FOLLISTIM AQ (follitropin beta injection) is indicated in women for induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure. FOLLISTIM AQ is also indicated in women for the development of multiple follicles in ovulatory women participating in an assisted reproductive technology (ART) program. FOLLISTIM AQ (follitropin beta injection) is also indicated in men for induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism (HH) in whom the cause of infertility is not due to primary testicular failure.

Selected Safety Information About FOLLISTIM AQ:

• FOLLISTIM AQ is contraindicated in women and men who exhibit any of the following: prior hypersensitivity to recombinant human follicle-stimulating hormone (hFSH) products; high levels of FSH indicating primary gonadal failure; presence of uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders); hypersensitivity reactions to streptomycin or neomycin (FOLLISTIM AQ may contain traces of these antibiotics); tumor of the ovary, breast, uterus, testis, hypothalamus, or pituitary gland; and in women who exhibit pregnancy; heavy or irregular vaginal bleeding of undetermined origin; ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS).

• FOLLISTIM AQ should be used only by physicians who are experienced in infertility treatment. FOLLISTIM AQ is a potent gonadotropic substance capable of causing ovarian hyperstimulation syndrome (OHSS) with or without pulmonary or vascular complications and multiple births. Gonadotropin therapy requires the availability of appropriate monitoring facilities.

• In order to minimize the hazards associated with abnormal ovarian enlargement that may occur with FOLLISTIM AQ therapy, treatment should be individualized and the lowest effective dose should be used.

• OHSS is a medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical condition. OHSS occurs after gonadotropin treatment has been discontinued and it can develop rapidly, reaching its maximum about 7 to 10 days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to human chorionic gonadotropin (hCG) administration, 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 2 weeks after hCG administration. If serious OHSS occurs, treatment should be stopped and the patient should be hospitalized. During clinical trials with FOLLISTIM therapy, OHSS occurred in 7.6% of 105 women (OI) and 5.2% of 591 women (ART) treated with FOLLISTIM.

• Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic reactions both in association with, and separate from OHSS have been reported following gonadotropin therapy. Women with generally recognized risk factors for thrombosis, such as a 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 infarction. In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of ovulation induction or in vitro fertilization (IVF) treatment need to be weighed against the risks. It should be noted, that pregnancy itself also carries an increased risk of thrombosis.

• Ovarian torsion has been reported after treatment with FOLLISTIM AQ and after intervention with other gonadotropins. This may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

• Multi-fetal gestation and births have been reported with all gonadotropin treatments including FOLLISTIM AQ treatment. The woman and her partner should be advised of the potential risk of multi-fetal gestation and births before starting treatment.

• The incidence of congenital malformations after ART 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, sperm characteristics) and to the higher incidence of multi-fetal gestations after ART. There are no indications that the use of gonadotropins during ART is associated with an increased risk of congenital malformations.

• Since infertile women undergoing ART, and particularly IVF, often have tubal abnormalities the incidence of ectopic pregnancies might be increased. Early confirmation of an intrauterine pregnancy should be determined by hCG testing and transvaginal ultrasound.

• The risk of spontaneous abortions (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be a factor of the underlying infertility.

• There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.

• In most instances, treatment with FOLLISTIM AQ will result only in follicular growth and maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following the administration of FOLLISTIM AQ or when clinical assessment indicates that sufficient follicular maturation has occurred. The degree of follicular maturation and the timing of hCG administration can both be determined with the use of sonographic visualization of the ovaries and endometrial lining in conjunction with measurement of serum estradiol levels. The combination of transvaginal ultrasonography and measurement of serum estradiol levels is also useful for minimizing the risk of OHSS and multi-fetal gestations.

• Adverse reactions occurring in ≥2% of women in clinical trials undergoing ovulation induction with FOLLISTIM included: headache, abdominal distension, abdominal discomfort, abdominal pain- and lower abdominal pain, ovarian cyst, ovarian hyperstimulation syndrome, constipation, diarrhea, nausea, pelvic pain, uterine enlargement, vaginal hemorrhage, and injection site reaction.

• Adverse reactions occurring in ≥2% of women in clinical trials undergoing ART with FOLLISTIM included: headache, abdominal distension abdominal pain, ovarian hyperstimulation syndrome, constipation, diarrhea, nausea, pelvic pain, breast tenderness, metrorrhagia, ovarian enlargement, vaginal hemorrhage, injection site reaction, and rash.

• Adverse reactions occurring in ≥2% of men in clinical trials undergoing induction of spermatogenesis with FOLLISTIM included: headache, acne, injection site reaction, injection site pain, gynecomastia, rash, and dermoid cyst.

Before prescribing FOLLISTIM AQ Vial, please read the accompanying Prescribing Information.

Before prescribing FOLLISTIM AQ Cartridge, please read the accompanying Prescribing Information.

PREGNYL is indicated for the induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not due to primary ovarian failure, and who has been appropriately pretreated with human menotropins.

Selected Safety Information About PREGNYL:

• PREGNYL is contraindicated in patients with prior allergic reaction to human chorionic gonadotropin (HCG).

• PREGNYL should be used in conjunction with human menopausal gonadotropins. Only physicians experienced in infertility treatment should prescribe PREGNYL.

• Anaphylaxis has been reported with urinary-derived HCG products.

• The principal serious adverse reactions associated with PREGNYL are: (1) ovarian hyperstimulation, a syndrome of sudden ovarian enlargement, ascites with or without pain, and/or pleural effusion, (2) rupture of ovarian cysts with resultant hemoperitoneum, (3) multiple births, and (4) arterial thromboembolism.

• Other adverse reactions associated with PREGNYL use include, headache, irritability, restlessness, depression, fatigue, edema, and pain at the site of injection.

• Hypersensitivity reactions, both localized and systemic in nature, have been reported.

Before prescribing PREGNYL, please read the accompanying Prescribing Information.

Ganirelix Acetate Injection is indicated for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation.

Selected Safety Information About Ganirelix Acetate Injection:

• Ganirelix Acetate Injection is contraindicated in patients with a known hypersensitivity to Ganirelix Acetate or to any of its components, known hypersensitivity to gonadotropin-releasing hormone (GnRH) or any other GnRH analog, and in patients with known or suspected pregnancy.

• Ganirelix Acetate Injection should be prescribed by physicians who are experienced in infertility treatment. Before starting treatment with Ganirelix Acetate, pregnancy must be excluded.

• Cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported during post-marketing surveillance.

• The packaging of this product contains natural rubber latex which may cause allergic reactions.

• The most common adverse events occurring in ≥1% of patients treated with Ganirelix in clinical studies (N=794) are as follows: abdominal pain (gynecological) 4.8%, fetal death 3.7%, headache 3.0%, ovarian hyperstimulation syndrome (OHSS) 2.4%, vaginal bleeding 1.8%, injection site reaction 1.1%, nausea 1.1%, and abdominal pain (gastrointestinal) 1.0%.

Before prescribing Ganirelix Acetate Injection, please read the accompanying Prescribing Information.