Humegon™ (menotropins for injection, USP) is a purified preparation of gonadotropins. Menotropins are extracted from the urine of postmenopausal females and possess follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity. The ratio of FSH bioactivity and LH bioactivity in menotropins is adjusted to approximate unity by the addition of human chorionic gonadotropin purified from the urine of pregnant women. Each vial of Humegon™ contains 75 IU or 150 IU of follicle-stimulating hormone activity and 75 IU or 150 IU of luteinizing hormone activity, respectively, plus 10.5 mg lactose, hydrous NF; 0.25 mg monosodium phosphate, monohydrate USP; 0.25 mg disodium phosphate, anhydrous USP; sodium hydroxide NF or phosphoric acid NF to adjust pH; in a sterile, lyophilized form. Humegon™ is administered by intramuscular injection.
Humegon™ is biologically standardized for FSH and LH gonadotropin activities and the potencies are based on the results of in vivo bioassay, which are in agreement with the recommendations of the World Health Organization Expert Committee on Biological Standardization (1982).
Both FSH and LH as well as hCG are glycoproteins that are acidic and water soluble.
Therapeutic class: Infertility.
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The geometric mean absolute bioavailability of FSH from the 150 IU intramuscular (IM) dose compared to the 150 IU intravenous (IV) dose was 76%. Following single dose IM injections of 75, 150, and 300 IU Humegon™ to healthy male volunteers, FSH dose response was less than proportional between the 75 and 150 IU doses and between the 150 and 300 IU doses. The mean FSH elimination half-lives of 75, 150, and 300 IU IM were 37 hrs, 30 hrs, and 36 hrs, respectively, and 31 hrs following 150 IU IV administration.
Repeated daily IM administration of 150 IU Humegon™ to seven women on 8 consecutive days led to a gradual accumulation of FSH levels which plateaued in 3-4 days. It took 4-5 days for the elevated FSH levels to return to pretreatment levels. These findings underline the importance of very careful and frequent monitoring of the patient in order to reduce the danger of ovarian hyperstimulation.
Humegon™ administered for seven to twelve days produces ovarian follicular growth in women who do not have primary ovarian failure. Treatment with Humegon™ in most instances results only in follicular growth and maturation. In order to induce ovulation, human chorionic gonadotropin (hCG) must be given following the administration of Humegon™ when clinical assessment of the patient indicates that sufficient follicular maturation has occurred.
Humegon™ administered concomitantly with human chorionic gonadotropin (hCG) for at least three months induces spermatogenesis in men with primary or secondary pituitary hypofunction who have achieved adequate masculinization with prior hCG therapy.
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INDICATIONS AND USAGE
Humegon™ and hCG given in a sequential manner are indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient, in whom the cause of anovulation is functional and is not due to primary ovarian failure.
Humegon™ and hCG may also be used to stimulate the development of multiple follicles in ovulatory patients participating in an in vitro fertilization program.
Humegon™ with concomitant hCG is indicated for the stimulation of spermatogenesis in men who have primary or secondary hypogonadotropic hypogonadism, and idiopathic infertility.
Humegon™ with concomitant hCG has proven effective in inducing spermatogenesis in men with primary hypogonadotropic hypogonadism due to a congenital factor or prepubertal hypophysectomy and in men with secondary hypogonadotropic hypogonadism due to hypophysectomy, craniopharyngioma, cerebral aneurysm, or chromophobe adenoma.
SELECTION OF PATIENTS
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Humegon™ is contraindicated in women who have:
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Humegon™ is a drug that should only be used by physicians who are thoroughly familiar with infertility problems. It is a potent gonadotropic substance capable of causing mild to severe adverse reactions in women. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and its use requires the availability of appropriate monitoring facilities (see PRECAUTIONS/Laboratory Tests). In female patients it must be used with a great deal of care.
Overstimulation of the Ovary During Humegon™ Therapy:
Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain occurs in approximately 20% of those treated with Humegon TM and hCG, and generally regresses without treatment within two or three weeks.
