Pergonal® (menotropins for injection, USP) is a purified preparation of gonadotropins extracted from the urine of postmenopausal women. Each ampule of Pergonal® contains 75 IU or 150 IU of follicle-stimulating hormone (FSH) activity and 75 IU or 150 IU of luteinizing hormone (LH) activity, respectively, plus 10 mg lactose in a sterile, lyophilized form. Human Chorionic Gonadotropins (hCG), a naturally occurring hormone in post-menopausal urine, is detected in Pergonal®. Pergonal® is administered by intramuscular injection.
Pergonal® is biologically standardized for FSH and LH (ICSH) gonadotropin activities in terms of the Second International Reference Preparation for Human Menopausal Gonadotropins established in September, 1964 by the Expert Committee on Biological Standards of the World Health Organization.
Both FSH and LH are glycoproteins that are acidic and water soluble.
Therapeutic class: Infertility.
Pergonal® administered for seven to twelve days produces ovarian follicular growth in women who do not have primary ovarian failure. Treatment with Pergonal® in most instances results only in follicular growth and maturation. In order to effect ovulation, human chorionic gonadotropin (hCG) must be given following the administration of Pergonal® when clinical assessment of the patient indicates that sufficient follicular maturation has occurred.
Pergonal® 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.
Pergonal® 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.
Pergonal® and hCG may also be used to stimulate the development of multiple follicles in ovulatory patients participating in an in vitro fertilization program.
Pergonal® with concomitant hCG is indicated for the stimulation of spermatogenesis in men who have primary or secondary hypogonadotropic hypogonadism.
Pergonal® 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.
Patient selection should be made based on a documented lack of pituitary function. Prior to hormonal therapy, these patients will have low testosterone levels and low or absent gonadotropin levels. Patients with primary hypogonadotropic hypogonadism will have a subnormal development of masculinization, and those with secondary hypogonadotropic hypogonadism will have decreased masculinization.
Pergonal® is contraindicated in women who have:
Pergonal® is contraindicated in men who have:
1.Normal gonadotropin levels indicating normal pituitary function.
2.Elevated gonadotropin levels indicating primary testicular failure.
3.Infertility disorders other than hypogonadotropic hypogonadism.
Pergonal® 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.
Ovarian Enlargement: to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain occurs in approximately 20% of those treated with Pergonal® 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 Pergonal®-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 Pergonal® 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" below). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with the Ovarian Hyperstimulation Syndrome (OHSS).
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 symptomatic, consisting of bed rest, fluid and electrolyte management, and analgesics if needed. The phenomenon of hemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity, and 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 symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result in 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 divided into three phases: the acute, the chronic, and the resolution phases. 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: 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: 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: 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 Pergonal® therapy. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical 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 Pergonal® and hCG, 80% resulted in single births, 15% in twins, and 5% of the total pregnancies resulted in three or more concepti. The patient and her husband should be advised of the frequency and potential hazards of multiple gestation before starting treatment.
Hypersensitivity/Anaphylactic Reactions: Hypersensitivity/anaphylactic reactions associated with Pergonal® administration have been reported in some patients. These reactions presented as generalized urticaria, facial edema, angioneurotic edema, and/or dyspnea suggestive of laryngeal edema. The relationship of these symptoms to uncharacterized urinary proteins is uncertain.
General: Careful attention should be given to diagnosis in the selection of candidates for Pergonal® therapy (see " and Usage -- Selection of Patients ").
Information for Patients: Prior to therapy with Pergonal®, 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 " section) and the risk of multiple births should also be discussed.
Treatment for Induction of Ovulation
In most instances, treatment with Pergonal® results only in follicular growth and maturation. In order to effect ovulation, hCG must be given following the administration of Pergonal® 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 sonographic visualization of the ovaries. The combination of both estradiol levels and ultrasonography are 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 above clinical indices provide an indirect estimate of the estrogenic effect upon the target organs, and therefore should only be used adjunctively with more direct estimates of follicular development, i.e., serum estradiol and ultrasonography.
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:
When used in conjunction with indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:
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 tests with which he/she is thoroughly familiar.
Drug Interactions: No clinically significant drug/drug or drug/food adverse interactions have been reported during Pergonal® therapy.
Carcinogenesis and Mutagenesis: Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic potential of Pergonal®.
Pregnancy: Pregnancy Category X. See " Contraindications " section.
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 Pergonal® is administered to a nursing woman.
The following adverse reactions, reported during Pergonal® therapy, are listed in decreasing order of potential severity:
The following medical events have been reported subsequent to pregnancies resulting from Pergonal® therapy:
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.
There have been no reports of abuse or dependence with Pergonal®.
Aside from possible ovarian hyperstimulation (see " "), little is known concerning the consequences of acute overdosage with Pergonal®.
Pergonal® is supplied in a sterile lyophilized form as a white to off-white powder or pellet in ampules containing 75 IU or 150 IU FSH/LH activity. The following package combinations are available:
By biological assay, one IU of LH for the Second International Reference Preparation (2nd-IRP) for hMG is biologically equivalent to approximately 1 / 2 U of hCG.
Lyophilized powder may be stored refrigerated or at room temperature (3°-25°C/37°-77°F). Protect from light. Use immediately after reconstitution. Discard unused material.
The results of the clinical experience and effectiveness of the administration of Pergonal® to 1,286 patients in 3,002 courses of therapy are summarized below. The values include patients who were treated with other than the recommended dosage regime. The values for the presently recommended dosage regime are essentially the same.
Results by diagnosis group are summarized below (these values include patients who were treated with other than the present recommended dosage regime):
Clinical results of the treatment of men with primary or secondary hypogonadotropic hypogonadism are as follows:
In the Serono Cooperative study, with an adequate treatment period of 3 to 8 months, 60 of 70 men with primary hypogonadotropic hypogonadism and 8 of 11 men with secondary hypogonadotropic hypogonadism responded with mean increases in their sperm counts from less than 5 to 24 million spermatozoa per milliliter of ejaculate. Forty-one wives of 54 men with primary hypogonadotropic hypogonadism desiring offspring and 7 wives of men with secondary hypogonadotropic hypogonadism conceived. Patients treated with Pergonal® and hCG for less than 3 months or with Pergonal® alone did not respond to therapy.
A world-wide data search revealed that of 160 recorded pregnancies as the result of use of Pergonal®-hCG in men, there were 7 spontaneous abortions, one ectopic pregnancy and 3 congenital anomalies at birth (esophageal atresia in a female infant which was later corrected by surgery, unilateral cryptorchidism, inguinal hernia).
Caution: Federal law prohibits dispensing without prescription.
SERONO LABORATORIES, INC.
Randolph, MA 02368 USA
by: Laboratoires Serono, SA
© SERONO LABORATORIES, INC. 1969, 1994
Revised: November 1994