Menotropins are purified injections of the human pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Menotropins are sometimes referred to as human menopausal gonadotropins or hMG. Menotropins are obtained from the urine of postmenopausal women; they are then standardized and purified in accordance with standards established by the World Health Organization. Menotropins are used in combination with chorionic gonadotropin (hCG). The primary clinical use is for controlled ovarian stimulation protocols as part of assisted reproductive technology (ART) cycles. Menotropins therapy is associated with increased rates of multiple births compared to the general population. Subcutaneous injection of menotropins usually allows for patient self-administration or partner administration versus the intramuscular products previously available. Ovarian hyperstimulation syndrome (OHSS) may occur during menotropins use and therapy is carefully monitored in each cycle with physical exam, ultrasound, and estradiol concentrations to limit the risk of OHSS complications.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Injectable Administration
-Menopur is administered by subcutaneous injection only.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Subcutaneous Administration
Menopur product only:
Reconstitution:
-Refer to the manufacturer provided "Instructions for Use" for proper preparation and administration.
-The patient, their partner, or a caregiver may administer after proper training by the care team.
-Patients needing more than 1 vial to prepare their dose or who are mixing Menopur with Bravelle (urofollitropin) within the same syringe need to carefully follow the manufacturer provided instructions. Menopur and Bravelle (urofollitropin) may be mixed and administered in the same syringe.
-Use reconstituted injections immediately and discard any unused portions.
Subcutaneous injection:
-Administer subcutaneously into the lower abdomen, 1 to 2 inches below the navel, on the right or left side.
-Gently pinch a fold of cleaned skin at the chosen injection site. Hold the syringe at a 90-degree angle to the skin. Quickly insert the needle all the way into the skin fold. Inject subcutaneously with a steady motion until all fluid is injected. Let go of the skin fold and pull the needle straight out.
-Alternate sides (left or right side) with each dose administration.
-Dispose of used needles and syringes in an FDA-cleared sharps disposal container right away after use.
Among recipients of menotropins, abdominal pain or cramping (5% to 17.6%) and nausea (4% to 12%) are fairly common side effects; vomiting was reported in 4.2% or less of treated patients. Back pain (3.2% or less), diarrhea (2.8% or less) and constipation (1.6% or less) were also reported. Nausea, vomiting, diarrhea, and abdominal pain may also occur with ovarian hyperstimulation during menotropins treatment. [51374 ]
An injection site reaction may occur (localized pain, ecchymosis, swelling, irritation, mild erythema, or itching). Subcutaneous administration of Menopur led to injection site pain in 5.4% of patients and an injection site reaction in 9.6% to 11.8% of patients.
The use of menotropins in combination with human chorionic gonadotropin (hCG) at therapeutic doses is generally well-tolerated for the treatment of infertility. Side effects related to menotropins may vary with dosage administered, route, and reason for therapeutic use. Among menotropins recipients for ovarian stimulation, the following events were reported: headache (5.2% to 34.1%), migraine (2.4%), malaise (2.6% to 2.8%), hot flashes (0.6% to 2.6%), and dizziness (2.6%). Fatigue may also occur.
Among menotropins recipients, 1.8% to 2.6% reported mastalgia or breast tenderness.
Mild to moderate uncomplicated ovarian enlargement that may be accompanied by abdominal distension and/or abdominal discomfort occurs in approximately 5% to 10% of those treated with menotropins and hCG and generally regresses without treatment within 2 or 3 weeks. Adnexal or ovarian torsion as a complication of ovarian enlargement has also been reported during menotropins therapy. Pelvic pain, cramps, or discomfort was noted in 0.4% to 3.9% of patients. There were also reports of enlarged abdomen (2.1% to 6%) or abdominal fullness (3.2% to 9.2%). Ovarian enlargement or ovarian cyst formation may occur. Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important to minimize the risk of ovarian hyperstimulation. If the ovaries are abnormally enlarged on the last day of menotropins therapy, hCG should not be administered in order to reduce the chance of developing ovarian hyperstimulation. Prohibit intercourse in those with significant ovarian enlargement because of the danger of hemoperitoneum resulting from ovarian cyst rupture.
