Menopur 75 IU: Indications, Dosage, Precautions, Adverse Effects
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Menopur 75 IU - Product Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Female Infertility, Follicle Stimulation, Ovulation Induction
Class: Gonadotropins
Form: Subcutaneous (SC), Powder
Ingredients: menotropins, lactose monohydrate, polysorbate 20, and sodium phosphate, phosphoric buffer (sodium phosphate dibasic, heptahydrate, phosphoric acid)

Menotropins for Injection USP

Summary of Product Information

Route of Administration Dosage Form/Strength Clinically Relevant Non-
medicinal Ingredients
Subcutaneous (SC) injection Lyophilized powder for
reconstitution and injection
Lactose Monohydrate;
Polysorbate 20,
Sodium Phosphate Buffer
(Sodium Phosphate Dibasic,
Heptahydrate and Phosphoric
Acid).

Description

Menopur (menotropins for injection, USP) is a preparation of gonadotropins, extracted from the urine of postmenopausal women, which has undergone additional steps for purification. Each vial of Menopur contains 75 International Units (IU) of Follicle Stimulating Hormone (FSH) activity and 75 IU of Luteinizing Hormone (LH) activity, plus 21 mg Lactose Monohydrate and 0.005 mg, Polysorbate 20 and Sodium Phosphate Buffer (Sodium Phosphate Dibasic, Heptahydrate and Phosphoric Acid) in a sterile, lyophilized form intended for reconstitution with sterile 0.9% Sodium Chloride Injection, USP.

Menopur is administered by subcutaneous (SC) injection. Human Chorionic Gonadotropin (hCG), a naturally occurring hormone in postmenopausal urine, is present in Menopur and contributes to the overall luteinizing hormone activity.

Both FSH and LH are glycoproteins that are acidic and water soluble.

Indications and Clinical Use

Menopur (menotropins for injection) is indicated for:

  • The development of multiple follicles and pregnancy in the ovulatory patient participating in an ART (Assisted Reproductive Technologies) program.

Selection of Patients

  1. A thorough gynecologic and endocrinologic evaluation, including an assessment of pelvic anatomy, must be performed before treatment with Menopur. Patients with tubal obstruction should receive Menopur only if enrolled in an IVF 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. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Menopur therapy.
  5. Evaluation of the partner’s fertility potential should be included in the work-up.

Geriatric Populations

Menopur is not used in geriatric populations.

Pediatric Populations

Menopur is not used in pediatric populations.

Contraindications

Menopur is contraindicated in women who have:

  1. A high FSH (Follicle Stimulating Hormone) level indicating primary ovarian failure.
  2. Uncontrolled thyroid or adrenal dysfunction.
  3. An organic intracranial lesion such as a pituitary tumour.
  4. Abnormal vaginal bleeding of undetermined origin.
  5. Ovarian cysts or enlargement not due to Polycystic Ovarian Syndrome.
  6. Prior hypersensitivity to menotropins or Menopur or to any ingredient in the formulation or component of the container. For complete list, see dosage forms, composition and packaging section of the product monograph.
  7. Menopur is not indicated in women who are pregnant. There are limited human data on the effects of menotropins when administered during pregnancy.
  8. Sex hormone dependent tumours of reproductive tract and accessory organs.

Warnings and Precautions

Menopur 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 Warnings and Precautions Laboratory Tests).

Overstimulation of the Ovary during Menopur Therapy

Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement, which may be accompanied by abdominal distension and/or abdominal pain, occurs in approximately 5 to 10% of women treated with menotropins and hCG, and generally regresses without treatment within two or three weeks. The lowest dose consistent with expectation of good results and careful monitoring of ovarian response, can further minimize the risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Menopur therapy, hCG should not be administered in this course of treatment; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome (OHSS).

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). 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 OHSS. In the IVF clinical study, 0399E, OHSS occurred in 7.2% of the 373 Menopur treated women.

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 Laboratory Tests), the hCG should be withheld.

