for each patient.

Measurement of serum estradiol concentrations is recommended starting 1 week after the beginning of each course of human gonadotropin and continuing through the day of human chorionic gonadotropin (hCG) administration. This is necessary to determine the optimal dose and to detect ovarian hyperstimulation. Ultrasound examination is recommended during human gonadotropin therapy and prior to administration of hCG to provide information on the number and size of mature follicles, to follow development, and to minimize the risk of ovarian hyperstimulation syndrome and multiple gestation.

The usual initial dosage of human gonadotropin to produce follicular maturation is 75 IU of FSH/LH daily, administered i.m., for 9 to 12 days until evidence of follicular maturation occurs. Follicles of 17 mm or more in diameter, as revealed by ultrasound, can be considered mature. Human gonadotropin should not be administered for longer than 12 days in a single course of therapy. A single dose of chorionic gonadotropin of 5 000 to 10 000 USP units should be given 1 day after the last dose of human gonadotropin if the following criteria are met: total urinary estrogens or estrone-1-glucuronide reach levels of 150 to 250 ng/24 hours; or serum concentrations of 300 to 600 pg/mL estradiol are achieved; and between 1 and 3 follicles are 17 mm or more in diameter.

Following administration of chorionic gonadotropin, the couple should be encouraged to have daily sexual intercourse beginning on the day prior to administration of chorionic gonadotropin until ovulation occurs.

Clinical confirmation of ovulation is obtained through the indices of progesterone production. Increasing progesterone secretion by the corpus luteum and a concomitant increase in basal body temperature are indirect signs of ovulation. Urinary pregnanediol levels higher than 2 mg/24 hours, indicate that ovulation has occurred. A serum progesterone level of over 10 ng/mL (30 nmol/L) also provides adequate proof of a functional corpus luteum. Lower concentrations of serum progesterone may be supplemented by luteal phase injections of up to 5 000 IU hCG.

If there is evidence of ovulation but no pregnancy, repeat this dosage regimen for at least 2 more courses.

If necessary, on the basis of serum estradiol determinations, the dose of human gonadotropin may be increased to 150 Units FSH/LH/day for 9 to 12 days. Again follow this dose with 5 000 to 10 000 Units of hCG 1 day after the last dose of human gonadotropin. Generally, a dose of 150 IU of FSH/LH/day is the most effective dose. If evidence of ovulation is present, but pregnancy does not ensue, repeat the same dose for 2 more courses. Doses larger than 150 IU FSH/LH/day are not routinely recommended.

Human chorionic gonadotropin (hCG) should not be administered under the following circumstances: a) if the ovaries are abnormally enlarged following the last dose of human gonadotropin because the hyperstimulation syndrome is more likely to occur; b) if the total daily urinary estrogen excretion is greater than 100 g daily; c) urinary estriol excretion is greater than 50 µg daily; or d) if 4 or more follicles over 17 mm in diameter are detected using ultrasonography. The couple should be advised not to have sexual intercourse for 1 week.

Patients should be closely monitored for 2 weeks following human gonadotropin and chorionic gonadotropin treatment to ensure that hyperstimulation does not occur. If the ovaries become abnormally enlarged or abdominal pain occurs, administration of human gonadotropin should be stopped. Most ovarian hyperstimulation occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days post-ovulation.

Men: Prior to treatment with human gonadotropin and hCG, hCG alone is required to stimulate spermatogenesis in males with primary or secondary hypogonadotropic hypogonadism.

The recommended dose of human gonadotropin is 1 ampul 3 times a week, administered i.m., and 2 000 IU hCG twice a week. To insure detecting spermatozoa in the ejaculate, treatment should continue for a minimum of 4 months, as it takes 74 ± 4 days in the human male for germ cells to reach the spermatozoa stage.

If evidence of increased spermatogenesis does not occur following 4 months of human gonadotropin and hCG therapy, treatment can be continued at the same dosage or human gonadotropin may be increased to 150 IU FSH/LH 3 times weekly. The dosage of hCG, however, must not be changed.

Reconstitution: Reconstitute each ampul with 1 mL of sodium chloride injection 0.9% to obtain a solution containing 75 IU of FSH activity/mL and 75 IU of LH activity/mL. Use immediately after reconstitution.

Availability And Storage: Each box contains: 1 ampul of freeze-dried human gonadotropin and 1 ampul of sodium chloride injection USP 0.9%. Each ampul contains: 75 IU of FSH activity and 75 IU of LH activity. Nonmedicinal ingredients: disodium hydrogen phosphate (anhydrous), mannitol, sodium dihydrogen phosphate (anhydrous). LH activity is standardized by the addition of hCG. Each ampul of diluent contains: 1 mL of sodium chloride injection USP 0.9%. Store at 2 to 25°C. Protect from light.

HUMEGON® Organon Human Gonadotropin Human Gonadotropins

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