Follistim AQ

1 INDICATIONS AND USAGE FOLLISTIM ® AQ Cartridge (follitropin beta) injection, is indicated: In Women for: FOLLISTIM AQ Cartridge is a gonadotropin 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 ( 1.1 ) Pregnancy in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle ( 1.2 ) 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 ( 1.3 ) 1.1 Induction of Ovulation and Pregnancy in Anovulatory Infertile Women in Whom the Cause of Infertility is Functional and Not Due to Primary Ovarian Failure Prior to initiation of treatment with FOLLISTIM AQ Cartridge: Women should have a complete gynecologic and endocrinologic evaluation. Primary ovarian failure should be excluded. The possibility of pregnancy should be excluded. Tubal patency should be demonstrated. The fertility status of the male partner should be evaluated. 1.2 Pregnancy in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle Prior to initiation of treatment with FOLLISTIM AQ Cartridge: Women should have a complete gynecologic and endocrinologic evaluation and diagnosis of cause of infertility. The possibility of pregnancy should be excluded. The fertility status of the male partner should be evaluated. In Men for: 1.3 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 Prior to initiation of treatment with FOLLISTIM AQ Cartridge: Men should have a complete medical and endocrinologic evaluation. Hypogonadotropic hypogonadism should be confirmed and primary testicular failure should be excluded. Serum testosterone levels should be normalized with human chorionic gonadotropin (hCG) treatment. The fertility status of the female partner should be evaluated.

2 DOSAGE AND ADMINISTRATION See Dose Conversion Table 1 for FOLLISTIM AQ Cartridge with Pen Injector ( 2.1 ) In Anovulatory Women Undergoing Ovulation Induction ( 2.2 ): Starting daily dose of 50 international units of FOLLISTIM AQ Cartridge is administered subcutaneously for at least the first 7 days. The dose is increased by 25 or 50 international units at weekly intervals until follicular growth and/or serum estradiol levels indicate an adequate response. When an acceptable pre-ovulatory state is achieved, final oocyte maturation is achieved with 5,000 to 10,000 international units of urinary human chorionic gonadotropin (hCG). The woman and her partner should have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent. In Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization or Intracytoplasmic Sperm Injection Cycle ( 2.3 ): Starting dose of 200 international units (actual cartridge doses) of FOLLISTIM AQ Cartridge is administered subcutaneously for at least the first 7 days of treatment. Subsequent doses can be adjusted down or up based upon ovarian response as determined by ultrasound evaluation of follicular growth and serum estradiol levels. Dosage reduction in high responders can be considered from the 6th day of treatment onward according to individual response. Final oocyte maturation is induced with a dose of 5,000-10,000 international units of urinary hCG. Oocyte (egg) retrieval is performed 34 to 36 hours later. Induction of Spermatogenesis in Men ( 2.4 ): Pretreatment with urinary hCG alone (1,500 international units twice weekly) is required. If serum testosterone levels have not normalized after 8 weeks of hCG treatment, the dose may be increased to 3,000 international units twice a week. After normalization of serum testosterone levels, administer 450 international units per week (225 international units twice weekly or 150 international units three times weekly) of FOLLISTIM AQ Cartridge subcutaneously with the same pre-treatment hCG dose used to normalize testosterone levels. 2.1 General Dosing Information Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the solution is not clear and colorless or has particles in it, the solution should not be used. Do not add any other medicines into the FOLLISTIM AQ Cartridge. FOLLISTIM AQ Cartridge with the pen injector device delivers on average an 18% higher amount of follitropin beta when compared to reconstituted FOLLISTIM delivered with a conventional syringe and needle. When administering FOLLISTIM AQ Cartridge, a lower starting dose and lower dose adjustments (as compared to reconstituted FOLLISTIM) should be considered. For that purpose the following Dose Conversion Table is provided: Table 1: FOLLISTIM AQ Cartridge Administered Subcutaneously with the FOLLISTIM Pen Dose Conversion Table Each value represents an 18% difference rounded to the nearest 25 IU increment. Lyophilized recombinant FSH dosing with ampules or vials, using conventional syringe FOLLISTIM AQ Cartridge dosing with the FOLLISTIM Pen 75 IU 50 IU 150 IU 125 IU 225 IU 175 IU 300 IU 250 IU 375 IU 300 IU 450 IU 375 IU 2.2 Recommended Dosing in Anovulatory Women Undergoing Ovulation Induction The dosing scheme is stepwise and is individualized for each woman [see Clinical Studies (14.1) ] . A starting daily dose of 50 international units of FOLLISTIM AQ Cartridge is administered [see Dosage and Administration (2.1) ] subcutaneously daily for at least the first 7 days. Subsequent dosage adjustments are made at weekly intervals based upon ovarian response. If an increase in dose is indicated by the ovarian response, the increase should be made by 25 or 50 international units of FOLLISTIM AQ Cartridge at weekly intervals until follicular growth and/or serum estradiol levels indicate an ad …

