Menotropins (Monograph)

Brand name: Menopur
Drug class: Gonadotropins
ATC class: G03GA
VA class: HS400
CAS number: 9002-68-0

Introduction

Purified preparation of FSH and LH, which are human pituitary gonadotropins extracted from urine of postmenopausal women.

Uses for Menotropins

Infertility—Assisted Reproductive Technology (ART) Programs

Used as a component of infertility regimens to induce multiple follicular maturation and pregnancy in ovulatory women undergoing controlled ovarian hyperstimulation in ART programs such as in vitro fertilization (IVF).

A less-purified menotropins preparation (Repronex) containing higher amounts of extraneous urinary proteins previously was used for multiple follicular development and ovulation induction as part of an ART program or in women with functional anovulation (i.e., secondary to pituitary insufficiency and not due to primary ovarian failure); this preparation is no longer commercially available in the US.

The optimum controlled ovarian hyperstimulation regimen is controversial; individualize treatment decisions.

Women approved for treatment with gonadotropins must have ovaries that respond to FSH and LH stimulation; primary ovarian failure and pregnancy must be ruled out before initiating treatment with menotropins. (See Contraindications under Cautions.)

Menotropins Dosage and Administration

General

• Should be prescribed by clinicians experienced in infertility treatment. Appropriate monitoring facilities required for gonadotropin treatment.

• Prior to initiating treatment with menotropins, perform a complete gynecologic and endocrinologic evaluation to assess pelvic anatomy and rule out early pregnancy. Exclude a diagnosis of primary ovarian failure. Evaluate male partner’s fertility potential.

• Administer menotropins daily until follicular maturation (as determined by serum estradiol concentrations and ovary ultrasound examinations) occurs.

• When ultrasound assessment and serum estradiol concentrations show sufficient follicular maturation, discontinue menotropins; administer human chorionic gonadotropin (hCG) after (generally 1 day after) the last dose of menotropins to complete final follicular maturation and induce ovulation.

• Do not administer hCG if the ovaries show an excessive response to treatment with gonadotropins because of an increased risk of ovarian hyperstimulation syndrome (OHSS). (See OHSS under Cautions.)

• Individualize dosage of menotropins based upon patients' ovarian response. Administer lowest possible effective dosage to minimize risk associated with abnormal ovarian enlargement.

Administration

Sub-Q Administration

Administer by sub-Q injection into the lower abdomen, 1–2 inches below the navel; rotate injection site and alternate between left and right sides. May be self-administered by patient.

Insert the entire length of the needle into a skinfold created by the thumb and forefinger; release skinfold when withdrawing needle.

Menotropins may be administered together with urofollitropin (Bravelle) in same syringe.

Reconstitution

Reconstitute vial containing 75 units each of FSH and LH activity as a sterile lyophilized powder with 1 mL of 0.9% sodium chloride injection (provided by manufacturer). Gently swirl vial until lyophilized powder dissolves; do not shake.

If more than 1 vial is required to prepare the intended dose or if menotropins is to be mixed with urofollitropin (Bravelle) in the same syringe, the reconstituted solution of menotropins may be used (instead of 0.9% sodium chloride injection) to reconstitute up to 5 more vials of drug (menotropins or urofollitropin).

Administer immediately following reconstitution.

Dosage

Dosage expressed in international units (IU, units) of FSH and LH activity; each unit of menotropins represents 1 unit of FSH and 1 unit of LH activity.

Adults

Infertility

Sub-Q

Initially, 225 units daily for 5 days (beginning on cycle day 2 or 3) for women who have received a gonadotropin-releasing hormone (GnRH) agonist for pituitary suppression as part of an ART cycle. Thereafter, daily dosage may be adjusted in increments or decrements of ≤150 units; do not make dosage adjustments more frequently than every 2 days.

Initial dosage of 225 units daily also has been used in women who will receive a GnRH antagonist^{† [off-label]} for pituitary suppression.

