Humegon™

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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CLINICAL PHARMACOLOGY

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.

Women:
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.

Men:
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

Women:
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.

Men:
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

Women:

1. Before treatment with Humegon™ is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. Except for those patients enrolled in an in vitro fertilization program, 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, urinary pregnanediol, and endometrial biopsy. Patients with tubal pathology should receive Humegon™ only if enrolled in an in vitro fertilization program.
2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.
3. Careful examination should be made to rule out the presence of an early pregnancy.
4. Patients in late reproductive life have a greater predilection to endometrial carcinoma as well as a higher incidence of anovulatory disorders. Cervical dilation and curettage should always be done for diagnosis before starting Humegon™ therapy in such patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities.
5. Evaluation of the partner's fertility potential should be included in the workup.

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CONTRAINDICATIONS

Women:
Humegon™ is contraindicated in women who have:

1. A high FSH level indicating primary ovarian failure.
2. Uncontrolled thyroid and adrenal dysfunction.
3. An organic intracranial lesion such as a pituitary tumor.
4. The presence of any cause of infertility other than anovulation, unless they are candidates for in vitro fertilization.
5. Abnormal bleeding of undetermined origin.
6. Ovarian cysts or enlargement not due to polycystic ovary syndrome.
7. Prior hypersensitivity to menotropins.
8. Humegon™ is contraindicated in women who are pregnant and may cause fetal harm. There are limited human data on the effects of Humegon™ when administered during pregnancy.

1. Normal gonadotropin levels indicating normal pituitary function.
2. Elevated gonadotropin levels indicating primary testicular failure.
3. Infertility disorders other than hypogonadotropic hypogonadism.

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WARNINGS

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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PRECAUTIONS

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.

Laboratory Tests:

Women:
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:

a) Changes in vaginal cytology;
b) Appearance and volume of cervical mucus;
c) Spinnbarkeit; and
d) Ferning of cervical mucus.

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) A rise in basal body temperature;
b) Increase in serum progesterone; and
c) Menstruation following the shift in basal body temperature.

a) Fluid in the cul-de-sac;
b) Ovarian stigmata; and
c) 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 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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ADVERSE REACTIONS

Women:
The following adverse reactions, reported during Humegon™ therapy, are listed in decreasing order of potential severity:

1. Pulmonary and vascular complications (see WARNINGS),
2. Ovarian Hyperstimulation Syndrome (see WARNINGS),
3. Hemoperitoneum,
4. Adnexal torsion (as a complication of ovarian enlargement),
5. Mild to moderate ovarian enlargement,
6. Ovarian cysts,
7. Abdominal pain,
8. Sensitivity to Humegon™,
   (Febrile reactions after the administration of Humegon™ 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 ach es, joint pains, nausea, headache and malaise have been received.)
9. Gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal cramps, bloating),
10. Pain, rash, swelling and/or irritation at the site of injection,
11. Body rashes,
12. Dizziness, tachycardia, dyspnea, tachypnea.

1. Ectopic pregnancy
2. Congenital abnormalities
   From a large clinical trial comprising of 6,096 cycles (2,166 women) with 594 babies examined, the incidence of congenital malformation with Humegon™/hCG therapy was 1.7%. Of the major malformations (nine babies, 1.5%) there were two cases each of anencephaly and harelip, and one each of cleft palate, polydactyly, umbilical hernia, congenital dislocation of hip and equinovarus. There was one case (0.2%) of minor malformation (anomaly of auricle). The congenital anomaly rate after Humegon™ therapy is then no higher than that expected for the general population. 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.

DRUG ABUSE AND DEPENDENCE
There have been no reports of abuse or dependence with Humegon™

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OVERDOSAGE

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

Women:

1. Dosage: The dose of Humegon™ to produce maturation of the follicle must be individualized for each patient. It is recommended that the initial dose to any patient should be 75 IU of FSH/LH per day, ADMINISTERED INTRAMUSCULARLY, for seven to twelve days followed by hCG, 5,000 U to 10,000 U, one day after the last dose of Humegon™. Administration of Humegon™ should not exceed 12 days in a single course of therapy. The patient should be treated until indices of estrogenic activity, as indicated under "Precautions" above, are equivalent to or greater than those of the normal individual. If serum or urinary estradiol determinations or ultrasonographic visualizations are available, they may be useful as a guide to therapy. 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. If there is evidence of ovulation but no pregnancy, repeat this dosage regime for at least two more courses before increasing the dose of Humegon™ to 150 IU of FSH/LH per day for seven to twelve days. As before, this dose should be followed by 5,000 U to 10,000 U of hCG one day after the last dose of Humegon™. A Humegon™ dose of 150 IU of FSH/LH per day has proven to be the most effective dose especially for in vitro fertilization. If evidence of ovulation is present, but pregnancy does not ensue, repeat the same dose for two more courses. Doses larger than this are not routinely recommended.
   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™.

2. Administration: Dissolve the contents of one vial of Humegon™ in one to two mL of sterile saline and ADMINISTER INTRAMUSCULARLY immediately. Any unused reconstituted material should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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HOW SUPPLIED

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:

• 1 vial 75 IU Humegon™ and 1 vial 2 mL Sodium Chloride Injection, USP.
  NDC 0052-0300-17
• 5 vials 75 IU Humegon™ and 5 vials 2 mL Sodium Chloride Injection, USP.
  NDC 0052-0300-22
• 1 vial 150 IU HumegonTM and 1 vial 2 mL Sodium Chloride Injection, USP.
  NDC 0052-0304-17

Lyophilized powder may be stored refrigerated or at room temperature 2ş-30şC (35ş-86şF). Protect from light. Use immediately after reconstitution. Discard unused material.

CLINICAL STUDIES

Women:
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%

IVF, GIFT, ZIFT
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§

Men:
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.

Caution: Federal law prohibits dispensing without prescription.