Menotropins therapy can result in ovarian hyperstimulation syndrome (OHSS). In the IVF clinical trial, OHSS occurred in 7.2% of the 373 Menopur treated women. Do not administer hCG if the ovaries are abnormally enlarged on the last day of menotropins therapy. OHSS is a medical event distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a 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 OHSS are severe pelvic pain, nausea, vomiting, and weight gain. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute pulmonary distress, and thromboembolic reactions. Transient liver function test abnormalities suggestive of hepatic dysfunction, with or without morphologic changes on liver biopsy, have been reported in association with OHSS. OHSS occurs after gonadotropin treatment has been discontinued, and it can develop rapidly, reaching its maximum 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, hCG must be withheld. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, women should be assessed for the development of OHSS for at least 2 weeks after hCG administration. If serious OHSS occurs, gonadotropins, including hCG, should be stopped and consider if hospitalization is needed. Treatment of OHSS is primarily symptomatic and overall should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, avoid diuretic use except in the late phase of resolution as described below. The management of OHSS may be divided into 3 phases as follows: ACUTE PHASE: Management should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of limited intravenous fluids, electrolytes, human serum albumin, is intended 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. CHRONIC PHASE: After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction. RESOLUTION PHASE: As third space fluid returns to the intravascular compartment, a fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. 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. Do not remove ascitic, pleural, and pericardial fluid unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. OHSS increases the risk of injury to the ovary. Avoid pelvic examination or sexual intercourse as these may cause rupture of an ovarian cyst, which may result in hemoperitoneum. If bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible. A physician experienced in the management of OHSS, or who is experienced in the management of fluid and electrolyte imbalances, should be consulted.
Thromboembolic events such as thromboembolism both in association with and separate from the ovarian hyperstimulation syndrome (OHSS) have been reported after 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 thrombo-phlebitis, deep venous thrombosis, 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 been fatal.
Serious pulmonary conditions (e.g. atelectasis, acute respiratory distress syndrome (ARDS), and exacerbation of asthma such as wheezing or bronchospasm) have been reported in women treated with menotropins. Increased cough (1.6% to 2.6%), sinus tachycardia, and tachypnea have also been reported during menotropins therapy.
Allergic reactions with menotropins are rare (less than 1%) but may be either local or systemic in nature. Reactions have included anaphylactoid reactions, angioedema, facial or laryngeal edema, dyspnea or shortness of breath (1% to 2.1% of patients), rash (unspecified), and generalized urticaria and pruritus. Flushing (2.4%) has also been reported. Febrile reactions suggestive of allergic response have also been reported after the administration of menotropins. Reports of flu-like symptoms have been indicative of an allergic response in some individuals and may include fever, chills, myalgia, arthralgia, nausea, headache, and malaise. Acne vulgaris has been reported postmarketing.
Vaginal bleeding was noted in 3.1% to 7.9% of patients who received menotropins with one product.
There have been infrequent reports of new primary malignancy (ovarian neoplasm), both benign and malignant, in women who have had multiple drug therapy for controlled ovarian stimulation; however, a causal relationship has not been established.
The use of menotropins requires an experienced clinician who specializes in infertility treatment. Before menotropins use, perform a complete gynecologic and endocrinologic evaluation and diagnose the cause of infertility; the diagnosis should include an evaluation of the fertility of the partner. Menotropins use is contraindicated in patients with an uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders). Menotropins will only be effective at inducing ovulation in patients with an intact ovarian response. Those with primary ovarian failure (as indicated by high levels of FSH) will not respond to menotropins treatment. Patients with pituitary adenoma or other pituitary or hypothalamic tumors will also not respond to menotropins treatment. Menotropins treatment is also contraindicated in patients with uncontrolled thyroid disease or untreated adrenal insufficiency.
Because fertility protocols that include menotropins may stimulate the growth of hormonally-dependent tissues, menotropins use is contraindicated in patients with abnormal or dysfunctional uterine bleeding of undetermined origin or sex-hormone dependent neoplasms of the reproductive tract and accessory organs, such as ovarian cancer, breast cancer, or uterine cancer. There have been infrequent reports of ovarian neoplasms, both benign and malignant, in patients who have had multiple drug therapy for controlled ovarian stimulation; however, a causal relationship has not been established.
Menotropins are contraindicated in patients with ovarian cyst or enlargement that is not due to polycystic ovarian syndrome (PCOS). Abnormal ovarian enlargement may occur with menotropins therapy; use the lowest effective dose and individualize to patient response. Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important during menotropins administration to minimize the risk of ovarian hyperstimulation syndrome (OHSS). If the ovaries are abnormally enlarged on the last day of menotropins therapy, hCG should not be administered in order to reduce the chance of developing OHSS. Prohibit intercourse in patients with significant ovarian enlargement because of the danger of hemoperitoneum resulting from rupture of ovarian cysts.