When menotropins is administered with urofollitropin (e.g., Bravelle), initial total daily dosage should not exceed 225 units (menotropins 150 units and urofollitropin 75 units, or menotropins 75 units and urofollitropin 150 units).

Maximum daily dosage of menotropins or menotropins in combination with urofollitropin should not exceed 450 units.

Treatment duration >20 days not recommended.

Prescribing Limits

Adults

Infertility

Sub-Q

Maximum 450 units daily of menotropins or menotropins in combination with urofollitropin.

Do not exceed 20 days of treatment.

Special Populations

No special population dosage recommendations at this time.

Cautions for Menotropins

Contraindications

• Known hypersensitivity to menotropins or any ingredient in the formulation.

• Primary ovarian failure.

• Uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, pituitary disorders).

• Pituitary or hypothalamic tumors.

• Abnormal intrauterine bleeding of undetermined origin.

• Ovarian cysts or enlargement of undetermined origin (not due to polycystic ovary syndrome [PCOS]).

• Sex-hormone-dependent neoplasms of the reproductive tract and accessory organs.

• Pregnancy.

Warnings/Precautions

Warnings

Abnormal Ovarian Enlargement

Uncomplicated ovarian enlargement observed during treatment with gonadotropins, including menotropins. Individualization of treatment, use of lowest effective menotropins dosage, and careful monitoring of ovarian response recommended.

If ovaries are abnormally enlarged following the last dose of menotropins, withhold hCG administration during the current course of treatment to minimize the risk of development of OHSS. Advise patient to avoid sexual intercourse due to risk of hemoperitoneum resulting from ruptured ovarian cysts. (See OHSS under Cautions.)

OHSS

Risk of potentially severe OHSS, which is characterized by an apparent dramatic increase in vascular permeability that may result in rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium.

OHSS may progress rapidly; initially manifested by severe pelvic pain, nausea, vomiting, and weight gain. Other manifestations may include abdominal pain/distention, diarrhea, severe ovarian enlargement, dyspnea, and oliguria. Hypovolemia, hemoconcentration, electrolyte imbalance, ascites, hemoperitoneum, pleural effusion, hydrothorax, acute pulmonary distress, and thromboembolic events may occur.

Transient liver function test abnormalities, which may be accompanied by morphologic changes (as detected by liver biopsy), reported.

Independent risk factors for developing OHSS include young age, low body weight, PCOS, higher doses of exogenous gonadotropins, previous episodes of OHSS, and elevated serum estradiol concentrations.

OHSS occurs most often after completion of gonadotropin treatment and can develop rapidly, reaching maximum severity after 7–10 days; monitor patient carefully for ≥2 weeks after hCG administration. OHSS usually resolves spontaneously with the onset of menses. OHSS is more severe and protracted if pregnancy occurs.

If severe OHSS occurs, discontinue gonadotropin treatment, consider hospitalizing patient, and consult a clinician experienced in the management of OHSS or fluid and electrolyte imbalances. Treatment of OHSS is primarily symptomatic (e.g., bed rest, fluid and electrolyte management, analgesics); avoid diuretics except in late phase of OHSS resolution. If bleeding requiring surgical intervention occurs, control bleeding and retain as much ovarian tissue as possible.

Thromboembolism

Thromboembolic events both in association with and separate from OHSS reported in patients receiving gonadotropin treatment; fatal in rare cases.

Pulmonary Complications

Serious pulmonary conditions (e.g., atelactasis, ARDS, exacerbation of asthma) reported in patients receiving gonadotropin treatment; fatal in rare cases.

Ovarian Torsion

Ovarian torsion reported after treatment with gonadotropins. Early diagnosis and immediate detorsion can limit damage to ovary caused by reduced blood flow.

Multiple Births

Multiple ovulations resulting in multiple gestations and births reported in patients receiving gonadotropins, including menotropins.

