Gonal-f RFF Redi-ject

1 INDICATIONS AND USAGE Gonal-f ® RFF Redi-ject ® is a prefilled gonadotropin-containing auto-injection device indicated for: Induction of ovulation and pregnancy in oligo-anovulatory women in whom the cause of infertility is functional and not due to primary ovarian failure ( 1.1 ) Development of multiple follicles in ovulatory women as part of an Assisted Reproductive Technology (ART) cycle ( 1.2 ) 1.1 Induction of Ovulation and Pregnancy in Oligo-Anovulatory Women in whom the Cause of Infertility is Functional and Not Due to Primary Ovarian Failure. Prior to initiation of treatment with Gonal-f ® RFF Redi-ject ® : 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 1.2 Development of Multiple Follicles in Ovulatory Women as Part of an Assisted Reproductive Technology (ART) Cycle. Prior to initiation of treatment with Gonal-f ® RFF Redi-ject ® : 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

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions and Anaphylaxis [see Warnings and Precautions (5.1) ] Abnormal Ovarian Enlargement [see Warnings and Precautions (5.2) ] Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.3) ] Atelectasis, acute respiratory distress syndrome and exacerbation of asthma [see Warnings and Precautions (5.4) ] Thromboembolic events [see Warnings and Precautions (5.4) ] Ovarian Torsion [see Warnings and Precautions (5.5) ] Multi-fetal Gestation and Birth [see Warnings and Precautions (5.6) ] Congenital Malformations [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: headache, abdominal pain, ovarian hyperstimulation ( 6.1 ) The most common adverse reactions (≥5%) in ART include: abdominal pain, nausea, abdominal enlargement, headache, injection site bruising ( 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 studies (one ovulation induction study and one ART study). Ovulation Induction In a multiple cycle (3), assessor-blind, multinational, multicenter, active comparator study vs. a recombinant FSH comparator, a total of 83 oligo-anovulatory infertile women were randomized and underwent ovulation induction 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 Study 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%) Neoplasm Ovarian Cyst 3 (3.6%) Reproductive, Female Ovarian Hyperstimulation 6 (7.2%) Application Site Injection Site Pain 4 (4.8%) Injection Site Inflammation 2 (2.4%) Assisted Reproductive Technology In a single cycle, assessor-blind, multinational, multicenter, active comparator study vs. 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 Study 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%) Application Site Edema 6 (2.5%) Reproductive, Female Ovarian Hyperstimulation 11 (4.6%) 6.2 Postmarketing Experience The following adverse reactions have been reported during postmarketing use of Gonal-f ® RFF. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Gonal - f ® RFF cannot be reliably determined. Body as a Whole - General: hypersensitivity reactions including anaphylactoid reactions [see Warnings and Precautions (5.1) ] Respiratory System: asthma Vascular disorders: thromboembolism [see Warnings and Precautions (5.4) ]

4 CONTRAINDICATIONS Gonal-f ® RFF Redi-ject ® is contraindicated in women who exhibit: Prior hypersensitivity to recombinant FSH products 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) ] Sex hormone dependent tumors of the reproductive tract and accessory organs Tumors of pituitary gland or hypothalamus Abnormal uterine bleeding of undetermined origin Ovarian cyst or enlargement of undetermined origin, not due to polycystic ovary syndrome Gonal-f ® RFF Redi-ject ® is contraindicated in women who exhibit ( 4 ): Hypersensitivity to recombinant FSH preparations 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 organ. Tumors of pituitary gland or hypothalamus Abnormal uterine bleeding of undetermined origin Ovarian cyst or enlargement of undetermined origin, not due to polycystic ovary syndrome

