Action And Clinical Pharmacology: Menotropins is a purified preparation of gonadotropins extracted from the urine of postmenopausal women.
Indications And Clinical Uses: Women: Menotropins and human chorionic gonadotropin (hCG) given in a sequential manner are indicated for the induction of ovulation and to enable pregnancy in the anovulatory infertile patient, in whom the cause of anovulation is functional and is not due to primary ovarian failure.
Men: Menotropins with concomitant hCG is indicated for the stimulation of spermatogenesis in men who have primary or secondary hypogonadotropic hypogonadism.
Menotropins 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.
Contra-Indications: Women: High levels of FSH indicating primary ovarian failure. The presence of uncontrolled 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. Abnormal vaginal bleeding of undetermined origin. Ovarian cysts or enlargement not due to polycystic ovarian syndrome. A prior hypersensitivity to menotropins.
Pregnancy: Pergonal may cause fetal harm when administered to a pregnant woman. There are limited human data on the effects of menotropins when administered during pregnancy.
Men: Normal gonadotropin levels indicating normal pituitary function. Elevated gonadotropin levels indicating primary testicular failure. Infertility disorders other than hypogonadotropic hypogonadism.
Manufacturers’ Warnings In Clinical States: Caution: Menotropins 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. Because of the potential hazards involved with the use of menotropins, physicians must become thoroughly familiar with the Indications, Contraindications, Warnings, and Precautions before instituting treatment. 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 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 menotropins and hCG, and generally regresses without treatment within two or three weeks.
The Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly (within 24 hours to several days) 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 Warnings, Pulmonary and Vascular Complications).
OHSS occurred 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. OHSS develops rapidly and most often after treatment with menotropins or hCG has been discontinued, reaching its maximum at about seven to ten days following treatment. Patients, therefore, should be followed for at least 2 weeks after menotropins or hCG administration. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs. 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 pericardial cavity has been seen to occur and should be thoroughly assessed in the following manner: fluid intake and output; weight; hematocrit; serum and urinary electrolytes; urine specific gravity; BUN and creatinine, and 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 fluids 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 hemaperitoneum, 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 3 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: 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 i.v. 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 following gonadotropin therapy. In addition, thromboembolic events both in association with, and separate from, OHSS have been reported following 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 menotropins and hCG, 80% resulted in single births, 15% in twins, and 5% of the total pregnancies resulted in 3 or more concepti. The patient and her husband should be advised of the frequency and potential hazards of multiple gestation before starting treatment.
Precautions: Careful attention should be given to diagnosis in the selection of candidates for menotropins therapy.
Women: Before treatment with menotropins is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of basal body temperature, serial vaginal smears, examination of cervical mucus, determination of serum (or urinary) progesterone, and endometrial biopsy. Primary ovarian failure should be excluded by the determination of serum gonadotropin levels. Careful examination should be made to rule out the presence of early pregnancy. Patients in late reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. Cervical dilation and curettage should always be done for diagnosis before starting therapy in such patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities. Evaluation of the husband’s fertility potential must also be performed before starting therapy.
In order to minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with menotropins-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 menotropins therapy, hCG should not be administered in this course of therapy; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.
Men: Patient selection should be made based on a documented lack of pituitary function. Prior to hormonal therapy, these patients will have low or absent urinary gonadotropin levels. Patients with primary hypogonadotropic hypogonadism will have a subnormal development of masculinization, and those with secondary hypogonadotropic hypogonadism will have decreased masculinization.
Information for the Patient: 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 Effects) and the risk of multiple births should also be discussed.
Laboratory Tests – Women (Treatment for Induction of Ovulation): In most instances, treatment with menotropins results only in follicular growth and maturation. In order to effect ovulation, hCG must be given following the administration of menotropins when clinical assessment of the patient indicates that sufficient follicular maturation has occurred. This may be estimated by measuring serum (or urinary) estrogen levels and sonographic 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 detecting ovarian enlargement and minimizing the risk of OHSS and multiple gestation.
Urinary and/or plasma estrogen determinations provide an indirect index of follicular maturity since as the follicles grow and develop, they secrete estrogens in increasing amounts. However, plasma and/or urinary estrogen levels represent the sum of ovarian activity. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma and/or urinary estrogens do not give an indication of the number of follicles.
Other clinical parameters which may have potential use for monitoring menotropins therapy include: changes in the vaginal cytology, appearance and volume of the cervical mucus, spinnbarkeit, and ferning of the cervical mucus.
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: a rise in basal body temperature, increase in serum progesterone, and menstruation following the shift in basal body temperature.
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: fluid in the cul-de-sac, ovarian stigmata, and collapsed follicle.
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 interactions have been reported.
Carcinogenesis and Mutagenesis: Carcinogenicity and mutagenicity studies have not been performed.
