Ferring Pharmaceuticals Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use MENOPUR ® safely and effectively. See full prescribing information for MENOPUR.
MENOPUR ® (menotropins for injection) for subcutaneous use.
Initial U.S. Approval: 1975
INDICATIONS AND USAGE
MENOPUR® (menotropins for injection) is a gonadotropin indicated for:
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Lyophilized powder for injection: containing 75 IU FSH and 75 IU of LH activity, supplied as lyophilized powder or pellet in sterile vials with diluent vials and Q•Cap® vial adapters. (3)
MENOPUR is contraindicated in women who exhibit:
WARNINGS AND PRECAUTIONS
The most common adverse reactions (≥2%) in ART include: abdominal cramps; abdomen enlarged; abdominal pain; headache; injection site pain and reaction; injection site inflammation; OHSS (6.1)
No drug/drug interaction studies have been conducted for MENOPUR in humans. (7)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
Development of Multiple Follicles and Pregnancy in Ovulatory Women as Part of an Assisted Reproductive Technology (ART) Cycle
Prior to initiation of treatment with MENOPUR® (menotropins for injection):
The recommended dosing scheme for patients undergoing IVF follows a stepwise approach and is individualized for each woman. The recommended initial dose of MENOPUR for women who have received a GnRH agonist for pituitary suppression is 225 International Units. MENOPUR may be administered together with BRAVELLE and the total initial dose when the products are combined should not exceed 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).
Lyophilized powder for Injection containing 75 International Units FSH and 75 International Units of LH activity, supplied as lyophilized powder or pellet in sterile vials with diluent vials and Q•Cap® vial adapters.
MENOPUR is contraindicated in women who exhibit:
MENOPUR should only be used by physicians who are experienced in infertility treatment. MENOPUR contains gonadotropic substances capable of causing in women, Ovarian Hyperstimulation Syndrome (OHSS) with or without pulmonary or vascular complications [see Warnings and Precautions (5.2, 5.3)] and multiple births [see Warnings and Precautions (5.5)]. Gonadotropin therapy requires the availability of appropriate monitoring facilities [see Warnings and Precautions (5.10)]. Use the lowest effective dose.
In order to minimize the hazards associated with abnormal ovarian enlargement that may occur with MENOPUR therapy, treatment should be individualized and the lowest effective dose should be used [see Dosage and Administration (2.2)]. Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important to minimize the risk of ovarian stimulation [see Warnings and Precautions (5.10)].
If the ovaries are abnormally enlarged on the last day of MENOPUR therapy, hCG should not be administered in order to reduce the chance of developing Ovarian Hyperstimulation Syndrome (OHSS) [see Warnings and Precautions (5.2)]. Prohibit intercourse in women with significant ovarian enlargement because of the danger of hemoperitoneum resulting from rupture of ovarian cysts [see Warnings and Precautions (5.2)].
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 development 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 [see Warnings and Precautions (5.3)]. 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 [see Warnings and Precautions (5.1)], the 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 two weeks after hCG administration.
If serious OHSS occurs, gonadotropins, including hCG, should be stopped and consideration should be given as to whether the woman needs to be hospitalized. Treatment 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, diuretics should be avoided except in the late phase of resolution as described below. The management of OHSS may be divided into three phases as follows:
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. Pelvic examination or intercourse may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should be avoided.
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 this syndrome, or who is experienced in the management of fluid and electrolyte imbalances, should be consulted.
In the IVF clinical trial for MENOPUR, OHSS occurred in 7.2% of the 373 MENOPUR treated women.
Serious pulmonary conditions (e.g. atelectasis, acute respiratory distress syndrome, and exacerbation of asthma) have been reported in women treated with gonadotropins. In addition, thromboembolic events both in association with, and separate from the Ovarian Hyperstimulation Syndrome (OHSS) have been reported in women treated with gonadotropins. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the extremities. Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarctions. In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology need to be weighed against the risks. Pregnancy also carries an increased risk of thrombosis.
Ovarian torsion has been reported after treatment with gonadotropins. This may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst, and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.
Multi-fetal gestation and births have been reported with all gonadotropin therapy including therapy with MENOPUR.
In the IVF clinical trial of MENOPUR, multiple pregnancy as diagnosed by ultrasound occurred in 35.3% (n=30) of 85 total pregnancies.
Before beginning treatment with MENOPUR, advise the woman and her partner of the potential risk of multi-fetal gestation and birth.
The incidence of congenital malformations after some ART [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. There are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations.
Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased. Early confirmation of intrauterine pregnancy should be determined by β-hCG testing and transvaginal ultrasound.
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.
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have had multiple drug therapy for controlled ovarian stimulation; however, a causal relationship has not been established.
In most instances, treatment of women with MENOPUR will result only in follicular growth and maturation. In the absence of an endogenous LH surge, hCG is given when monitoring of the woman indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring follicular growth and maturation, timing of the ovulatory trigger, detecting ovarian enlargement and minimizing the risk of the OHSS and multiple gestation.
The clinical confirmation of ovulation is obtained by direct or indirect indices of progesterone production as well as sonographic evidence of ovulation.
