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 rff ( 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 postmarketing 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 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 the 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 (5.5) ] , 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 (5.3) ] . 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 dosage and administration (2.3 , 2.4) ] , 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 rff 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. ohss occurred in 6 of 83 (7.2%) gonal-f rff treated women in an induction of ovulation trial; none were classified as severe. in an art trial, ohss occurred in 11 of 237 (4.6%) gonal-f rff treated women and 1 (0.42%) was classified as severe. 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 rff. in addition, thromboembolic events both in association with, and separate from ohss have been reported in women treated with gonadotropins, including gonal-f rff. 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 events 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 events have resulted in death. in women with recognized risk factors, the benefits of ovulation induction and assisted reproductive technology (art) need to be weighed against the risks. it should be noted that pregnancy also carries an increased risk of thrombosis. 5.4 ovarian torsion ovarian torsion has been reported after treatment with gonadotropins, including gonal-f rff. this may be related to ohss, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries. early diagnosis and immediate detorsion limit damage to the ovary due to reduced blood supply. 5.5 abnormal ovarian enlargement in order to minimize the hazards associated with abnormal ovarian enlargement that may occur with gonal-f rff therapy, individualize treatment and use the lowest effective dose [see dosage and administration (2.3 , 2.4) ] . 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 (5.12)] . if the ovaries are abnormally enlarged on the last day of gonal-f rff therapy, do not administer hcg in order to reduce the chance of developing ohss [see warnings and precautions (5.2) ] . prohibit intercourse for women with significant ovarian enlargement after ovulation because of the danger of hemoperitoneum resulting from rupture of ovarian cysts [see warnings and precautions (5.2) ]. 5.6 multi-fetal gestation and birth multi-fetal gestation and births have been reported with all gonadotropin therapy, including therapy with gonal-f rff. in a trial of induction of ovulation, 20% of live births were multiple births in women receiving gonal-f rff over three treatment cycles. in an art trial, 35.1% of live births were multiple births in women receiving gonal-f rff. 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 rff. 5.7 embryofetal toxicity 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. 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 is no evidence that the use of gonadotropins during ivf or icsi is associated with an increased risk of congenital malformations. 5.8 ectopic pregnancy since infertile women undergoing art often have tubal abnormalities, the incidence of ectopic pregnancy may be increased in women who become pregnant as a result of art. 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. 5.9 spontaneous abortion the risk of spontaneous abortion (miscarriage) is increased with gonadotropin products, including gonal-f rff. however, causality has not been established. the increased risk may be a factor of the underlying infertility. 5.10 ovarian neoplasms 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. 5.11 laboratory tests in most instances, treatment of women with gonal-f rff results only in follicular recruitment and development. in the absence of an endogenous lh surge, hcg is given to trigger ovulation when monitoring of the patient indicates that sufficient follicular development has occurred. this may be estimated by ultrasound alone or in combination with measurement of serum estradiol concentrations. 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 ovarian hyperstimulation syndrome 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: urinary or serum luteinizing hormone (lh) rise a rise in basal body temperature increase in serum progesterone menstruation following a shift in basal body temperature sonographic evidence of ovulation: collapsed follicle fluid in the cul-de-sac features consistent with corpus luteum formation secretory endometrium

