Follitropin Alfa

GONAL-f is indicated for: GONAL-f is a gonadotropin indicated for: Women: Induction of ovulation and pregnancy in oligo-anovulatory infertile women for whom the cause of infertility is functional and not due to primary ovarian failure. ( 1.1 ) Development of multiple follicles in ovulatory infertile women as part of Assisted Reproductive Technology (ART) cycles. ( 1.2 ) Men: Induction of spermatogenesis in infertile men with primary and secondary hypogonadotropic hypogonadism for whom the cause of infertility is not due to primary testicular failure. ( 1.3 )

1.1 Induction of ovulation and pregnancy in oligo-anovulatory infertile women for whom the cause of infertility is functional and not due to primary ovarian failure.

1.2 Development of multiple follicles in ovulatory infertile women as part of an assisted reproductive technology (ART) cycle.

1.3 Induction of spermatogenesis in infertile men with primary and secondary hypogonadotropic hypogonadism for whom the cause of infertility is not due to primary testicular failure.

For Injection: 450 International Units of white lyophilized powder in a multiple-dose vial For Injection: 1050 International Units of white lyophilized powder in a multiple-dose vial For Injection: 450 International Units in a multiple-dose vial.( 3 ) For Injection: 1050 International Units in a multiple-dose vial. ( 3 )

GONAL-f is contraindicated in women and men who exhibit: Prior hypersensitivity to recombinant FSH products or one of their excipients. Reactions have included anaphylaxis [see Warning and Precautions (5.1) ] High levels of FSH indicating primary gonadal failure The presence of uncontrolled non-gonadal endocrinopathies (for example, thyroid, adrenal, or pituitary disorders) Sex hormone dependent tumors of the reproductive tract and accessory organs Tumors of pituitary gland or hypothalamus GONAL-f is also contraindicated in women who exhibit: Abnormal uterine bleeding of undetermined origin Ovarian cyst or enlargement of undetermined origin GONAL-f is contraindicated in women and men who exhibit ( 4 ): Prior hypersensitivity to recombinant FSH products or one of their excipients High levels of FSH indicating primary gonadal failure Uncontrolled non-gonadal endocrinopathies Sex hormone dependent tumors of the reproductive tract and accessory organs Tumors of pituitary gland or hypothalamus GONAL-f is also contraindicated in women who exhibit ( 4 ): Abnormal uterine bleeding of undetermined origin Ovarian cyst or enlargement of undetermined origin

Hypersensitivity Reactions and Anaphylaxis: If occurs, initiate appropriate therapy including supportive measures, and discontinue GONAL-f ( 5.1 ) Ovarian Hyperstimulation Syndrome: If serious, stop gonadotropins, including hCG, and determine if the woman needs to be hospitalized. Treatment is primarily symptomatic and consists of bed rest, fluid and electrolyte management, and analgesics ( 5.2 ) Pulmonary and Vascular Complications: In women with recognized risk factors, the benefits of induction of ovulation and ART need to be weighed against the risks. During or after use of GONAL-f, monitor for venous or arterial thromboembolic events ( 5.3 ) Ovarian Torsion: Early diagnosis and immediate detorsion limit damage to the ovary due to reduced blood supply ( 5.4 ) Abnormal Ovarian Enlargement: If the ovaries are abnormally enlarged on the last day of GONAL-f therapy, inform women not to administer hCG and to avoid intercourse ( 5.5 ) Multi-fetal Gestation and Births: The rate of multiple births is dependent on the number of embryos transferred. Advise the woman and her partner of the potential risk of multi-fetal gestation and birth before beginning therapy with GONAL-f ( 5.6 ) Embryofetal Toxicity: Inform women that the incidence of congenital malformations (birth defects) after some Assisted Reproductive Technology (ART) [specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)] may be slightly higher than after spontaneous conception. There is no evidence that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations ( 5.7 ) Ectopic Pregnancy: Advise women who become pregnant following ART and have: abdominal/pelvic pain (particularly on one side); shoulder, neck or rectal pain; and nausea and vomiting to seek immediate medical attention. Confirm the presence of an intrauterine pregnancy early by β-hCG testing and transvaginal ultrasound ( 5.8 ) Spontaneous Abortion: The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products, however, causality has not been established ( 5.9 ) Ovarian Neoplasm: Both benign and malignant ovarian neoplasms are reported in women who have had multiple drug therapy for controlled ovarian stimulation, however, causality has not been established ( 5.10 )

5.1 Hypersensitivity Reactions and Anaphylaxis In the post-marketing experience, serious systemic hypersensitivity reactions, including anaphylaxis, have been reported with use of GONAL-f and GONAL-f RFF. Symptoms have included dyspnea, facial edema, pruritus, and urticaria. If an anaphylactic or other serious allergic reaction occurs, initiate appropriate therapy including supportive measures if cardiovascular instability and/or respiratory compromise occur, and discontinue further use.