11 DESCRIPTION Follitropin alfa, 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 consisting of 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 those of human follicle stimulating hormone. The molecular weight is approximately 31 kDa (14 kDa for alpha subunit and 17 kDa for beta subunit). Gonal-f ® RFF Redi-ject ® (follitropin alfa) injection is a sterile, clear and colorless to slightly yellow solution in disposable, prefilled single-patient-use pen intended for the subcutaneous use. Each Gonal-f ® RFF Redi-ject ® pen delivers 300 International Units (22 mcg) follitropin alfa in 0.48 mL and the inactive ingredients: dibasic sodium phosphate (0.43 mg), m-cresol (1.47 mg), methionine (0.05 mg), monobasic sodium phosphate (0.19 mg), poloxamer (0.05 mg), sucrose (29.47 mg) and Water for Injection USP. Phosphoric acid and/or sodium hydroxide may be used to adjust the pH to 7. Each Gonal-f ® RFF Redi-ject ® pen delivers 450 International Units (33 mcg) follitropin alfa in 0.72 mL and the inactive ingredients: dibasic sodium phosphate (0.65 mg), m-cresol (2.21 mg), methionine (0.07 mg), monobasic sodium phosphate (0.29 mg), poloxamer (0.07 mg), sucrose (44.20 mg) and Water for Injection USP. Phosphoric acid and/or sodium hydroxide may be used to adjust the pH to 7. Each Gonal-f ® RFF Redi-ject ® pen delivers 900 International Units (66 mcg) follitropin alfa in 1.44 mL and the inactive ingredients: dibasic sodium phosphate (1.3 mg), m-cresol (4.42 mg), methionine (0.15 mg), monobasic sodium phosphate (0.58 mg), poloxamer (0.15 mg), sucrose (88.41 mg) and Water for Injection USP. Phosphoric acid and/or sodium hydroxide may be used to adjust the pH to 7. Under current storage conditions, Gonal-f ® RFF Redi-ject ® may contain up to 10% of oxidized follitropin alfa.

2 DOSAGE AND ADMINISTRATION Ovulation Induction ( 2.2 ) Initial starting dose of the first cycle - 75 International Units of Gonal-f ® RFF Redi-ject ® per day for 14 days, administered subcutaneously Individualization doses after 14 days Doses larger than 300 International Units of FSH per day are not recommended Assisted Reproductive Technology ( 2.3 ) Initial starting dose of the first cycle - 150 International Units per day, administered subcutaneously Dosage adjustments after 3-5 days and by 75-150 International Units at each adjustment Do not administer doses greater than 450 International Units per day 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. Gonal-f ® RFF Redi-ject ® is a pre-filled disposable auto-injection device intended for multiple dose use. Gonal-f ® RFF Redi-ject ® can be set in 12.5 International Units increments. Administer Gonal-f ® RFF Redi-ject ® subcutaneously in the abdomen as described in Instructions for Use Do not attempt to mix any other medications inside of the device with Gonal-f ® RFF Redi-ject ® . Instruct women to remove the Gonal-f ® RFF Redi-ject ® from the refrigerator at least 30 minutes prior to use in order to allow Gonal-f ® RFF Redi-ject ® to warm to room temperature and avoid the discomfort of a cold injection. 2.2 Recommended Dosing for Ovulation Induction 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. A starting daily dose of 75 International Units of Gonal-f ® RFF Redi-ject ® is administered subcutaneously daily for 14 days in the first cycle of use. In subsequent cycles of treatment, the starting dose (and dosage adjustments) of Gonal-f ® RFF Redi-ject ® should be determined based on the history of the ovarian response to Gonal-f ® RFF Redi-ject ® . The following should be considered when planning the woman's individualized dose: Appropriate Gonal-f ® RFF Redi-ject ® dose adjustment(s) should be used to prevent multiple follicular growth and cycle cancellation. The maximum, individualized, daily dose of Gonal-f ® RFF Redi-ject ® is 300 International Units per day. In general, do not exceed 35 days of treatment. 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 adjustments in dose, up to 37.5 International Units, every 7 days. Treatment should continue until follicular growth and/or serum estradiol levels indicate an adequate ovarian response. When pre-ovulatory conditions are reached, administer human chorionic gonadotropin (hCG) to induce final oocyte maturation and ovulation. 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 Redi-ject ® therapy [see Warnings and Precautions (5.2 , 5.3 , 5.11) ] . 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. Discourage intercourse when the risk for OHSS is increased [see Warnings and Precautions (5.2 , 5.3) ] . 2.3 Recommended Dosing for Assisted Reproductive Technology The dosing scheme follows a stepwise approach and is individualized for each woman. Beginning on cycle day 2 or 3, a starting dose of 150 International Units of Gonal-f ® RFF Redi-ject ® is administered subcutaneously 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 Redi-ject ® 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 Redi-ject ® 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. The administration of hCG should be withheld in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of Gonal-f ® RFF Redi-ject ® therapy [see Warnings and Precautions (5.2 , 5.3 , 5.11) ]. Doses greater than 450 International Units per day are not recommended.