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 rff. give careful attention to the diagnosis of infertility and the selection of candidates for gonal-f rff therapy [see dosage and administration (2.3 , 2.4) ] . 2.2 preparation of gonal-f rff and selection of injection site store lyophilized vials refrigerated or at room temperature (2°-25°c/36°-77°f) and protected from light. prior to administration, visually inspect parenteral drug products for particulate matter and discoloration, whenever solution and container permit. following reconstitution of the contents of a single-use vial of gonal-f rff into a pre-filled syringe containing 1 ml sterile water for injection, usp, the syringe will deliver 75 international units of follitropin alfa. dissolve contents of one or more single-use vials of gonal-f rff in 1 ml of sterile water for injection, usp (concentration not to exceed 450 international units/ml). an 18-gauge needle is provided for reconstitution. remove the needle and replace with a 29-gauge needle for injection. discard any unused reconstituted material (do not store). administer gonal-f rff subcutaneously in the abdomen, upper arm, or upper leg as described in patient information and instructions for use. 2.3 dosing for induction of ovulation prior to initiation of treatment with gonal-f rff: perform a complete gynecologic and endocrinologic evaluation exclude primary ovarian failure exclude the possibility of pregnancy demonstrate tubal patency evaluate the fertility status of the male partner the dosing scheme is stepwise and is individualized for each woman [see clinical studies (14.1) ] . starting doses less than 37.5 international units have not been studied in clinical trials and are not recommended. administer a starting dose of 75 international units of gonal-f rff subcutaneously daily for 14 days in the first cycle of use. in subsequent cycles of treatment, determine the starting dose (and dosage adjustments) of gonal-f rff based on the woman's history of the ovarian response to gonal-f rff. if indicated by the ovarian response after the initial 14 days, make an incremental adjustment in dose, up to 37.5 international units. if indicated by the ovarian response, make additional incremental adjustments in dose, up to 37.5 international units, every 7 days. continue treatment until follicular growth and/or serum estradiol levels indicate an adequate ovarian response. consider the following when planning the woman's individualized dose: use the lowest dose of gonal-f rff consistent with the expectation of good results. use appropriate gonal-f rff dose adjustment(s) to prevent multiple follicular growth and cycle cancellation. the maximum, individualized, daily dose of gonal-f rff is 300 international units per day. in general, do not exceed 35 days of treatment. discontinue gonal-f rff treatment, if the ovaries are abnormally enlarged or abdominal pain occurs. when pre-ovulatory conditions are reached, administer human chorionic gonadotropin (hcg) to induce final oocyte maturation and ovulation. encourage the woman and her partner to have intercourse daily, beginning on the day prior to the administration of hcg and until ovulation becomes apparent. withhold hcg in cases where the ovarian monitoring suggests an increased risk of ovarian hyperstimulation syndrome (ohss) on the last day of gonal-f rff therapy (for example estradiol greater than 2,000 pg per ml) [see warnings and precautions (5.2 5.3 , 5.5 , 5.11) ] . discourage intercourse when the risk for ohss is increased [see warnings and precautions (5.2 , 5.5) ]. individualize the initial dose administered in subsequent cycles based on the woman's response in the preceding cycle. as in the initial cycle, do not administer doses larger than 300 international units of fsh per day. follow the above recommendations to minimize the chance of development of ohss. 2.4 dosing for multiple follicle development as part of an assisted reproductive technology (art) cycle prior to initiation of treatment with gonal-f rff: 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 the dosing scheme follows a stepwise approach and is individualized for each woman: beginning on cycle day 2 or 3, administer subcutaneously a starting dose of 150 international units of gonal-f rff daily until sufficient follicular development, as determined by ultrasound in combination with measurement of serum estradiol levels, is attained. in most cases, therapy should not exceed 10 days. in women under 35 years of age whose endogenous gonadotropin levels are suppressed, initiate gonal-f rff administration at a dose of 150 international units per day. in women 35 years of age and older whose endogenous gonadotropin levels are suppressed, initiate gonal-f rff administration at a dose of 225 international units per day. adjust the dose after 5 days based on the woman's ovarian response, as determined by ultrasound evaluation of follicular growth and serum estradiol levels. do not make additional dosage adjustments more frequently than every 3-5 days or by more than 75-150 international units at each adjustment. continue treatment until adequate follicular development is evident, and then administer hcg to induce final follicular maturation in preparation for oocyte retrieval. withhold hcg administration in cases where the ovarian monitoring suggests an increased risk of ohss on the last day of gonal-f rff therapy [see warnings and precautions (5.2 , 5.3 , 5.5 , 5.11) ]. do not use doses greater than 450 international units per day. 2.5 missed dose do not double the next dose if the woman misses or forgets to take a dose of gonal-f rff.