Direct or indirect indices of progesterone production:
Sonographic evidence of ovulation:
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.
In two single cycle, open label, multinational, multicenter, comparative trials, a total of 434 normal ovulatory infertile women were randomized and received subcutaneously administered MENOPUR as part of an in vitro fertilization (IVF) cycle (both trials) or intracytoplasmic sperm injection (ICSI) cycle (one of the two trials). All women received pituitary down-regulation with gonadotropin releasing hormone (GnRH) agonist before stimulation. Adverse Reactions occurring at an incidence of ≥ 2% in women receiving MENOPUR are shown in Table 1.
|Body System/Preferred Term||N||%|
|Body as a whole||Abdominal cramps||13||3.0|
|Injection site pain + reaction||17||3.9|
|Injection site inflammation||10||2.3|
|Urogenital||Ovarian Hyperstimulation Syndrome (OHSS)||27||6.2|
In addition, thrombophlebitis was reported in less than 1% of subjects.
In an open label, US, multicenter, comparative IVF and ICSI trial, MENOPUR and BRAVELLE were administered in the same syringe to 60 normal ovulatory infertile women. OHSS, post retrieval cramping and nausea and spontaneous abortion were the most common adverse reactions occurring at an incidence of ≥ 5% in women receiving the combination of MENOPUR and BRAVELLE.
In another open label, US multicenter, comparative trial for ovulation induction in anovulatory or oligovulatory infertile women, 76 subjects received subcutaneous or intramuscular injections of MENOPUR. The most common adverse reactions occurring at an incidence of ≥ 5% in women receiving MENOPUR were: headache; OHSS; injection site reaction, abdominal cramps, fullness and pain; and nausea.
The following adverse reactions have been reported during postmarketing use of gonadotropins. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to MENOPUR cannot be reliably determined.
Gastrointestinal disorders: abdominal pain, abdominal pain lower, abdominal distension, nausea, vomiting, abdominal discomfort
General disorders and administration site conditions: injection site reactions (most frequently reported injection site reaction was injection site pain), fatigue
Nervous system disorders: headache, dizziness
Reproductive system disorders: OHSS [see Warnings and Precautions (5.2)], pelvic pain, ovarian cyst, breast complaints (including breast pain, breast tenderness, breast discomfort, and breast swelling)
Skin and subcutaneous tissue disorders: acne, rash
Vascular disorders: hot flush
Pregnancy Category X [see Contraindications (4)].
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from MENOPUR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Aside from possible OHSS [see Warnings and Precautions (5.2)] and multiple gestations [see Warnings and Precautions (5.5)], there is no additional information on the consequences of acute overdosage with MENOPUR.
MENOPUR is a preparation of gonadotropins (FSH and LH activity), extracted from the urine of postmenopausal women, which has undergone additional steps for purification.
MENOPUR is a sterile, lyophilized powder intended for subcutaneous (SC) injection after reconstitution with sterile 0.9% Sodium Chloride Injection, USP. Each vial of MENOPUR contains 75 International Units of follicle-stimulating hormone (FSH) activity and 75 International Units 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).
The biological activity of MENOPUR is determined using the bioassays for FSH (ovarian weight gain assay in female rats) and LH (seminal vesicle weight gain assay in male rats), modified to increase the accuracy and reproducibility of these assays. The FSH and LH activity assays are standardized using the Fourth International Standard for Urinary FSH and Urinary LH, November 2000, by the Expert Committee on Biological Standardization of the World Health Organization (WHO ECBS). Both FSH and LH are glycoproteins that are acidic and water-soluble. Human Chorionic Gonadotropin (hCG) is detected in MENOPUR.
MENOPUR has been mixed in vitro with BRAVELLE with no evidence of aggregation.
Therapeutic class: Infertility
MENOPUR, administered for 7 to 20 days, produces ovarian follicular growth and maturation in women who do not have primary ovarian failure. Treatment with MENOPUR in most instances results only in follicular growth and maturation. When sufficient follicular maturation has occurred, hCG must be given to induce ovulation.
Two open-label, randomized, controlled trials were conducted to assess the pharmacokinetics of MENOPUR. Study 2003-02 compared single doses of subcutaneous administration of the US and European (EU) formulations of MENOPUR in 57 healthy, pre-menopausal females who had undergone pituitary suppression. The study established that the two formulations are bioequivalent. Study 2000-03 assessed single and multiple doses of MENOPUR administered subcutaneously and intramuscularly in a 3 phase crossover design in 33 healthy, pre-menopausal females who had undergone pituitary suppression. The primary pharmacokinetic endpoints were FSH AUC and Cmax values. The results are summarized in Table 2.
|PK Parameters||Single Dose|
(225 IU × 1 day then 150 IU × 6 days)
|Cmax* (mIU/mL)||8.5 (2.5)||7.8 (2.4)||15.0 (3.6)||12.5 (2.3)|
|Tmax (hr)||17.9 (5.8)||27.5 (25.4)||8.0 (3.0)||9.0 (7.0)|
|726.2 (243.0)||656.1 (233.7)||622.7 (153.0)||546.2 (91.2)|
The subcutaneous route of administration trends toward greater bioavailability than the intramuscular route for single and multiple doses of MENOPUR.