10 OVERDOSAGE Aside from possible OHSS [see Warnings and Precautions (5.3) ] and multiple gestations [see Warnings and Precautions (5.6) ], there is no additional information on the consequences of acute overdosage with Gonal-f ® RFF Redi-ject ® .

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

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Follicle stimulating hormone (FSH), the active component in Gonal-f ® RFF Redi-ject ® , is required for normal follicular growth, follicular maturation, and gonadal steroid production. 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. Gonal-f ® RFF Redi-ject ® 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 Gonal-f ® RFF Redi-ject ® when monitoring of the woman indicates that appropriate follicular development parameters have been achieved. There is inter-woman variability in response to FSH administration. 12.3 Pharmacokinetics Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 International Units of Gonal-f ® RFF Redi-ject ® to 21 pre-menopausal healthy female volunteers who were pituitary down-regulated with a GnRH agonist. The descriptive statistics for the pharmacokinetic parameters are presented in Table 3. Table 3: Pharmacokinetic parameters of FSH following administration of Gonal-f ® RFF Redi-ject ® (300 International Units subcutaneously in a single dose) Parameter Healthy Volunteers (N=21) Mean % CV Abbreviations are: C max : peak concentration (above baseline) t max : time of C max t 1/2 : elimination half life AUC last (IU hr/L) 884 20% C max (IU/L) 9.83 23% t max (hr) 15.5 43% t 1/2 (hr) 53 52% Absorption The absorption rate of Gonal-f ® RFF Redi-ject ® following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of Gonal-f ® RFF Redi-ject ® are absorption rate-limited. Distribution Human tissue or organ distribution of FSH has not been determined for Gonal-f ® RFF Redi-ject ® . Metabolism/Excretion FSH metabolism and excretion following administration of Gonal-f ® RFF Redi-ject ® have not been studied in humans.

12.1 Mechanism of Action Follicle stimulating hormone (FSH), the active component in Gonal-f ® RFF Redi-ject ® , is required for normal follicular growth, follicular maturation, and gonadal steroid production. 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. Gonal-f ® RFF Redi-ject ® 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 Gonal-f ® RFF Redi-ject ® when monitoring of the woman indicates that appropriate follicular development parameters have been achieved. There is inter-woman variability in response to FSH administration.

12.3 Pharmacokinetics Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 International Units of Gonal-f ® RFF Redi-ject ® to 21 pre-menopausal healthy female volunteers who were pituitary down-regulated with a GnRH agonist. The descriptive statistics for the pharmacokinetic parameters are presented in Table 3. Table 3: Pharmacokinetic parameters of FSH following administration of Gonal-f ® RFF Redi-ject ® (300 International Units subcutaneously in a single dose) Parameter Healthy Volunteers (N=21) Mean % CV Abbreviations are: C max : peak concentration (above baseline) t max : time of C max t 1/2 : elimination half life AUC last (IU hr/L) 884 20% C max (IU/L) 9.83 23% t max (hr) 15.5 43% t 1/2 (hr) 53 52% Absorption The absorption rate of Gonal-f ® RFF Redi-ject ® following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of Gonal-f ® RFF Redi-ject ® are absorption rate-limited. Distribution Human tissue or organ distribution of FSH has not been determined for Gonal-f ® RFF Redi-ject ® . Metabolism/Excretion FSH metabolism and excretion following administration of Gonal-f ® RFF Redi-ject ® have not been studied in humans.

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3 DOSAGE FORMS AND STRENGTHS Gonal-f® RFF Redi-ject is a clear and colorless to slightly yellow solution available as: • Injection: Gonal-f ® RFF Redi-ject ® 300 International Units per 0.48 mL in prefilled, single-patient-use pen • Injection: Gonal-f ® RFF Redi-ject ® 450 International Units per 0.72 mL in prefilled, single-patient-use pen • Injection: Gonal-f ® RFF Redi-ject ® 900 International Units per 1.44 mL in prefilled, single-patient-use pen Injection: Gonal-f ® RFF Redi-ject ® 300 International Units per 0.48 mL in prefilled, single-patient-use pen ( 3 ) Injection: Gonal-f ® RFF Redi-ject ® 450 International Units per 0.72 mL in prefilled, single-patient-use pen ( 3 ) Injection: Gonal-f ® RFF Redi-ject ® 900 International Units per 1.44 mL in prefilled single-patient-use pen ( 3 )