adverse reactions (≥2%) in development of multiple follicles in art include: abdominal pain, headache, abdominal enlargement, injection site bruising, nausea, injection site pain, ovarian hyperstimulation, injection site inflammation, injection site reaction, and injection site edema ( 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. the safety of gonal-f rff was examined in two clinical trials (one ovulation induction trial and one art trial). induction of ovulation in a multiple cycle (a maximum of three cycles), assessor-blind, multinational, multicenter, active-comparator trial versus a recombinant fsh comparator, a total of 83 oligo-anovulatory infertile women were randomized and underwent induction of ovulation with gonal-f rff. adverse reactions occurring in at least 2.0% of women receiving gonal-f rff are listed in table 1. table 1: common adverse reactions reported at a frequency of ≥ 2% in an ovulation induction trial system organ class/adverse reactions gonal-f rff [n=83 total number of women treated with gonal-f rff (176 treatment cycles up to 3 treatment cycles per woman )] n number of women with the adverse reaction (%) central and peripheral nervous system headache 22 (26.5%) gastrointestinal system abdominal pain 10 (12.0%) nausea 3 (3.6%) flatulence 3 (3.6%) diarrhea 3 (3.6%) reproductive, female ovarian hyperstimulation 6 (7.2%) ovarian cyst 3 (3.6%) application site injection site pain 4 (4.8%) injection site inflammation 2 (2.4%) development of multiple follicles as part of an assisted reproductive technology (art) cycle in a single cycle, assessor-blind, multinational, multicenter, active-comparator trial versus a recombinant fsh comparator, a total of 237 normal ovulatory infertile women were randomized and received gonal-f rff 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 2.0% of women are listed in table 2. table 2: common adverse reactions reported at a frequency of ≥ 2% in an assisted reproductive technologies trial system organ class/adverse reactions gonal-f rff (n=237 total number of women treated with gonal-f rff ) n number of women with the adverse reaction (%) gastrointestinal system abdominal pain 55 (23.2%) nausea 19 (8.0%) body as a whole- general abdomen enlarged 33 (13.9%) central and peripheral nervous system headache 44 (18.6%) application site disorders injection site bruising 23 (9.7%) injection site pain 13 (5.5%) injection site inflammation 10 (4.2%) injection site reaction 10 (4.2%) injection site edema 6 (2.5%) reproductive, female ovarian hyperstimulation 11 (4.6%) 6.2 postmarketing experience the following adverse reactions have been reported during postapproval use of gonal-f rff. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. body as a whole - general: hypersensitivity reactions including anaphylaxis respiratory system: asthma exacerbation vascular disorders: thromboembolism

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 us 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 gonal-f rff- or gonal-f-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 rff 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 rff. 8.3 females and males of reproductive potential because gonal-f rff is not indicated in pregnant women, verify a negative pregnancy test before administering gonal-f rff 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 rff in postmenopausal women have not been established and it is not indicated in this population.

crease in the number of viable fetuses and difficult and prolonged delivery. no teratogenic effect has been observed. in the us 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 gonal-f rff- or gonal-f-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.

gonist for pituitary down-regulation. absorption the mean (%cv) time to c max is 15.5 hrs (43%). elimination the mean (%cv) elimination half-life of follitropin alfa is 53 hrs (52%) and is dependent on the absorption rate. drug interaction studies no studies evaluating the drug interaction potential of follitropin alfa have been conducted.

a pregnancy for which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hcg administration. rate cycle 1 72% non-inferior to comparator recombinant human fsh based on a two-sided 95% confidence interval, intent-to-treat analysis. 28% secondary efficacy outcomes. the trial was not powered to demonstrate differences in these outcomes. cycle 2 89% 41% cycle 3 92% 45% 14.2. development of multiple follicles as part of an assisted reproductive technology (art) cycle the efficacy of gonal-f rff was evaluated in a randomized, assessor-blind, multinational, multicenter active-controlled trial in ovulatory, infertile women treated for one cycle with controlled ovarian stimulation as part of an art [in vitro fertilization (ivf), or intracytoplasmic sperm injection (icsi)] cycle. women were randomized to either gonal-f rff (n=237), administered subcutaneously, or a comparator recombinant human fsh product. randomization was stratified by insemination technique (ivf versus icsi). all women received a gnrh agonist for pituitary down-regulation before receiving stimulation with recombinant fsh. the primary endpoint was the mean number of fertilized oocytes the day after insemination. the initial doses of gonal-f rff were 150 international units per day for women less than 35 years of age and 225 international units per day for women 35 years of age and older. the maximal dose given for both age groups was 450 international units per day. treatment outcomes for gonal-f rff are summarized in table 4. table 4: treatment outcomes in art trial outcome value (n) mean number of 2pn oocytes per woman non-inferior to comparator recombinant human fsh based on a two-sided 95% confidence interval, intent-to-treat analysis. 6.3 (237) mean number of 2pn oocytes per woman receiving ivf subgroup analyses. the trial was not powered to demonstrate differences in subgroups. 6.1 (88) mean number of 2pn oocytes per woman receiving icsi 6.5 (132) clinical pregnancy a clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 35-42 after hcg administration. rate per attempt secondary efficacy outcomes. the trial was not powered to demonstrate differences in these outcomes. 33.5% (218) clinical pregnancy rate per embryo transfer 35.8% (204) mean treatment duration in days (range) 9.7 [3-21] (230)

light. use immediately after reconstitution [see dosage and administration (2.2) ] . sterile water for injection, usp is provided in a pre-filled syringe. separate needles are provided for reconstitution (18 g) and administration (29 g). note: no antimicrobial or other substance has been added to the sterile water for injection for the single-dose vials. sterile water for injection is not suitable for intravascular injection without its first having been made approximately isotonic by the addition of a suitable solute.

