Repronex 75 unit

In an early pharmacokinetic study including 16 healthy female volunteers, 300 IU menotropins were administered subcutaneously (SC) and intramuscularly (IM) in a crossover study, after patients' endogenous FSH and LH were suppressed. Measurements of serum FSH concentrations indicated that SC administration leads to higher values for both C_max and AUC_{(0 -∞)} when compared to IM injections.

The subcutaneous and intramuscular routes were not bioequivalent. Compared to IM administration, the SC administration of menotropins results in an increase of FSH C_max and AUC_{(0- ∞)} by 35 and 20% respectively.

Clinical studies for ovulation induction (in women with anovulatory or oligo-ovulatory infertility) and in vitro fertilization showed enhanced follicular development, induction of ovulation, and clinical pregnancies.

No clinically significant drug/drug or drug/food adverse interactions have been reported during menotropins therapy.

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 Repronex 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: 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.

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 woman.

Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic potential of menotropins.

Careful attention should be given to diagnosis in the selection of candidates for menotropins therapy (see Indications; Precautions).

See Contraindications.

Prior to therapy with Repronex( menotropins for injection), 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 be discussed.

Before treatment with Repronex 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 urine) progesterone, urinary pregnanediol and endometrial biopsy. Patients with tubal pathology should receive menotropins only if enrolled in an in vitro fertilization program.

Primary ovarian failure should be excluded by the determination of gonadotropin levels. Careful examination should be made to rule out the presence of an early pregnancy.

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 Repronex therapy in such patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities.

Evaluation of the partner's fertility potential should be included in the workup.

Multiple pregnancies have occurred following treatment with Repronex IM and SC. In a clinical trial for ovulation induction in which Repronex IM and Repronex SC were directly compared, the rates of multiple pregnancies were as follows. Of the four clinical pregnancies with Repronex IM, two were single and two were multiple pregnancies. Both multiple pregnancies were triplet pregnancies. Of the six clinical pregnancies with Repronex SC, three were single and three were multiple pregnancies. The three multiple pregnancies included one twin pregnancy and two quadruplet pregnancies.

In a clinical trial of IVF patients in which Repronex IM and Repronex SC were directly compared, the rates of multiple pregnancies were as follows: Of the twenty four continuing pregnancies on Repronex IM, fourteen were single and ten were multiple pregnancies. The ten multiple pregnancies included three triplet and seven twin pregnancies. Of the twenty nine continuing pregnancies on Repronex SC, fourteen were single and fifteen were multiple pregnancies. The fifteen multiple pregnancies included three quadruplet, three triplet and nine twin pregnancies. The patient and her partner should be advised of the frequency and potential hazards of multiple gestation before starting treatment.

Hypersensitivity/anaphylactic reactions associated with menotropins 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.

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.

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.

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). 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. OHSS occurred in 3 of 125 (2.4%) Repronex treated women during the In Vitro Fertilization (IVF) clinical study. None of these cases was classified as severe. In the Ovulation Induction (OI) clinical study, 4 of 72 (5.5%) Repronex treated women developed OHSS and of this number, one case was classified as severe (1.4%). 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.

Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain, occurs in approximately 5 to 10% of those treated with Repronex 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 Repronex -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 Repronex therapy, hCG should not be administered in this course of therapy; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.

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.

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 menotropins 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.

Repronex has been marketed in the United States since 1997. All adverse events reported have been non-serious and expected reactions, and were predominantly injection site reactions, as well as fever, malaise and nausea. These reactions abated and resolved without sequelae.

Aside from ovarian hyperstimulation (see Warnings), little is known concerning the consequences of acute overdosage with menotropins.

The dose of Repronex (menotropins for injection) to produce maturation of the follicle must be individualized for each patient. It is recommended that the initial dose of Repronex to any patient should be 150 IU (for any patient receiving leuprolide or other GnRH therapy) of FSH/LH per day, for five days. Based on clinical monitoring (ultrasound results and serum estradiol concentrations) subsequent dosing should be adjusted according to individual patient response. Adjustments in dose should not be made more frequently than once every two days and should not exceed more than 75 to 150 IU per adjustment. The maximum daily dose of Repronex should not exceed 450 IU and dosing beyond 12 days is not recommended.

If patient response to Repronex is appropriate, hCG (5000 to 10 000 USP units) should be given one day following the last dose of Repronex. The hCG should be withheld if the serum estradiol is greater than 2000 pg/mL, if the ovaries are abnormally enlarged or if abdominal pain occurs, and the patient should be advised to refrain from intercourse. These precautions may reduce the risk of development of the Ovarian Hyperstimulation Syndrome and multiple gestation.

During treatment with both Repronex 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. Most of the Ovarian Hyperstimulation Syndrome occurs after treatment has been discontinued and reaches its maximum at about seven to ten days post-ovulation. If there is inadequate follicle development, or follicle development or ovulation without subsequent pregnancy, the course of treatment with gonadotropins may be repeated.

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. 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 Repronex.

Dissolve the contents of one to six vials of Repronex in one to two mL of 0.9% Sodium Chloride Injection and administer subcutaneously or intramuscularly immediately. Any unused reconstituted material should be discarded.

The lower abdomen (alternating sides) should be used for subcutaneous administration.

The recommended initial dose of Repronex for patients who have received GnRH agonist or antagonist pituitary suppression is 225 IU. Based on clinical monitoring (including serum estradiol levels and vaginal ultrasound results) subsequent dosing should be adjusted according to individual patient response. Adjustments in dose should not be made more frequently than once every two days and should not exceed more than 75 to 150 IU per adjustment. The maximum daily dose of Repronex given should not exceed 450 IU and dosing beyond 12 days is not recommended.

Once adequate follicular development is evident, hCG (5000-10 000 USP units) should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of therapy. This should reduce the chance of developing OHSS.