Gonal-f RFF Redi-ject FOLLITROPIN FOLLITROPIN FOLLITROPIN SUCROSE METACRESOL SODIUM PHOSPHATE, DIBASIC, DIHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE METHIONINE POLOXAMER 188 Gonal-f RFF Redi-ject FOLLITROPIN FOLLITROPIN FOLLITROPIN SUCROSE METACRESOL SODIUM PHOSPHATE, DIBASIC, DIHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE METHIONINE POLOXAMER 188 Gonal-f RFF Redi-ject FOLLITROPIN FOLLITROPIN FOLLITROPIN SUCROSE METACRESOL SODIUM PHOSPHATE, DIBASIC, DIHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE METHIONINE POLOXAMER 188

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f ® RFF Redi-ject ® . However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test. Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (greater than or equal to 40 International Units per kg per day, greater than or equal to 5 times the lowest clinical dose of 75 International Units) for extended periods, through reduced fecundity.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f ® RFF Redi-ject ® . However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test. Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (greater than or equal to 40 International Units per kg per day, greater than or equal to 5 times the lowest clinical dose of 75 International Units) for extended periods, through reduced fecundity.

BLA021684

Gonal-f RFF Redi-ject

FOLLITROPIN

44087-1115

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL - 300 IU/0.48 mL Package Carton NDC 44087-1115-1 GONAL-f ® RFF Redi-ject ® 300 IU/0.48 mL (follitropin alfa) injection For subcutaneous injection Do not shake Rx only 1 Gonal-f ® RFF Redi-ject ® 5 needles for injection (29 gauge) EMD SERONO PRINCIPAL DISPLAY PANEL - 300 IU/0.48 mL Package Carton

Manufactured by: EMD Serono, Inc., Rockland, MA 02370 U.S.A. U.S. License number: 1773

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use) 17.1 Dosing and Use of Gonal-f ® RFF Redi-ject ® Instruct women on the correct usage and dosing of Gonal-f ® RFF Redi-ject ® [see Dosage and Administration (2.2 , 2.3) ] . Instruct women to view the dose display in bright light and to adjust the position of the Gonal-f ® RFF Redi-ject ® to minimize dose window glare. Caution women not to change the dosage or the schedule of administration unless she is told to do so by her healthcare provider. Instruct women to remove the Gonal-f ® RFF Redi-ject ® from the refrigerator at least 30 minutes prior to use in order to allow Gonal-f ® RFF Redi-ject ® to warm to room temperature and avoid the discomfort of a cold injection. 17.2 Duration and Necessary Monitoring in Women Undergoing Therapy with Gonal-f ® RFF Redi-ject ® Prior to beginning therapy with Gonal-f ® RFF Redi-ject ® , inform women about the time commitment and monitoring procedures necessary for treatment [see Dosage and Administration (2.2 , 2.3) and Warnings and Precautions (5.11) ]. 17.3 Instructions Regarding a Missed Dose Inform the woman that if she misses or forgets to take a dose of Gonal-f ® RFF Redi-ject ® , the next dose should not be doubled and she should call her healthcare provider for further dosing instructions. 17.4 Ovarian Hyperstimulation Syndrome Inform women regarding the risks of OHSS [see Warnings and Precautions (5.3) ] and OHSS-associated symptoms including lung and blood vessel problems [see Warnings and Precautions (5.4) ] and ovarian torsion [see Warnings and Precautions (5.5) ] with the use of Gonal-f ® RFF Redi-ject ® . 17.5 Multi-fetal Gestation and Birth Inform women regarding the risk of multi-fetal gestation and birth with the use of Gonal-f ® RFF Redi-ject ® [see Warnings and Precautions (5.6) ]