inister hcg and to avoid intercourse [see warnings and precautions (5.5) ] . multi-fetal gestation and birth advise the woman and her partner of the potential risk of multi-fetal gestation and birth before beginning therapy with gonal-f rff [see warnings and precautions (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 [see warnings and precautions (5.7) ] . ectopic pregnancy inform women undergoing art that the incidence of ectopic pregnancy may be increased with these procedures, particularly for women with tubal abnormalities. advise women who become pregnant and have: abdominal/pelvic pain (particularly on one side); shoulder, neck or rectal pain; and nausea and vomiting to seek immediate medical attention [see warnings and precautions (5.8) ] . spontaneous abortion inform women that the risk of spontaneous abortion (miscarriage) is increased with gonadotropin products (including gonal-f rff). however, causality has not been established. the increased risk may be a factor of the underlying infertility [see warnings and precautions (5.9) ] . lactation advise women not to breastfeed because the secretion of prolactin during lactation can result in inadequate response to ovarian stimulation with gonal-f rff [see use in specific populations (8.2) ]. dosing and use of gonal-f rff single-use vials instruct women on the correct usage and dosing of gonal-f rff [see dosage and administration (2.3 , 2.4) ] . instruct women to reconstitute one or more vials of gonal-f rff using 1 ml sterile diluent and the 18g 1-1/2" pink mixing needle provided. instruct women to safely remove mixing needle and replace with 29g ½" needle for injection. caution women not to change the dosage or the schedule of administration unless she is told to do so by her healthcare provider. duration and necessary monitoring in women undergoing therapy with gonal-f rff prior to beginning therapy with gonal-f rff, inform women about the time commitment and monitoring procedures necessary for treatment [see dosage and administration (2.3 , 2.4) and warnings and precautions (5.11) ]. instructions regarding a missed dose inform the woman that if she misses or forgets to take a dose of gonal-f rff, she should not double the next dose and should call her healthcare provider for further dosing instructions [see dosage and administration (2.5) ].