If severe OHSS occurs, treatment must be stopped and the patient should be hospitalized.

A physician experienced in the management of the syndrome, or who is experienced in the management of fluid and electrolyte imbalances, should be consulted.

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 OHSS 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.

Multiple Pregnancies

Multiple pregnancies have occurred following treatment with Menopur SC. In the clinical trial of IVF patients in study 0399E, the rates of multiple pregnancies were as follows: Of the 23 continuing pregnancies, fifteen were single and eight were multiple pregnancies. The eight multiple pregnancies included one triplet and seven twin pregnancies. In the IVF study 2002-02 study, the rates of multiple pregnancies were as follows: Of the thirty continuing pregnancies, thirteen were single and sixteen were multiple pregnancies. The multiple pregnancies included two quadruplet, five triplet and ten twin pregnancies.

The patient and her partner should be advised of the potential risk of multiple births before starting treatment.

General

Careful attention should be given to the diagnosis of infertility in the selection of candidates for Menopur therapy (see Indications and Clinical Use – Selection of Patient).

The drug substance of this drug product is manufactured from human urine. Although the risk is theoretical, and no case of transmission of an infectious agent linked to the use of urine–derived gonadotropins has ever been identified, the risk of transmitting infectious agents cannot be completely excluded.

Information for Patients

Prior to therapy with Menopur, 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

The combination of both estradiol levels and ultrasonography are useful for monitoring the growth and development of follicles, timing of hCG administration, as well as minimizing the risk of the OHSS and multiple gestations.

The clinical confirmation of ovulation is determined by:

  1. A rise in basal body temperature;
  2. Increase in serum progesterone; and
  3. 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:

  1. Fluid in the cul-de-sac;
  2. Ovarian stigmata; and
  3. Collapsed follicle.

Because of the subjectivity of the various tests for the determination of follicular maturation and ovulation, it cannot be over–emphasized that the physician should choose tests with which he/she is thoroughly familiar.

Carcinogenesis and Mutagenesis

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

Renal and Hepatic Insufficiency

The safety and efficacy of Menopur in renal and hepatic insufficiency have not been studied.

Immune:

Local and generalized allergic reactions are known adverse reactions that may be associated with administration of gonadotropin preparations. Two events of anaphylaxis and one event of allergic reaction (hypersensitivity) have been reported from post–market experience.

Special Populations

Pregnancy

See Contraindications section.

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 menotropins are administered to a nursing woman.

Pediatric Patients

Menopur is not used in pediatric populations.

Geriatric Populations

Menopur is not used in geriatric populations.

Adverse Reactions

Adverse Drug Reactions Overview

Sixty-eight percent (67.7%) of patients treated with Menopur, compared to 75% of patients treated with the precursor compound Repronex, experienced adverse events (AEs). The percentage of patients experiencing AEs following treatment with Menopur is similar to the percentage of patients reporting AEs following treatment with recombinant FSH (Gonal-F).

In general, treatment with Menopur did not appear to increase the incidence or severity of the expected AEs of abdominal pain, cramps, fullness and enlargement, OHSS, nausea and injection site reactions. Furthermore, within each study, Menopur was found to be well–tolerated locally.

In the three studies (0399E, 2000–01 and 2000–02) where pregnancy was a major outcome, there was no difference across treatment groups in the percentage of patients experiencing miscarriage, ectopic pregnancies (all <2%) or elective abortions (all <3%). There also was no notable difference in the percentage of patients with multiple gestations. The number of patients with cycle cancellation due to poor response was small. The most commonly reported serious adverse event was OHSS. The number of patients with OHSS cases considered serious was about 3% in all treatment groups.

No remarkable changes in clinical laboratory parameters or physical examination findings ⁄ vital signs were observed with Menopur treatment in any of the studies in which these parameters were assessed.

The percentage of patients experiencing any AEs or expected AEs did not increase as a function of mean total dose of Menopur SC.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug–related AEs and for approximating rates.