INSTRUCTIONS FOR USE GONAL-f® RFF Redi-ject® (follitropin alfa) injection for subcutaneous use GONAL-f® RFF Redi-ject® (follitropin alfa) injection Important Read these instructions completely before you begin . Gonal-f RFF Redi-ject (follitropin alfa) injection is for use under the skin only (subcutaneous). Only use Gonal-f RFF Redi-ject if your healthcare provider trains you on how to use it correctly. Warning : Do not reuse needles . Warning : Do not share the pen and needles with another person, because doing so can cause an infection. The pen comes in 3 different IU amounts Use the attached treatment diary to make sure you take the correct dose. Consult your healthcare provider on proper use of your treatment diary. You might need to use more than one pen to give today's intended dose. Contact your healthcare provider with any questions. The Dose Information Display is used for setting your dose, to confirm a completed dose, and to display the amount remaining to complete your intended dose. Gather your supplies ▯ Take the carton out of the refrigerator at least 30 minutes before you inject to let it warm to room temperature. Caution: Do not use a microwave or other heating element to warm up the pen. ▯ Prepare a clean, flat surface, such as a table or countertop, in a well-lit area. ▯ Identify a firm, vertical surface, such as the side of your Gonal-f RFF Redi-ject carton or a wall. ▯ Fill in the first 5 columns of the treatment diary. Refer to the treatment diary for sample entries. ▯ You will also need a sharps container, alcohol pads, and a writing utensil (not included). Step 1 Get Ready ▯ Wash your hands with soap and water and dry them well. Caution: Do not shake the pen. If you shake the pen, air bubbles may appear in the medicine. ▯ Remove the pen and a new needle from the carton. ▯ Check the expiration date on the pen label. Warning: Do not use an expired pen. Get a new pen from your healthcare provider or pharmacist. Step 2 Choose and prepare your injection site Note: Your healthcare provider should show you the injection sites to use around your stomach area. ▯ Select your injection site and wipe the skin with an alcohol pad to clean the site. ▯ Choose a different injection site each time you give your injection to reduce redness, irritation, or other skin problems. Step 3 Attach your needle ▯ Pull off the pen cap. ▯ Make sure the plastic reservoir that holds the medicine is not cracked. Confirm the medicine is clear, colorless, and does not contain particles. If the plastic is cracked or if the liquid is discolored or cloudy, get a new pen from your healthcare provider or pharmacist. ▯ Check that the needle's peel-off seal is not broken. If it is, get a new needle. ▯ Peel off the needle seal. ▯ Push the needle on the clear, plastic end of the pen, and twist the needle until you cannot twist it anymore. Caution: Do not attach the needle too tightly, the needle could be difficult to remove after the injection. ▯ Pull off the outer needle cap and save it for removing the needle after the injection. ▯ Keeping the needle pointing up, carefully pull off the green inner needle shield and throw it away. Warning: Do not recap the needle with the green inner needle shield, you could get a needle stick injury. Important If Then Using a new pen Check for a droplet of liquid at the tip of the needle. If you see a droplet go to Step 4 Dial your Dose If no droplet is seen, or you are unsure, follow the instructions in Appendix B . Re-using a pen You do not have to check for droplets of liquid at the tip of the needle. Go to Step 4 Dial your Dose Step 4 Dial your dose Note: Call your healthcare provider if you are unsure of today's intended dose. Caution: Do not push or pull the dose knob while you turn it to avoid damaging it. ▯ Turn the dose knob until your intended dose shows in the Dose Information Display. Note: You can turn the dose knob backward if you turn it past your intended dose. Step 5 Inject your dose Important ▯ Make sure the Dose Information Display matches the intended dose recorded in Column 5 in your treatment diary. Example: If your intended dose is 150 IU, confirm that the Dose Information Display reads 150. Caution: You might bend the needle if you do not insert the needle straight in at a 90° angle . ▯ Hold the pen at a 90° angle to the injection site, and push the needle into your skin. ▯ Place your thumb in the middle of the dose knob. Use your thumb to press the dose knob straight down as far as it will go. Caution: Do not release the dose knob until you remove the needle from your skin. Hold the dose knob down for a slow count of 5 before you remove the needle from your skin. Then release the knob after removal of the needle from your skin. ▯ Remove the needle from your skin, release the dose knob, and put the pen on the table. ▯ After injecting, fill in "Yes" or "No" in Column 6 of the treatment diary to record if the Dose Information Display shows "0". Warning: If the Dose Information Display does not show "0", you did not complete your dose. ▯ Fill in Column 7 of the treatment diary with the number in the Dose Information Display. ▯ You will need to use a second pen to inject the number shown in the Dose Information Display to complete your dose. Step 6 Remove and throw away your needle Warning: You must remove the needle from the pen and throw away after each injection to avoid