In order to minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with Humegon™-hCG therapy, the lowest dose consistent with expectation of good results should be used. Careful monitoring of ovarian response can further minimize the risk of overstimulation.
If the ovaries are abnormally enlarged on the last day of Humegon™ therapy, hCG should not be administered in this course of therapy; this will reduce the chances of development, of the Ovarian Hyperstimulation Syndrome.
The Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly to become a serious medical event. It is characterized by an apparent dramatic increase in vascular permeability which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see Pulmonary and Vascular Complications).
OHSS occurs in approximately 0.4% of patients when the recommended dose is administered and in 1.3% of patients when higher than recommended doses are administered. Cases of OHSS are more common, more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see PRECAUTIONS/ Laboratory Tests), the hCG should be withheld.
If OHSS occurs, treatment should be stopped and the patient hospitalized. Treatment is primarily sympomatic, consisting of bed rest, fluid and electrolyte management, an analgesics if needed. The phenomenon hemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity, an the pericardial cavity has been seen to occur and should be thoroughly assessed in the following manner: 1) fluid intake and output, 2) weight, 3) hematocrit, 4) serum and urinary electrolytes, 5) urine specific gravity, 6) BUN and creatinine, and 7) abdominal girth. These determinations are to be performed daily or more often if the need arises.
With OHSS there is an increased risk of injury to the ovary. The ascitic, pleural, and pericardial fluid should not be removed unless absolutely necessary to relieve symptom, such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result it hemoperitoneum, and should therefore be avoided. If this does occur, and if bleeding becomes such that surgery is required, the surgical treatment should be designed to control bleeding and to retain as much ovarian tissue as possible. Intercourse should be prohibited in those patients in whom significant ovarian enlargement occurs after ovulation because of the danger of hemoperitoneum resulting from ruptured ovarian cysts.
The management of OHSS may be divides into three phases: an acute, a chronic, and a resolution phase. Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below.
Acute Phase: Management during the acute phase should be designed to prevent hemoconcentration due to loss of intravascular volume to the third space and to minimize the risk of thromboembolic phenomena and kidney damage. Treatment is designed to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Management includes administration of limited intravenous fluids, electrolytes, and human serum albumin. Monitoring for the development of hyperkalemia is recommended.
Chronic Phase: After stabilizing the patient during the acute phase, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction.
Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the return of third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase if necessary to combat pulmonary edema.
Pulmonary and Vascular Complications: Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome have been reported following Humegon™ therapy. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death.
Multiple Births: Data from a clinical trial revealed the following results regarding multiple births: Of the pregnancies following therapy with Humegon™ and hCG, 80% resulted In single births. The patient and her partner should be advised of the frequency and potential hazards of multiple gestation before starting treatment.
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General: Careful attention should be given to diagnosis in the selection of candidates for Humegon™ therapy (see INDICATIONS AND USAGE/SELECTION OF PATIENTS).
Information for Patients: Prior to therapy with Humegon™ , patients should be informed of the duration of treatment and the monitoring of their condition that will be required. Possible adverse reactions (see ADVERSE REACTIONS) and the risk of multiple births should also be discussed.
Treatment for Induction of Ovulation
In most instances, treatment with Humegon™ results only in follicular growth and maturation. In order to induce ovulation, hCG must be given following the administration of Humegon™ when clinical assessment of the patient indicates that sufficient follicular maturation has occurred. This may be directly estimated by measuring serum (or urinary) estrogen levels and monographic visualization of the ovaries. The combination of both estradiol levels and ultrasonography is useful for monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation.
Other clinical parameters which may have potential use for monitoring menotropins therapy include:
The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:
Because of the subjectivity of the various tests for the determination of follicular maturation and ovulation, it cannot be overemphasized that the physician should choose the test(s) with which he/she is thoroughly familiar.
Drug Interactions: No clinically significant drug/drug or drug/food adverse interactions have been reported during Humegon™ therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic potential of Humegon™.
Pregnancy: Pregnancy Category X. See CONTRAINDICATIONS.
Males: No animal studies have been performed that examine the potential teratogenic effect associated with Humegon™ therapy when prescribed for male infertility.