5.2 Ovarian Hyperstimulation Syndrome (OHSS) Ovarian Hyperstimulation Syndrome (OHSS) is a medical entity 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 [see Warnings and Precautions (5.6) ] , weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions [see Warnings and Precautions (5.4) ] . 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 Dosage and Administration (2.2 , 2.3) ] , withhold hCG. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, assess women for the development of OHSS for at least two weeks after hCG administration. If serious OHSS occurs, stop gonadotropins, including GONAL-f and hCG, and consider whether the woman needs to be hospitalized. Treatment is primarily symptomatic and overall consists of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, avoid diuretics except in the late phase of resolution as described below. The management of OHSS is divided into three phases as follows: Acute Phase : Management is directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Thoroughly assess daily or more often, based on the clinical need, 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. 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 intercourse, as these may cause rupture of an ovarian cyst, which may result in hemoperitoneum. If bleeding occurs and requires surgical intervention, 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.

5.3 Pulmonary and Vascular Complications Serious pulmonary conditions (for example, atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported in women treated with gonadotropins, including GONAL-f. In addition, thromboembolic events both in association with, and separate from OHSS have been reported in women treated with gonadotropins, including GONAL-f. 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. […]

The following serious adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions and Anaphylaxis [see Warnings and Precautions (5.1) ] Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2) ] Pulmonary and Vascular Complication [see Warnings and Precautions (5.3) ] Ovarian Torsion [see Warnings and Precautions (5.4) ] Abnormal Ovarian Enlargement [see Warnings and Precautions (5.5) ] Multi-fetal Gestation and Birth [see Warnings and Precautions (5.6) ] Embryofetal Toxicity [see Warnings and Precautions (5.7) ] Ectopic Pregnancy [see Warnings and Precautions (5.8) ] Spontaneous Abortion [see Warnings and Precautions (5.9) ] Ovarian Neoplasms [see Warnings and Precautions (5.10) ] The most common adverse reactions (≥5%) in ovulation induction include: ovarian cyst, headache, abdominal pain, OHSS, nausea, flatulence, pain and intermenstrual bleeding. ( 6.1 ) The most common adverse reactions (≥5%) in development of multiple follicles in ART include: headache, nausea, pelvic pain and abdominal pain. ( 6.1 ) The most common adverse reactions (>5%) in hypogonadotropic hypogonadal men participating in induction of spermatogenesis include: acne, injection site pain, fatigue, gynecomastia and seborrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088, Ext 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Study 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. Women: The safety of GONAL-f was examined in four clinical trials that enrolled 691 women [two trials for ovulation induction (454 women) and two trials for ART (237 women)]. Induction of Ovulation In a randomized, open-labeled, multicenter, active-controlled trial in oligo-anovulatory infertile women, conducted in the U.S., a total of 118 oligo-anovulatory infertile women were randomized to and underwent ovulation induction with GONAL-f versus a comparator urofollitropin. Adverse reactions occurring in at least 5.0% of women receiving GONAL-f are listed in Table 1. Table 1: Common Adverse Reactions Reported at a Frequency of ≥ 5% in an U.S. Ovulation Induction Trial System Organ Class/Adverse Reactions GONAL-f N=118 total number of women treated with GONAL-f (288 treatment cycles up to 3 treatment cycles per woman ) n number of women with the adverse reaction (%) Body as a Whole – General Pain 6 (5.1%) Central and Peripheral Nervous System Headache 12 (10.2%) Gastrointestinal System Abdominal Pain 9 (7.6%) Nausea 7 (5.9%) Flatulence 7 (5.9%) Reproductive, Female Intermenstrual Bleeding 6 (5.1) Ovarian Hyperstimulation 8 (6.8%) Ovarian Cyst 17 (14.4%) Development of Multiple Follicles as part of an Assisted Reproductive Technology (ART) Cycle In a randomized, open-labeled, active-comparator trial conducted in the U.S., a total of 56 normal ovulatory infertile women were randomized and received GONAL-f versus a urofollitropin comparator as part of an ART [in vitro fertilization (IVF) or intracytoplasmic sperm injection cycle (ICSI)] cycle. All women received pituitary down-regulation with gonadotropin releasing hormone (GnRH) agonist before stimulation. Adverse Reactions occurring in at least 5.0% of women are listed in Table 2. Table 2: Common Adverse Reactions Reported at a Frequency of ≥ 5% in an U.S. ART Trial System Organ Class/Adverse Reactions GONAL-f (N=56 total number of women treated with GONAL-f ) n number of women with the adverse reaction (%) Central and Peripheral Nervous System Headache 7 (12.5%) Gastrointestinal System Abdominal Pain 3 (5.4%) Nausea 4 (7.1%) Reproductive, Female Pelvic Pain 4 (7.1) Induction of Spermatogenesis: The safety of GONAL-f for induction of spermatogenesis in men with primary or secondary hypogonadotropic hypogonadism was examined in 3 open-label, non-randomized, multi-center, multi-national, escalating dose clinical trials (Trials 1, 2 and 3) conducted in 76 adult men (aged 16 to 48 years) with primary or secondary hypogonadotropic hypogonadism (defined as serum testosterone <100 ng/mL and low or normal FSH and LH) and azoospermia (sperm concentration <0.1×10 6 /mL). Of the 76 men enrolled, 63 received treatment with GONAL-f. During these trials, there was one serious adverse reaction of gynecomastia requiring surgical excision of breast tissue in a 50 year old man who received 9 months of therapy with GONAL-f. Pathology report showed gynecomastia with no atypia. There were no discontinuations due to adverse reactions. Adverse reactions reported in Trials 1, 2 and 3 by ≥2 patients during treatment with GONAL-f are shown in Table 3. Table 3. Common Adverse Reactions in Men with Azoospermia and Primary or Secondary Hypogonadotropic Hypogonadism Receiving GONAL-f in Trials 1, 2 and 3 for Induction for Spermatogenesis N=63 n (%) Acne 17 (27) Injection site pain 7 (11) Gynecomastia 4 (6) Seborrhea 3 (5) Fatigue 6 (10) Libido decreased 2 (3)

