Menotropins

MENOPUR ® (menotropins for injection) is a gonadotropin indicated for: Development of multiple follicles and pregnancy in ovulatory women as part of an Assisted Reproductive Technology (ART) cycle ( 1 ) 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): Perform a complete gynecologic and endocrinologic evaluation, and diagnose the cause of infertility Exclude the possibility of pregnancy Evaluate the fertility status of the male partner Exclude a diagnosis of primary ovarian failure

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. 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: Prior hypersensitivity to MENOPUR or menotropins products or one of their excipients High levels of FSH indicating primary ovarian failure [see Indications and Usage (1) ] Pregnancy MENOPUR may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. MENOPUR is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the woman becomes pregnant while taking this drug, the woman should be apprised of the potential hazard to a fetus. Presence of uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders) [see Indications and Usage (1) ] Sex hormone dependent tumors of the reproductive tract and accessory organs Tumors of pituitary gland or hypothalamus Abnormal uterine bleeding of undetermined origin Ovarian cyst or enlargement of undetermined origin, not due to polycystic ovary syndrome MENOPUR is contraindicated in women who exhibit: Prior hypersensitivity to MENOPUR or menotropins products or one of their excipients ( 4 ) High levels of FSH indicating primary ovarian failure ( 4 ) Pregnancy ( 4 ) Presence of uncontrolled non-gonadal endocrinopathies ( 4 ) Sex hormone dependent tumors of the reproductive tract and accessory organ ( 4 ) Tumors of pituitary gland or hypothalamus ( 4 ) Abnormal uterine bleeding of undetermined origin ( 4 ) Ovarian cyst or enlargement of undetermined origin, not due to polycystic ovary syndrome ( 4 )

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. Abnormal Ovarian Enlargement ( 5.1 ) Ovarian Hyperstimulation Syndrome (OHSS) ( 5.2 ) Pulmonary and Vascular Complications ( 5.3 ) Ovarian Torsion ( 5.4 ) Multi-fetal Gestation and Birth ( 5.5 ) Congenital Malformation ( 5.6 ) Ectopic Pregnancy ( 5.7 ) Spontaneous Abortion ( 5.8 ) Ovarian Neoplasms ( 5.9 )

5.1 Abnormal Ovarian Enlargement 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) ] .

5.2 Ovarian Hyperstimulation Syndrome (OHSS) 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: 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. 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.

5.3 Pulmonary and Vascular Complications 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.

5.4 Ovarian Torsion 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.

5.5 Multi-fetal Gestation and Birth Multi-fetal gestation and births have been reported with all gonadotropin therapy including therapy with MENOPUR. […]

The following serious adverse reactions are discussed elsewhere in the labeling: Abnormal Ovarian Enlargement [see Warnings and Precautions (5.1) ] Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2) ] Atelectasis, acute respiratory distress syndrome and exacerbation of asthma [see Warnings and Precautions (5.3) ] Thromboembolic events [see Warnings and Precautions (5.3) ] Ovarian Torsion [see Warnings and Precautions (5.4) ] Multi-fetal Gestation and Birth [see Warnings and Precautions (5.5) ] Congenital Malformations [see Warnings and Precautions (5.6) ] Ectopic Pregnancy [see Warnings and Precautions (5.7) ] Spontaneous Abortion [see Warnings and Precautions (5.8) ] Ovarian Neoplasms [see Warnings and Precautions (5.9) ] 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial Experience 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. Table 1: MENOPUR Administered Subcutaneously in Women Undergoing IVF and ICSI. Adverse Reactions with Incidence of 2% or Greater Occurring on or After GnRH Administration. Body System/Preferred Term IVF n=434 N % Body as a whole Abdominal cramps 13

3.0 Abdomen enlarged 10

2.3 Abdominal pain 29

6.7 Headache 27

6.2 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.

6.2 Postmarketing Experience 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

No drug/drug interaction studies in humans have been conducted for MENOPUR. No drug/drug interaction studies have been conducted for MENOPUR in humans. ( 7 )

Pregnancy Category X. Do not use MENOPUR in pregnant women. ( 4 , 8.1 ) Nursing Mothers: It is not known whether this drug is excreted in human milk. ( 8.3 ) Pediatric Use: Safety and efficacy not established. ( 8.4 ) Renal and Hepatic Insufficiency: Safety, efficacy, and pharmacokinetics of MENOPUR in women with renal or hepatic insufficiency have not been established. ( 8.6 )

8.1 Pregnancy Teratogenic effects Pregnancy Category X [see Contraindications (4) ] .

8.3 Nursing Mothers 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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.6 Renal and Hepatic Insufficiency Safety, efficacy, and pharmacokinetics of MENOPUR in women with renal or hepatic insufficiency have not been established.

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.