have abnormal bleeding from your uterus or vagina from an unknown cause. have ovarian cysts or large ovaries from an unknown cause. before you start using gonal-f rff tell your healthcare provider about all of your medical conditions, including if you: have or have had asthma have been told by a healthcare provider that you have an increased risk for blood clots (thrombosis) have ever had a blood clot (thrombosis), or anyone in your family has ever had a blood clot (thrombosis) have had stomach (abdominal) surgery have had twisting of your ovary (ovarian torsion) had or have a cyst on your ovary have polycystic ovarian disease are pregnant or think you may be pregnant. gonal-f rff is not for pregnant women. your healthcare provider will give you a pregnancy test before you start using gonal-f rff. are breastfeeding. it is not known if gonal-f rff passes into your breast milk. you and your healthcare provider should decide if you will take gonal-f rff or breastfeed. you should not do both. are not an adult. gonal-f ® is not for children. it is not known if gonal-f is safe or works in children. 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 gonal-f rff? read the " instructions for use " that comes with gonal-f rff for information about the right way to use gonal-f rff. use gonal-f rff exactly as your healthcare provider tells you to. gonal-f rff is given by injection under your skin. you can inject gonal-f rff under the skin in the stomach (abdomen), upper arm, or upper leg. do not inject gonal-f rff at home until your healthcare provider has taught you the right way to inject it. change your injection site as your healthcare provider showed you. do not change your dose or the time you are scheduled to use gonal-f rff unless your healthcare provider tells you to. if you miss or forget to take a dose, do not double your next dose. ask your healthcare provider for instructions. your healthcare provider will do blood and urine hormone tests while you are using gonal-f rff. make sure you follow-up with your healthcare provider to have your blood and urine tested when told to do so. call your healthcare provider if you have any questions about your dose or how to use gonal-f rff. your healthcare provider may do ultrasound scans of your ovaries. make sure you follow-up with your healthcare provider to have your ultrasounds. what are the possible side effects of gonal-f rff? gonal-f rff may cause serious side effects, including: severe allergic reactions . women who have used gonal-f ® , gonal-f ® rff or gonal-f ® redi-ject ® in the past may have a severe allergic reaction right away when they use gonal-f rff again. this severe allergic reaction may lead to death. if you have any of the following symptoms of a severe allergic reaction, stop using gonal-f rff and go to the nearest hospital emergency room right away: shortness of breath swelling of your face itchy, red bumps or rash on your skin (hives) ovarian hyperstimulation syndrome (ohss). ohss is both a serious and common side effect. using gonal-f rff may cause ohss. ohss is a serious medical condition that can happen when your ovaries produce too many eggs (overstimulated). ohss can cause fluid to suddenly build up in the area of your stomach, chest, and heart, and can cause blood clots to form. in rare cases ohss has caused death. ohss may also happen after you stop using gonal-f rff. stop using gonal-f rff and call your healthcare provider right away if you have symptoms of ohss, including: trouble breathing nausea diarrhea severe lower stomach (pelvic) area pain vomiting decreased urine output weight gain lung problems. gonal-f rff may cause serious lung problems including fluid in your lungs (atelectasis), trouble breathing (acute respiratory distress syndrome), and worsening of asthma. blood clots. gonal-f rff may increase your chance of having blood clots in your blood vessels. blood clots can cause: blood vessel problems (thrombophlebitis) stroke loss of your arm or leg blood clot in your lung (pulmonary embolus) heart attack twisting (torsion) of your ovary. gonal-f rff may increase the chance of your ovary twisting if you already have certain conditions such as ohss, pregnancy and previous abdominal surgery. twisting of your ovary may lead to blood flow being cut off to your ovary. ovaries that are too large. gonal-f rff may cause your ovaries to be abnormally large. symptoms of large ovaries include bloating or pain in your lower stomach (pelvic) area. pregnancy with and birth of multiple babies. gonal-f rff may increase your chance of having a pregnancy with more than 1 baby. having a pregnancy and giving birth to more than 1 baby at a time increases the health risk for you and your babies. your healthcare provider should tell you about your chances of multiple births. birth defects. a baby born after an art cycle may have an increased chance of having birth defects. your chances of having a baby with birth defects may increase depending on: your age certain sperm problems your genetic background and that of your partner a pregnancy with more than 1 baby at a time ectopic pregnancy (pregnancy outside your womb). gonal-f rff may increase your chance of having a pregnancy that is abnormally outside of your womb. your chance of having a pregnancy outside of your womb is increased if you also have fallopian tube problems. call your healthcare provider right away if you have symptoms of an ectopic pregnancy including: stomach or pelvic pain especially on one side neck pain nausea and vomiting shoulder pain rectal pain miscarriage. your chance of loss of an early pregnancy may be increased if you had difficulty becoming pregnant. tumors of the ovary . if you have used medicines like gonal-f rff more than 1 time to get pregnant, you may have an increased chance of having tumors in your ovary(ies) (including cancer). common side effects of gonal-f rff include: headache ohss nausea stomach pain swelling and pain at the injection site gas stomach bloating diarrhea ovarian cyst tell your healthcare provider if you have any side effect that bothers you or that does not go away. these are not all the possible side effects of gonal-f rff. for more information, call your healthcare provider or pharmacist. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store gonal-f rff? before you use gonal-f rff for the first time, store your vials: in the refrigerator between 36°f to 46°f (2°c to 8°c) until the expiration date, or store your vials at room temperature between 68°f to 77°f (20°c to 25°c) until the expiration date. after you use gonal-f rff throw away (discard) unused material. store your gonal-f rff vials in a safe place. store gonal-f rff away from light. keep gonal-f rff and all medicines out of the reach of children. general information about the safe and effective use of gonal-f rff. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use gonal-f rff for a condition for which it was not prescribed. do not give gonal-f rff to other people, even if they have the same condition that you have. it may harm them. you can ask your pharmacist or healthcare provider for information about gonal-f rff that is written for health professionals. for more information, go to www.fertilitylifelines.com, or call 1-866-538-7879. what are the ingredients in gonal-f rff? active ingredient: follitropin alfa (r-hfsh) inactive ingredients : dibasic sodium phosphate dihydrate, methionine, monobasic sodium phosphate dihydrate, phosphoric acid and or sodium hydroxide, polysorbate 20, sucrose this patient package insert has been approved by the u.s. food and drug administration. 12//2020