3 DOSAGE FORMS AND STRENGTHS FOLLISTIM AQ Cartridge is a clear and colorless solution available as: Injection: 300 international units per 0.36 mL in a single-patient-use cartridge Injection: 600 international units per 0.72 mL in a single-patient-use cartridge Injection: 900 international units per 1.08 mL in a single-patient-use cartridge Injection: FOLLISTIM AQ Cartridge 300 International Units per 0.36 mL in a single-patient-use cartridge ( 3 ) Injection: FOLLISTIM AQ Cartridge 600 International Units per 0.72 mL in a single-patient-use cartridge ( 3 ) Injection: FOLLISTIM AQ Cartridge 900 International Units per 1.08 mL in a single-patient-use cartridge ( 3 )

4 CONTRAINDICATIONS FOLLISTIM AQ Cartridge is contraindicated in women and men who exhibit: Prior hypersensitivity to recombinant hFSH products or any component of FOLLISTIM AQ Cartridge. Reactions including anaphylaxis have been reported [see Adverse Reactions (6.2) ] High levels of FSH indicating primary gonadal failure Presence of uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders) [see Indications and Usage (1.1 , 1.2 , 1.3) ] Hypersensitivity reactions to streptomycin or neomycin. FOLLISTIM AQ may contain traces of these antibiotics Tumors of the ovary, breast, uterus, testis, hypothalamus or pituitary gland FOLLISTIM AQ Cartridge is also contraindicated in women who exhibit: Pregnancy [see Use in Specific Populations (8.1) ] Heavy or irregular vaginal bleeding of undetermined origin Ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS) Women and men who exhibit: Prior hypersensitivity to recombinant hFSH products ( 4 ) High levels of FSH indicating primary gonadal failure ( 4 ) Presence of uncontrolled non-gonadal endocrinopathies ( 4 ) Hypersensitivity reactions related to streptomycin or neomycin ( 4 ) Tumors of the ovary, breast, uterus, testis, hypothalamus or pituitary gland ( 4 ) Women who exhibit: Pregnancy ( 4 , 8.1 ) Heavy or irregular vaginal bleeding of undetermined origin ( 4 ) Ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS) ( 4 )

6 ADVERSE REACTIONS 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 [see Warnings and Precautions (5.3) ] Thromboembolism [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 Anomalies [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 women undergoing ovulation induction are ovarian hyperstimulation syndrome, ovarian cyst, abdominal discomfort, abdominal pain and lower abdominal pain. ( 6.1 ) The most common adverse reactions (≥2%) in women undergoing controlled ovarian stimulation as part of an IVF or ICSI cycle are pelvic discomfort, headache, ovarian hyperstimulation syndrome, pelvic pain, nausea and fatigue. ( 6.1 ) The most common (≥2%) adverse reactions in men undergoing induction of spermatogenesis are headache, acne, injection site reaction, injection site pain, gynecomastia, rash and dermoid cyst. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon USA LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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 reactions 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. Ovulation Induction In a single cycle, multi-center, assessor-blind, parallel group, comparative study, a total of 172 chronic anovulatory women who had failed to ovulate and/or conceive with clomiphene citrate therapy, were randomized and treated with FOLLISTIM (105) or a urofollitropin comparator. Adverse reactions with an incidence of greater than 2% in either treatment group are listed in Table 2. Table 2: Common Adverse Reactions Reported at a Frequency of ≥2% in an Assessor-Blind, Comparative Study of Anovulatory Women Receiving Ovulation Induction System Organ Class/Adverse Reactions Treatment Number (%) of Women FOLLISTIM N=105 n (%) Comparator N=67 n (%) Gastrointestinal disorders Abdominal discomfort 3 (2.9) 1 (1.5) Abdominal pain 3 (2.9) 2 (3.0) Abdominal pain lower 3 (2.9) 1 (1.5) Reproductive system and breast disorders Ovarian cyst 3 (2.9) 2 (3.0) Ovarian hyperstimulation syndrome 8 (7.6) 3 (4.5) General disorders and administration site conditions Pyrexia 0 (0.0) 2 (3.0) Adverse reactions reported commonly (greater than or equal to 2% of women treated with FOLLISTIM) in other ovulation induction clinical trials were headache, abdominal distension, constipation, diarrhea, nausea, pelvic pain, uterine enlargement, vaginal hemorrhage and injection site reaction. In Vitro Fertilization/Intracytoplasmic Sperm Injection In a single cycle, multi-center, double-blind, parallel group, comparative study, a total of 1509 women were randomized to receive controlled ovarian stimulation with either FOLLISTIM AQ Cartridge (751 women were treated with FOLLISTIM AQ Cartridge) or a comparator and pituitary suppression with a gonadotropin releasing hormone (GnRH) antagonist as part of an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle. Table 3 lists adverse reactions with an incidence of greater than 2% in the group of women treated with FOLLISTIM AQ Cartridge. Table 3: Common Adverse Reactions Reported at a Frequency of ≥2% in a Randomized, Double-blind, Active-controlled, Comparative Study of Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization or Intracytoplasmic Sperm Injection Cycle System Org …