6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following adverse reactions have been reported during postmarketing use of GONAL-f. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to GONAL-f cannot be reliably determined. Body as a Whole – General: Hypersensitivity reactions including anaphylaxis Respiratory System: Asthma exacerbation Vascular Disorders: Thromboembolism

Lactation: Advise not to breastfeed ( 8.2 )

8.1 Pregnancy Risk Summary GONAL-f is not indicated in pregnant women. The incidence of congenital malformations after some Assisted Reproductive Technology, specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), may be slightly higher than that 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 a higher incidence of multi-fetal gestations after IVF or ICSI. There is no human data that the use of gonadotropins (including GONAL-f) alone or as part of IVF or ICSI cycles, increases the risk of congenital malformations. The risk of spontaneous abortion (miscarriage) is increased in women who have used gonadotropin products (including GONAL-f) to achieve pregnancy. In animal studies, the continuous administration of recombinant human FSH during pregnancy resulted in a decrease in the number of viable fetuses and difficult and prolonged delivery. No teratogenic effect has been observed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Data on a limited number of exposed pregnancies indicate no adverse reactions of gonadotropins on pregnancy, embryonal or fetal development, parturition or postnatal development following controlled ovarian stimulation. Animal Data Embryofetal development studies with recombinant human FSH in rats, where dosing occurred during organogenesis, showed a dose dependent increase in difficult and prolonged parturition in dams, and dose dependent increases in resorptions, pre- and post-implantation losses, and stillborn pups at doses representing 5 and 41 times the lowest clinical dose of 75 International Units based on body surface area. Pre-/post-natal development studies with recombinant human FSH in rats, where dosing occurred from mid-gestation through lactation, showed difficult and prolonged parturition in all dams dosed at 41 times the lowest clinical dose of 75 International Units based on body surface area, along with maternal death and stillborn pups associated with the difficult and prolonged parturition. This toxicity was not observed in dams and offspring dosed at a level 5 times the lowest clinical dose of 75 International Units based on body surface area.

8.2 Lactation There are no data on the presence of GONAL-f in human milk, the effects on the breastfed infant, or the effects on milk production. Because the secretion of prolactin during lactation can result in inadequate response to ovarian stimulation, advise women not to breast feed during treatment with GONAL-f.

8.3 Females and Males of Reproductive Potential Because GONAL-f is not indicated in pregnant women, verify a negative pregnancy test before administering GONAL-f to a woman [see Dosage and Administration (2.3 , 2.4) ].

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

8.5 Geriatric Use Safety and effectiveness of GONAL-f in postmenopausal women have not been established and it is not indicated in this population.

GONAL-f stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to bring about final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given, following the administration of GONAL-f, when monitoring of the patient indicates that sufficient follicular development is achieved. GONAL-f stimulates spermatogenesis in men with hypogonadotropic hypogonadism when administered with hCG.