The safety of Menopur was examined in 3 clinical studies that enrolled a total of 575 patients receiving Menopur in the IVF and OI studies. All AEs (without regard to causality assessment) occurring at an incidence of ≥1 % in women treated with Menopur are listed in Table 1.

Table 1: Menopur SC and IM in female patients undergoing IVF and OI adverse events with onset on and after gnrh administration, costart classification (for incidence of 1% or greater)
IVF *
N = 499
OI **
N = 76
Body systems/Preferred term N % N %
Body as a whole        
Abdomen Enlarged 12 2.4 0 0.0
Abdominal Cramps 30 6.0 5 6.6
Abdomen Fullness 16 3.2 7 9.2
Abdominal Pain 88 17.6 7 9.2
Back Pain 16 3.2 0 0.0
Elevated Estradiol 12 2.4 0 0.0
Fever 7 1.4 0 0.0
Flu Syndrome 13 2.6 1 1.3
Flushing 12 2.4 0 0.0
Headache 170 34.1 12 15.8
Injection Site Pain 27 5.4 0 0.0
Injection Site Reaction 48 9.6 9 11.8
Malaise 14 2.8 2 2.6
Pain 16 3.2 2 2.6
Cardiovascular        
Migraine 12 2.4 0 0.0
Digestive        
Constipation 8 1.6 0 0.0
Diarrhea 14 2.8 2 2.6
Hemorrhoids 0 0.0 1 1.3
Nausea 60 12.0 6 7.9
Vomiting 21 4.2 2 2.6
Metabolic/Nutritional        
Peripheral edema 0 0.0 1 1.3
Musculoskeletal        
Joint disorder 6 1.2 0 0.0
Nervous        
Anxiety 1 0.2 1 1.3
Depression 3 0.6 1 1.3
Dizziness 13 2.6 0 0.0
Emotional lability 4 0.8 1 1.3
Respiratory        
Cough increased 8 1.6 2 2.6
Nasal Congestion 1 0.2 1 1.3
Pharyngitis 7 1.4 1 1.3
Respiratory disorder 29 5.8 3 3.9
Rhinorrhea 0 0.0 1 1.3
Sinusitis 6 1.2 0 0.0
Strep Throat 0 0.0 1 1.3
Skin/Appendages        
Puritus 5 1.0 0 0.0
Rash 5 1.0 0 0.0
Sweating 5 1.0 0 0.0
Urogenital        
Abortion 5 1.0 0 0.0
Breast pain 4 0.8 1 1.3
Breast tenderness 9 1.8 2 2.6
Dysmenorrhea 5 1.0 0 0.0
Ectopic pregnancy 5 1.0 0 0.0
Hot flash 3 0.6 2 2.6
Infection fungal 5 1.0 1 1.3
Menstrual disorder 16 3.2 0 0.0
OHSS 19 3.8 10 13.2
Ovarian cyst 7 1.4 0 0.0
Ovarian enlargement 0 0.0 1 1.3
Pelvic cramps 0 0.0 3 3.9
Pelvic discomfort 2 0.4 2 2.6
Persistent chemical pregnancy 0 0.0 1 1.3
Post retrieval pain 32 6.4 0 0.0
Spontaneous abortion 7 1.4 1 1.3
Urinary frequency 0 0.0 1 1.3
Urinary tract infection 7 1.7 1 1.3
Uterine spasm 8 1.6 3 3.9
Vaginal discharge 5 1.0 0 0.0
Vaginal hemorrhage 15 3.0 3 3.9
Vaginal spotting 18 3.6 2 2.6

* Includes IM and SC subjects from Protocol MFK/IVF/0399E and Menopur 2000-02

** Includes IM and SC subjects from Protocol Menopur 2000-01

Less Common Clinical Trials Adverse Drug Reaction

The following adverse events occurred in <1% of the 575 patients treated with Menopur:

Body as a whole: scites, chills and face edema
Cardiovascular: postural hypotension, palpitation and thrombosis
Digestive: decreased appetite, duodenitis, flatulence, gastroenteritis, gingivitis, heartburn, increased appetite, rectal pain, tooth disorder and upset stomach
Hemic/Lympatic: hematoma
Metabolic/Nutritional: weight gain
Musculoskeletal: bone pain, leg cramp, muscle pain and twitching
Nervous: sleeps disorder, thinking abnormal and vertigo
Respiratory: bronchitis, dyspnea, epistaxis, hyperventilation, pleural effusion and tonsillitis
Special senses: ear pain, eye disorder, eye pain and taste perversion
Urogenital: abnormal breast, cervical polyp, cystitis, hematuria, dysuria, renal pain, ovarian pain, oliguria, urination impaired, uterine disorder, uterine fibroids, uterine hemorrhage, vaginal and genital erythemia, and vaginal and genital swelling

Post-Market Adverse Drug Reactions

Since the first approval of Menopur in 1999, a total number of 73 adverse events have been reported. A total of 41 cases were spontaneously reported, 13 cases from regulatory authorities and 19 cases were serious related cases from clinical trials.

The most frequently reported event was ovarian hyperstimulation syndrome (OHSS), which was reported in 19 cases (2 spontaneously, 1 regulatory report and 16 cases from clinical trials). Two cases of OHSS also included vein thrombosis. OHSS and associated complications, such as thromboembolism, are well–known and related to gonadotropin therapy.

One case of pulmonary embolism without OHSS was reported. According to the literature data, there is a known risk of thromboembolic events without any signs of OHSS related to assisted reproductive technologies.

One case of borderline ovarian cancer was reported. The patient involved was treated with repeated treatment cycles with different gonadotropins and clomiphene citrate, which have been reported as co–suspected drugs. Several epidemiological studies indicated that ovulation induction drugs might be related to borderline ovarian tumors.

Two events of anaphylaxis and one event of allergic reaction (hypersensitivity) have been reported. Allergic reactions, both local and generalized, are known adverse reactions that might be associated following administration of gonadotropin preparations.

A total of 3 cases described injection site reactions, suggesting good local tolerability of Menopur.

Drug Interactions

No drug/drug interaction studies have been conducted for Menopur in humans.

Drug Abuse and Dependence

There have been no reports of abuse or dependence with menotropins.

Dosage and Administration

Dosing Considerations

There are great inter–individual variations in response of the ovaries to exogenous gonadotropins. This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. Menopur can be given alone or in combination with a gonadotropin–releasing hormone (GnRH) agonist or antagonist. Recommendations about dosage and duration of treatment may change depending on the actual treatment protocols.

To minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with Menopur therapy, the lowest dose consistent with the expectation of good results should be used. Menopur should be administered subcutaneously until adequate follicular development is indicated by ultrasound alone or in combination with measurement of serum estradiol levels.

Recommended Dose and Dosage Adjustment

Assisted Reproductive

The recommended initial dose of Menopur for patients who have received a GnRH antagonist or GnRH agonist for 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 150 IU per adjustment. The maximum daily dose of Menopur given should not exceed 450 IU and dosing beyond 20 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.

Missed Dose

If the patient misses a dose, the patient should be advised to take the missed dose and not to double dose.

Administration

Dissolve the contents of one to six vials of Menopur in 1 mL of sterile saline and Administer Subcutaneously immediately. Menopur has been shown to retain its potency and be compatible with Bravelle (urofollitropin for injection, purified) when they are mixed in the same syringe. Any unused reconstituted material should be discarded.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

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

Overdosage

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

Action and Clinical Pharmacology

Mechanism of Action

Menopur, administered for 7 to 20 days, produces ovarian follicular growth and maturation in women who do not have primary ovarian failure. In order to produce final follicular maturation and ovulation in the absence of an endogenous LH surge, hCG must be administered following Menopur treatment, at a time when patient monitoring indicates sufficient follicular development has occurred.