Pregnancy: Contraindicated in pregnancy.
Lactation: 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 menotropins are administered to a nursing mother.
Adverse Reactions: Women: The following adverse reactions reported are listed in decreasing order of potential severity: pulmonary and vascular complications (see Warnings); Ovarian Hyperstimulation Syndrome (see Warnings); hemoperitoneum; mild to moderate ovarian enlargement; abdominal pain; sensitivity to menotropins (febrile reactions after the administration of the drug have occurred. It is not clear whether or not these were pyrogenic responses or possible allergic reactions. In addition, reports of flu-like symptoms including fever, chills, musculoskeletal aches, joint pains, nausea, headache, and malaise have been received); ovarian cysts; gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal cramps, bloating); pain, rash, swelling, and/or irritation at site of injection; body rashes; dizziness, tachycardia, dyspnea, tachypnea, and breast tenderness.
The following medical events have been reported subsequent to pregnancies resulting from menotropins therapy: ectopic pregnancy; congenital abnormalities. [From a study of 287 completed pregnancies following menotropins-hCG therapy, 5 incidents of birth defects were reported (1.7%). One infant had multiple congenital anomalies consisting of imperforate anus, aplasia of the sigmoid colon, third degree hypospadias, cecovesicle fistula, bifid scrotum, meningocele, bilateral internal tibial torsion, and right metatarsus adductus. Another infant was born with an imperforate anus and possible congenital heart lesions; another had a supernumerary digit; another was born with hypospadias and exstrophy of the bladder; and the fifth child had Down’s syndrome. None of the investigators felt that these defects were drug-related. Subsequently, one report of an infant death due to hydrocephalus and cardiac anomalies has been received.]
Menotropins do not appear to influence the incidence of abortion in the subfertile individual. The abortion rate for the subfertile individual is reported to be 20% in primary infertility and 30% in secondary infertility. The abortion rate following menotropins and hCG therapy has been 25%.
Ovarian cancer has been reported in a very small number of infertile women who have been treated with fertility drugs. A causal relationship between treatment with fertility drugs and ovarian cancer has not been established.
Men: Gynecomastia may occur occasionally during menotropins-hCG therapy. This is a known effect of hCG treatment. Erythrocytosis (hct 50% hgb 17.8 g%) was recorded in 1 patient.
Drug Abuse and Dependence: There have been no reports of abuse or dependence with menotropins.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Aside from possible Ovarian Hyperstimulation Syndrome (see Warnings), little is known concerning the consequences of acute overdosage with menotropins.
Dosage And Administration: Women: The doses of menotropins and hCG for the induction of ovulation must be individualized. For instance, patients with normal intrinsic gonadotropins require a short course of therapy. Patients with low or absent gonadotropins require a longer period. The most generally effective doses are:
Menotropins: 150 IU (2 ampuls)/day for 8 to 12 days.
Human chorionic gonadotropin (hCG): 5 000 to 10 000 U one day after the last dose of menotropins. Administer menotropins in daily i.m. doses until the indices of estrogenic activity, as indicated under Precautions, Laboratory Tests, are equivalent to or greater than those of the normal individual. This generally occurs by the eighth to twelfth day. Administer 5 000 to 10 000 U of hCG i.m. If the patient does not respond to 12 days of menotropins administration, generally no response can be expected and therapy should be discontinued.
During treatment with both menotropins and hCG and during a 2-week post-treatment period, patients should be examined at least every other day for signs of excessive ovarian stimulation. It is recommended that menotropins administration be stopped if the ovaries become significantly enlarged or abdominal pain occurs. Most often OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 days postovulation. Patients should be followed for at least 2 weeks after hCG administration.
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 ensure insemination.
Men: Menotropins with concomitant hCG should be administered to men with pituitary hypofunction who have been adequately masculinized by prior treatment with hCG. Testosterone levels should be in the normal range, and there should be adequate development of the secondary sexual characteristics.
The recommended dose of menotropins is 1 ampul 3 times a week. The recommended dose of hCG is 2 000 U twice a week. Therapy should be carried on for a minimum of 4 months to ensure detecting spermatozoa in the ejaculate, as it takes approximately 74±4 days in the human male for germ cells to reach the spermatozoa stage.
Dissolve the contents of 1 ampul of menotropins in 1 to 2 mL of sterile saline and administer i.m. immediately. The reconstituted menotropins may lose potency with time.
Availability And Storage: Each ampul contains: FSH 75 IU and LH 75 IU plus lactose 10 mg in a sterile, lyophilized form. By biological assay, one IU of LH for the Second International Reference Preparation (2nd-IRP) for HMG (human menopausal gonadotropin) is biologically equivalent to approximately 1/2 U of human chorionic gonadotropin (hCG). Cartons of 1 ampul with diluent.
PERGONAL® Serono Menotropins Gonadotropins
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