The efficacy of MENOPUR was established in one randomized, open-label, multicenter, multinational (in Europe and Israel), comparative clinical trial of women undergoing in vitro fertilization (IVF) or IVF plus intracytoplasmic injection (ICSI) to achieve pregnancy.
All women began ovarian stimulation as part of an IVF cycle following pituitary suppression with a GnRH agonist. A total of 373 patients were randomized to the MENOPUR arm. Randomization was stratified by insemination technique [conventional IVF vs. ICSI]. Efficacy was assessed based on the primary efficacy parameter of continuing pregnancy. The initial daily dose of MENOPUR was 225 International Units administered subcutaneously for five days. Thereafter, the dose was individualized according to each patient's response, up to a maximum of 450 IU/day for a total maximum duration of stimulation of 20 days. Treatment outcomes are summarized in Table 3.
|Parameter||Subcutaneously Administered MENOPUR|
|Continuing Pregnancy (%)*||87 (23)†|
|Clinical Pregnancy (%)||98 (26)‡|
MENOPUR (menotropins for injection) 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 for Injection, USP:
75 International Units FSH and 75 International Units of LH activity, supplied as
NDC 55566-7501-2: Box of 5 vials + 5 vials diluent + 5 Q•Cap vial adapters
Instruct women on the correct usage and dosing of MENOPUR [see Dosage and Administration (2.2)]. Caution women not to change the dosage or the schedule of administration unless she is told to do so by her healthcare provider.
Prior to beginning therapy with MENOPUR, inform women about the time commitment and monitoring procedures necessary for treatment [see Dosage and Administration (2.2) and Warnings and Precautions (5.10)].
Inform the woman that if she misses or forgets to take a dose of MENOPUR, the next dose should not be doubled and she should call her healthcare provider for further dosing instructions.
Inform women regarding the risks of OHSS [see Warnings and Precautions (5.2)] and OHSS-associated symptoms including lung and blood vessel problems [see Warnings and Precautions (5.3)] and ovarian torsion [see Warnings and Precautions (5.4)] with the use of MENOPUR.
Inform women regarding the risk of multi-fetal gestation and birth with the use of MENOPUR [see Warnings and Precautions (5.5)]
Vials of sterile diluent of 0.9% Sodium Chloride Injection, USP manufactured for Ferring Pharmaceuticals Inc.
(menotropins for injection)
for subcutaneous use
Read this Patient Information before you start using MENOPUR® (menotropins for injection) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is MENOPUR?
MENOPUR is a prescription medicine that contains follicle stimulating hormone (FSH) and luteinizing hormone (LH). MENOPUR causes your ovaries to make multiple (more than 1) eggs as part of an Assisted Reproductive Technology (ART) cycle.
Who should not use MENOPUR?
Do not use MENOPUR if you:
What should I tell my healthcare provider before using MENOPUR?
Before you use MENOPUR, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I use MENOPUR?
What are possible side effects of MENOPUR?
MENOPUR may cause serious side effects, including:
The most common side effects of MENOPUR include:
These are not all the possible side effects of MENOPUR. For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
How should I store MENOPUR?
Keep MENOPUR and all medicines out of the reach of children.
General Information about the safe and effective use of MENOPUR.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MENOPUR for a condition for which it was not prescribed. Do not give MENOPUR to other people, even if they have the same condition you have. It may harm them.
This Patient Information summarizes the most important information about MENOPUR. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about MENOPUR that is written for health professionals.
For more information go to www.menopur.com, or call 1-888-FERRING (1-888-337-7464).
What are the ingredients in MENOPUR?
Active ingredient: menotropins
Inactive ingredients: lactose monohydrate, polysorbate, sodium phosphate buffer (sodium phosphate dibasic, heptahydrate and phosphoric acid)
(menotropins for injection)
for subcutaneous use
Your healthcare provider should show you how to mix and inject MENOPUR® (menotropins for injection) or MENOPUR mixed with BRAVELLE® (urofollitropin for injection, purified) before you do it for the first time. Before using MENOPUR or MENOPUR mixed with BRAVELLE for the first time, read this Instructions for Use carefully. Keep this leaflet in a safe place and read it when you have questions.
Supplies you will need to give your injection of MENOPUR or MENOPUR mixed with BRAVELLE. See Figure A.
Step 1. Preparing your MENOPUR or MENOPUR mixed with BRAVELLE.
If your healthcare provider tells you to use more than 1 vial of MENOPUR or tells you to mix your MENOPUR with BRAVELLE in the same syringe:
Step 2. Removing the Q•Cap and adding your needle for injection.
Step 3. Prepare Injection site for MENOPUR or MENOPUR mixed with BRAVELLE.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Menopur® 75 IU
(menotropins for injection)
5 single dose vials of Menotropins for Injection
5 single dose vials of 0.9% Sodium Chloride Injection, USP, 2 mL
5 Q•Cap® Vial Adapters
For exclusive use with
Ferring reproductive health products
|Labeler - Ferring Pharmaceuticals Inc. (103722955)|