Patients with generally recognized risk factors for thrombosis, such as personal or family history of thromboembolic disease, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins such as menotropins. In those with recognized risk factors, the benefits of ovulation induction and ART need to be weighed against the risks. Thromboembolic events both in association with, and separate from the ovarian hyperstimulation ayndrome (OHSS) have been reported in patients treated with gonadotropins such as menotropins. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the extremities and in rare cases have resulted in death.
Menotropins are contraindicated for use after conception has occurred as menotropins may cause fetal harm during pregnancy. If the patient becomes pregnant while receiving this drug, apprise the patient of the potential hazard to a fetus. The incidence of congenital malformations after some assisted reproductive technologies [specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)] may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics) and to the higher incidence of multi-fetal gestations after IVF or ICSI. Before beginning treatment with menotropins, advise the individual and their partner of the potential risks of multi-fetal gestation and birth. There are no indications that the use of gonadotropins during IVF or ICSI in order to produce pregnancy is associated with an increased risk of congenital malformations. The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be a factor of the underlying infertility.
Menotropins should be used with caution during breast-feeding; due to limited data, the manufacturer recommends consideration of discontinuation of breast-feeding or discontinuation of the drug, taking into account the importance of menotropins treatment to the individual seeking fertility treatment.
Adnexal or ovarian torsion has been reported after treatment with gonadotropins such as menotropins. This may be related to patient risk factors such as ovarian hyperstimulation syndrome (OHSS), previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst, and polycystic ovary syndrome (PCOS). Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.
Since infertile patients undergoing ovarian stimulation for ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased. Early confirmation of intrauterine pregnancy should be determined by beta-hCG testing and transvaginal ultrasound.
Tobacco smoking is a lifestyle choice that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should be encouraged to avoid tobacco consumption and pursue smoking cessation while pursuing fertility therapies such as the use of menotropins.
For the treatment of infertility as part of Assisted Reproductive Technology (ART):
-for the development of multiple follicles and pregnancy in ovulatory patients as part of an Assisted Reproductive Technology (ART) cycle:
Subcutaneous dosage (Menopur):
Adults: 225 International Units per day subcutaneously as the initial dose in the first cycle, then individualize. May adjust after 5 days and by no more than 150 International Units. Max: 450 International Units/day. Continue until adequate follicular development is evident, and then administer hCG. Withhold hCG in cases where the ovarian monitoring suggests an increased risk of ovarian hyperstimulation syndrome on the last day of menotropins therapy. Do not exceed 20 days of menotropins use in any cycle. NOTE: MENOPUR may be administered together with BRAVELLE (urofollitropin for injection, purified). Only a total starting dose of 225 International Units (150 International Units of Menopur and 75 International Units of BRAVELLE OR 75 International Units of MENOPUR and 150 International Units of BRAVELLE) was studied in a clinical trial.
Maximum Dosage Limits:
Dosage of menotropins depends upon the patient's age, sex, condition being treated, and the prescribing clinician's judgment. The following contains recommended maximum limits for FDA-approved dosages only.
-Adults
450 International Units/day subcutaneously for ovarian stimulation.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
The safety and efficacy of menotropins have not been established in patients with hepatic impairment.
Patients with Renal Impairment Dosing
The safety and efficacy of menotropins have not been established in patients with renal impairment.
*non-FDA-approved indication
There are no drug interactions associated with Menotropins products.
When administered for 7 to 20 days, menotropins produce ovarian follicular growth and maturation in patients with infertility who do not have primary ovarian failure. Treatment in most instances results only in follicular growth and maturation. When sufficient follicular maturation has occurred, hCG must be given to induce ovulation.
Menotropins are administered subcutaneously. Human tissue or organ distribution of FSH and LH has not been studied for the Menopur product. Metabolism of FSH and LH has not been studied for menotropins use in humans. During the pharmacokinetic studies, elimination half-lives for FSH in the multiple-dose phase were similar (11 to 13 hours) for subcutaneously administered Menopur versus intramuscular administration.
Affected Cytochrome P450 isoenzymes and drug transporters: None known
-Route-Specific Pharmacokinetics
Subcutaneous Route
Pharmacokinetic studies determined that the subcutaneous route was bioequivalent to the intramuscular route of administration for the Menopur product. The subcutaneous route of administration trended toward greater bioavailability of FSH, as determined by FSH exposure (AUC) and maximum concentration (Cmax) values, than the intramuscular route for single and multiple doses.
-Special Populations
Hepatic Impairment
The pharmacokinetics of menotropins in hepatic impairment have not been established.
Renal Impairment
The pharmacokinetics of menotropins in renal impairment have not been established.
Geriatric
No data are available; the pharmacokinetics of menotropins have been studied by the manufacturer in premenopausal subjects only.