Congenital Malformations

No indications that use of gonadotropins during IVF or intracytoplasmic sperm injection (ICSI) is associated with increased risk of congenital malformations. Incidence of congenital malformations after ART may be slightly higher than after spontaneous conception; may be related to multifetal gestations or differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics).

Ectopic Pregnancy

Infertile women undergoing ART often have tubal abnormalities; incidence of ectopic pregnancy may be increased in such women.

Spontaneous Abortion

Increased risk of abortion (miscarriage) with gonadotropin treatment; causality not established. Such increased risk may be a factor of the underlying infertility.

Ovarian Neoplasms

Benign and malignant ovarian neoplasms reported infrequently in women who received multiple-drug treatment for controlled ovarian stimulation; causal relationship not established.

Specific Populations

Pregnancy

Category X. (See Contraindications under Cautions.)

Menotropins may cause fetal harm when administered to a pregnant woman. Menotropins contraindicated in pregnant women. (See Contraindications.)

Lactation

Not known whether menotropins is distributed into human milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established. Not indicated for use in pediatric patients.

Geriatric Use

Not indicated for use in geriatric patients.

Hepatic Impairment

Safety and efficacy not established.

Renal Impairment

Safety and efficacy not established.

Common Adverse Effects

Abdominal pain, headache, OHSS, injection site pain and reaction, abdominal cramps, abdominal enlargement, injection site inflammation.

Drug Interactions

Formal drug interaction studies lacking.

Menotropins Pharmacokinetics

Absorption

Bioavailability

Increased after sub-Q compared with IM administration.

Distribution

Data lacking on distribution of FSH and LH in human tissues and organs.

Elimination

Metabolism

Data lacking on metabolism of FSH and LH in humans.

Half-life

Approximately 11–13 hours following multiple sub-Q doses of menotropins (225 units once, followed by 150 units daily for 6 days).

Special Populations

Data lacking on pharmacokinetics of menotropins in women with renal or hepatic insufficiency.

Stability

Storage

Parenteral

Injection

Store refrigerated or at room temperature (3–25°C); protect from light.

Use immediately after reconstitution; discard unused portion.

Compatibility

Parenteral

May be mixed with urofollitropin (Bravelle) in the same syringe.

Actions

• Preparation of gonadotropins (FSH and LH) extracted from urine of postmenopausal women. Has undergone additional processes (e.g., hormone adsorption and elution, anion and cation exchange, hydrophobic cation exchange) to remove impurities.

• hCG also detected in menotropins and contributes to LH activity.

• FSH acts on early antral follicles to stimulate growth, steroidogenesis, and expression of LH receptors.

• LH in synergy with FSH subsequently acts on the FSH-stimulated follicle to maintain growth and is eventually responsible for the process of luteinization and ovulation.

• Administration of menotropins for 7–20 days produces ovarian follicular growth and maturation in women who do not have primary ovarian failure; to induce ovulation, hCG must be given following menotropins treatment.

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information and instructions for use.

• Importance of patient informing clinician prior to beginning menotropins treatment about a personal or family history of thrombosis or history of ovarian torsion or ovarian cyst.

• Importance of instructing patients on the correct use and dosage of menotropins. Advise patients not to change the dosage or schedule of administration unless told to do so by a clinician.

• Importance of advising patients that if a dose is missed, the next dose should not be doubled; the clinician should be contacted to provide further dosing instructions.

• Importance of patient understanding and following instructions regarding reconstitution of menotropins, duration of treatment, and required monitoring procedures.

• Importance of informing patient of potential adverse effects (e.g., OHSS). Advise patients of the risk of OHSS-associated symptoms, including pulmonary and vascular complications and ovarian torsion.

• Importance of informing patient regarding the risk of multifetal gestation and birth with the use of menotropins treatment.

• Importance of patients informing a clinician if severe stomach or pelvic pain, stomach bloating, nausea, vomiting, diarrhea, difficulty breathing, decreased or absent urination, or sudden weight gain occurs.

• Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patient of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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