Gonal-f

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION Induction of Ovulation ( 2.3 ) Initial starting dose of the first cycle - 75 International Units of GONAL-f per day for 14 days, administered subcutaneously Individualize doses after 14 days Do not administer doses greater than 300 International Units per day Development of Multiple Follicles in Assisted Reproductive Technology (ART) ( 2.3 ) Initial starting dose of the first cycle - 150 International Units per day, administered subcutaneously Dosage adjustments after 3 to 5 days and by 75 to 150 International Units at each adjustment Do not administer doses greater than 450 International Units per day Males with Hypogonadotropic Hypogonadism and Azoospermia ( 2.4 ) Use in conjunction with hCG. Prior to concomitant therapy with GONAL-f and hCG, pretreat with 1,000 to 2,250 USP units of hCG alone two to three times per week to achieve normal serum testosterone levels, which may take 3 to 6 months. After normalization of serum testosterone, administer 150 International Units of GONAL-f subcutaneously three times a week and 1,000 USP units of hCG (or the dose required to maintain serum testosterone levels within the normal range) three times a week. 2.1 Important Dosage and Administration Information Only physicians who are experienced in infertility treatment, should treat women with GONAL-f. GONAL-f is a gonadotropin product 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 (5.6) ] . Gonadotropin therapy requires the availability of appropriate monitoring facilities [see Warnings and Precautions (5.11) ] . Use the lowest effective dose of GONAL-f. Give careful attention to the diagnosis of infertility and the selection of candidates for GONAL-f therapy [see Dosage and Administration (2.3 , 2.4) ] . 2.2 Preparation of GONAL-f and Selection of Injection Site Store lyophilized multiple-dose vials refrigerated or at room temperature (2°-25°C /36°-77°F) and protected from light. Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit. Instruct women and men to use the accompanying syringes, calibrated in International Units FSH for administration. The 27-gauge injection syringe (see figure below) has unit dose markings from 37.5 International Units to 600 International Units FSH for use with GONAL-f Multi-Dose. Instruct women and men to take a specific dose of GONAL-f Multi-Dose. Show women and men how to locate the syringe marking that corresponds to the prescribed dose. Each GONAL‑f Multi‑Dose Vial delivers 450 International Units or 1050 International Units of follitropin alfa, respectively Multi-Dose 450 International Units Vial: Dissolve the contents of one Multi-Dose vial (450 International Units) with 1 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP. Resulting concentration will be 600 International Units/mL. Following reconstitution as directed, product will deliver the equivalent of six 75 International Units doses. Multi-Dose 1050 International Units Vial: Dissolve the contents of one Multi-Dose vial (1050 International Units) with 2 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP. Resulting concentration will be 600 International Units/mL. Following reconstitution as directed, product will deliver the equivalent of fourteen 75 International Units doses. Discard unused reconstituted solution after 28 days. Administer GONAL-f subcutaneously in the abdomen, upper arm, or upper leg as described in Patient Information and Instructions for Use. Figure 2.3 Dosing for Ovulation Induction Prior to initiation of treatment with GONAL-f: Perform a complete gynecologic and endocrinologic evaluation Exclude primary ovarian failure Exclude the possibility of pregnancy Demonstrate tubal patency Evaluate the fer…

5 WARNINGS AND PRECAUTIONS 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 w…

4 CONTRAINDICATIONS 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

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.

6 ADVERSE REACTIONS 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 …