7 DRUG INTERACTIONS No drug-drug interaction studies have been performed.

8 USE IN SPECIFIC POPULATIONS Lactation: It is not known whether this drug is excreted in human milk. ( 8.2 ) 8.1 Pregnancy Risk Summary FOLLISTIM AQ Cartridge is contraindicated for use 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 [see Warnings and Precautions (5.6) ] . There is no human data that the use of gonadotropins (including FOLLISTIM AQ Cartridge) 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 gonadotropins products to achieve pregnancy [see Warnings and Precautions (5.8) ] . 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. 8.2 Lactation Risk Summary It is not known whether this drug is excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FOLLISTIM AQ Cartridge and any potential adverse effects on the breastfed child from FOLLISTIM AQ Cartridge or from the underlying maternal condition. 8.4 Pediatric Use FOLLISTIM AQ Cartridge is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use Clinical studies of FOLLISTIM AQ Cartridge have not been conducted in patients 65 years of age and older.

12.1 Mechanism of Action Women: Follicle-stimulating hormone (FSH), the active component in FOLLISTIM AQ Cartridge, is required for normal follicular growth, maturation, and gonadal steroid production. In women, the level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. FOLLISTIM AQ Cartridge stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to effect the final phase of follicle maturation, resumption of meiosis and rupture of the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following treatment with FOLLISTIM AQ Cartridge when patient monitoring indicates appropriate follicular development parameters have been reached. Men: FOLLISTIM when administered with hCG stimulates spermatogenesis in men with hypogonadotropic hypogonadism. FSH, the active component of FOLLISTIM, is the pituitary hormone responsible for spermatogenesis.

11 DESCRIPTION Follitropin beta, a gonadotropin [human follicle-stimulating hormone (hFSH)], is a glycoprotein hormone produced by recombinant DNA technology in a Chinese hamster ovary (CHO) cell line. It has a dimeric structure containing two glycoprotein subunits (alpha and beta). The alpha and beta subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structures are indistinguishable from that of hFSH. The molecular weight is approximately 40 kDa. FOLLISTIM AQ Cartridge (follitropin beta) injection is a sterile clear and colorless solution, containing either 300 International Units, 600 International Units, or 900 International Units of follitropin beta in disposable single-patient-use cartridges for subcutaneous use only with the FOLLISTIM Pen. Each cartridge delivers 300 International Units in 0.36 mL and the inactive ingredients: benzyl alcohol (3.6 mg; preservative), methionine (0.18 mg), polysorbate 20 (0.072 mg), sodium citrate (4.64 mg), sucrose (18 mg), and Water for Injection USP. Hydrochloric acid NF and/or sodium hydroxide NF are used to adjust the pH to 7. Each cartridge delivers 600 International Units in 0.72 mL and the inactive ingredients: benzyl alcohol (7.2 mg; preservative), methionine (0.36 mg), polysorbate 20 (0.144 mg), sodium citrate (9.3 mg), sucrose (36 mg), and Water for Injection USP. Hydrochloric acid NF and/or sodium hydroxide NF are used to adjust the pH to 7. Each cartridge delivers 900 International Units in 1.08 mL and the inactive ingredients: benzyl alcohol (10.8 mg; preservative), methionine (0.54 mg), polysorbate 20 (0.216 mg), sodium citrate (13.9 mg), sucrose (54 mg), and Water for Injection USP. Hydrochloric acid NF and/or sodium hydroxide NF are used to adjust the pH to 7. Under current storage conditions, FOLLISTIM AQ may contain up to 11% of oxidized follitropin beta.

10 OVERDOSAGE Aside from the possibility of Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2 , 5.3) ] and multiple gestations [see Warnings and Precautions (5.5) ] , there is no additional information concerning the consequences of acute overdosage with FOLLISTIM AQ Cartridge.

16 HOW SUPPLIED/STORAGE AND HANDLING FOLLISTIM AQ Cartridge (follitropin beta) injection is a clear and colorless solution in a disposable, prefilled single-patient-use glass cartridge with grey rubber piston and an aluminum crimp-cap with grey rubber inlay supplied in a box containing disposable, 29 gauge, ultra-fine, 1⁄2-inch, sterile BD Micro-FineTM Pen Needles (for use with FOLLISTIM Pen available separately) and in the following presentations: NDC 78206-129-01 FOLLISTIM AQ Cartridge 300 international units per 0.36 mL with silver crimp-caps and 5 BD Micro-Fine Pen Needles NDC 78206-130-01 FOLLISTIM AQ Cartridge 600 international units per 0.72 mL with gold crimp-caps and 7 BD Micro-Fine Pen Needles NDC 78206-131-01 FOLLISTIM AQ Cartridge 900 international units per 1.08 mL with blue crimp-caps and 10 BD Micro-Fine Pen Needles Pharmacy Storage: Store refrigerated 36°F to 46°F (2°C to 8°C) until dispensed. Do not freeze. Patient Storage: Store unused cartridge refrigerated at 36°F to 46°F (2°C to 8°C) until the expiration date, or at room temperature at up to 77°F (25°C) for 3 months or until expiration date, whichever occurs first. After first use, store at 36°F to 77°F (2°C to 25°C) and discard after 28 days. Store in the original carton to protect from light. Do not freeze.