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 if Humegon™ is administered to a nursing woman.
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The following adverse reactions, reported during Humegon™ therapy, are listed in decreasing order of potential severity:
DRUG ABUSE AND DEPENDENCE
There have been no reports of abuse or dependence with Humegon™
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Aside from possible ovarian hyperstimulation (see WARNINGS), little is known concerning the consequences of acute overdosage with Humegon™
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DOSAGE AND ADMINISTRATION
If the patient has not responded with evidence of increased spermatogenesis at the end of four months of
therapy, treatment may continue with 75 IU FSH/LH three times a week, or the dose can be increased to
150 IU FSH/LH three times a week, with the hCG dose unchanged.
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Humegon™ is supplied in sterile Iyophilized form as a white to off-white powder in vials containing 75 IU or
150 IU FSH/LH activity. The following package combinations are available:
Lyophilized powder may be stored refrigerated or at room temperature 2ş-30şC (35ş-86şF). Protect from light.
Use immediately after reconstitution. Discard unused material.
IVF, GIFT, ZIFT
Caution: Federal law prohibits dispensing without prescription.
During treatment with both Humegon™ and hCG and during a two-week post-treatment period, patients should be examined at least every other day for signs of excessive ovarian stimulation. It is recommended that Humegon™ administration be stopped if the ovaries become abnormally enlarged or abdominal pain occurs. Most of the Ovarian Hyperstimulation Syndrome occurs after treatment has been discontinued and reaches its maximum at about seven to ten days post-ovulation. Patients should be followed for at least two weeks after hCG administration.
For ovulation induction, the couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity. Care should be taken to insure insemination. In the light of the foregoing indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct the necessary laboratory studies, he/she should not use Humegon™.
The Induction of Ovulation
Results of clinical experience and effectiveness from the administration of Humegon™ to 2,682 patients in 7,204 courses of therapy are summarized below:
Patients Ovulating 73.2%†
Clinical Pregnancies 26.2%
Patients Aborting 22%*
Multiple Pregnancies 19.5%
† Data reported for 2,409 out of 2,682 patients
* Data reported for 678 out of 704 clinical pregnancies
Results of clinical experience and effectiveness from the administration of Humegon™ in 1,081 cycles of therapy are summarized below:
% Cycles with Oocyte Retrieval 85†
% Cycles with Transfers 65.6*
# Clinical Pregnancies 182
% Clinical Pregnancy/Cycle 16.8
% Clinical Pregnancy/Retrieval 19.8
% Clinical Pregnancy/Transfer 25.6
% Abortion 32.7§
† Data reported for 773 cycles
* Data reported for 791 cycles
§ Data reported for 174 out of 182 clinical pregnancies
Clinical results of treatment of men with hypogonadotropic hypogonadism and idiopathic infertility were summarized from the medical literature. Efficacy was evaluated in 246 patients, 22 with hypogonadotropic hypogonadism and 224 with idiopathic infertility. Treatment generally consisted of Humegon™, with or without concomitant administration of hCG 500-2,500 IU, two or three times per week for up to 48 months. Sperm count improved in 16 of 22 evaluable (73%) hypogonadotropic hypogonadism patients and in 86 of 224 evaluable (38%) idiopathic infertility patients. Overall, seven of 14 (50%) evaluable hypogonadotropic hypogonadism patients and 26 of 224 (12%) idiopathic infertility patients impregnated their partners following Humegon™ treatment.
New Jersey 07052
If the patient has not responded with evidence of increased spermatogenesis at the end of four months of therapy, treatment may continue with 75 IU FSH/LH three times a week, or the dose can be increased to 150 IU FSH/LH three times a week, with the hCG dose unchanged.
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Humegon™ is supplied in sterile Iyophilized form as a white to off-white powder in vials containing 75 IU or 150 IU FSH/LH activity. The following package combinations are available:
Lyophilized powder may be stored refrigerated or at room temperature 2ş-30şC (35ş-86şF). Protect from light. Use immediately after reconstitution. Discard unused material.
IVF, GIFT, ZIFT
Caution: Federal law prohibits dispensing without prescription.