Pharmacodynamics

Menopur is produced from urine of postmenopausal women. Human Chorionic Gonadotropin (hCG), a naturally occurring hormone in postmenopausal women, is present in Menopur and contributes to the overall luteinizing hormone (LH) activity.

Menopur which contains both FSH and LH activity induces ovarian follicular growth and development as well as gonadal steroid production in women who do not have ovarian failure. FSH is the primary driver of follicular recruitment and growth in early folliculogenesis, while LH is important for ovarian steroidogenesis and is involved in the physiological events leading to development of a competent pre-ovulatory follicle. Follicular growth can be stimulated by FSH in the total absence of LH, but resulting follicles develop abnormally and are associated with low oestradiol levels and inability to luteinize to a normal ovulatory stimulus. In line with the action of LH activity in enhancing steroidogenesis, estradiol levels associated with treatment of Menopur are higher than with recombinant FSH preparations. This should be considered when monitoring patient‘s response based on estradiol levels.

Pharmacokinetics

Absorption

The SC route of administration trends toward greater bioavailability than the IM route for single and multiple doses of Menopur.

Distribution

Human tissue or organ distribution of FSH and LH has not been studied for Menopur.

Metabolism

Metabolism of FSH and LH has not been studied for Menopur in humans.

Elimination

The elimination half–lives for FSH in the multiple–dose phase were the same at 13 hours for Menopur SC and Menopur IM.

Two open–label, randomized, controlled clinical studies were conducted to assess the pharmacokinetics of Menopur. Study 2003–02 (compared single doses of SC administration of the US and European (EU) formulations of Menopur in 57 pituitary–suppressed, healthy, premenopausal females. The study established bioequivalence of the two formulations. Study 2000–03 assessed single and multiple doses of Menopur administered SC and IM in a 3 phase crossover design in 33 pituitary–suppressed, healthy, pre–menopausal females. The primary pharmacokinetic endpoints were FSH AUC and Cmax values. The results are summarized in Tables 2 and 3.

Table 2
FSH Pharmacokinetic Parameters (±SD) Following Menopur Administration (Study 2003–02)
PK Parameters Single Dose (400 IU) SC
Cmax (mIU/mL) 13.8 + 3.0
Tmax (hr) 19.6 + 6.3
AUC0-120 (mIU.hr/mL) 1040 + 215
Table 3
FSH Pharmacokinetic Parameters Following Menopur Administration (Study 2000–03)
PK Parameters Single Dose
(225 IU)
Multiple Dose
(225 IU x 1 day then
150 IU x 6 days)
SC IM SC IM
Cmax (mIU/mL) 8.5 7.8 15 12.5
Tmax (hr) 17.9 26.8 8.0 9
AUC (hr–mIU/mL) 726.2 656.1 622.7 546.2

Single dose AUC120 and multiple dose AUCss

Storage and Stability

Lyophilized powder may be stored refrigerated or at room temperature (15° to 25°C). Protect from light. Use immediately after reconstitution. Discard unused material.

Dosage Forms, Composition and Packaging

Menopur (menotropins for injection, USP) is a purified preparation of gonadotropins extracted from the urine of post–menopausal women, which has undergone additional steps of purification. Each vial of Menopur contains 75 International Units (IU) FSH activity and 75 IU LH activity, plus 21 mg Lactose Monohydrate and 0.005 mg Polysorbate 20 and Sodium Phosphate buffer (Sodium Phosphate Dibasic, Heptahydrate and Phosphoric Acid) in a sterile, lyophilized form intended for reconstitution with sterile 0.9% Sodium Chloride Injection, USP. Menopur is administered by subcutaneous (SC) injection.

Menopur (menotropins for injection, USP) is supplied in sterile vials as a lyophilized, white to off–white powder or pellet.

Each vial of Menopur is accompanied by a vial of sterile diluent containing 2 mL of 0.9% Sodium Chloride Injection, USP: 75 IU FSH and 75 IU of LH activity, and supplied as: Box of 5 vials + 5 vials diluent