risk of infection. ▯ Lay the outer needle cap on its side on a flat surface. ▯ Hold the pen with the needle attached in one hand, and slip the needle into the outer needle cap without using your other hand. ▯ Push the capped needle against a firm, vertical surface, such as a Gonal-f RFF Redi-ject carton or a wall, until you hear a "click". ▯ Twist off the capped needle and throw it away in a FDA-cleared sharps disposal container. See Appendix C for proper disposal information. ▯ After removing the needle, recap the pen. ▯ If the pen is empty after your injection, throw it away in a FDA-cleared sharps disposal container. See Appendix C for proper disposal information. Step 7 Record your injection Important ▯ After injecting, fill in Column 7 of the treatment diary by recording the number you see in the Dose Information Display. ▯ If the Dose Information Display shows "0", you have completed your dose. ▯ If the Dose Information Display does not show "0", you did not complete your dose. You need to inject the number shown in the Dose Information Display using a second pen . – Follow the instructions in Appendix A : Completing an incomplete dose. – The amount you need to inject using the second pen might be less than expected because of the extra medicine (see note below). Always inject the amount you wrote in Column 7 of the treatment diary to complete your dose. – Refer to the treatment diary for sample entries. Note: The pen contains extra medicine to ensure that you receive the full amount indicated on the pen (300 IU, 450 IU, or 900 IU). Appendix A: Completing an incomplete dose ▯ The number recorded in Column 7 in the treatment diary indicates the number you need to dial with the second pen to complete today's intended dose. To complete the dose with a second pen, repeat Steps 1 through 7. Appendix B: How to create a droplet of liquid ▯ If you do not see a droplet of liquid on the tip of the needle when using a pen for the first time, turn the dose knob until the Dose Information Display reads "25". ▯ With the needle pointing up, gently tap the reservoir so that any air bubbles rise to the top. ▯ Hold the pen with the needle pointing up. Slowly press the dose knob in all the way. One or more tiny drops of liquid will appear at the tip of the needle. Release the dose knob. Make sure that the Dose Information Display reads "0". ▯ Go to Step 4 Dial your dose. Appendix C: How to throw away used needles and empty pens ▯ Put used needles and empty pens in a FDA-cleared sharps disposal container immediately after use. Warning: Do not throw away loose needles and pens in your household trash. ▯ If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: Made of heavy-duty plastic, Can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, Upright and stable during use, Leak resistant, and Properly labeled to warn of hazardous waste inside the container. ▯ When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal Do not reuse the needles Do not throw way (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. For more information, go to http:/www.fda.gov/safesharpsdisposal. Appendix D: How to store your pen ▯ Store all pens with the cap attached and away from light. ▯ Store new pens in the refrigerator between 36° F and 46° F (2°C and 8° C) until the expiration date, or at room temperature between 68° F and 77° F (20°C and 25°C) for up to 3 months or until the expiration date, whichever comes first. Store pen in the original carton to protect from light. ▯ Do not freeze the pen. ▯ Keep the pen out of reach of children. ▯ If you have medicine left in a pen after injecting, store it in the refrigerator or at room temperature for up to 28 days. After 28 days, you must throw away (discard) your pen in a FDA-cleared sharps disposal container. See Appendix C for proper disposal information. For more information, call 1-866-538-7879. To view the Instructions for Use video, please visit www.Rediject.com EMD Serono, Inc Rockland, MA 02370 US License number: 1773 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: August 2024 Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image

14 CLINICAL STUDIES The safety and efficacy of Gonal-f ® RFF were examined in two clinical studies (one ovulation induction study and one ART study). 14.1 Ovulation Induction (OI) Ovulation induction was evaluated in a randomized, assessor-blind, multinational, multicenter, active-controlled, study in oligo-anovulatory infertile women. Women were randomized to either Gonal-f ® RFF (n=83), administered subcutaneously, or a comparator recombinant human FSH. The use of insulin-sensitizing agents was allowed during the study. The study was designed to evaluate and compare mean ovulation rates in the first cycle of treatment. Results for Gonal-f ® RFF are presented in Table 4. Also presented in this table are secondary outcome results from cycle 1 through cycle 3. The study was not powered to demonstrate differences in any of the secondary outcomes. Table 4: Cumulative Ovulation and Clinical Pregnancy Rates in Ovulation Induction Cycle Gonal-f ® RFF (n=83) Cumulative Cumulative rates were determined per woman over cycles 1, 2, and 3. Percent Ovulation Cumulative Clinical Pregnancy Clinical pregnancy was defined as 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 study was not powered to demonstrate differences in these outcomes. Cycle 2 89% 41% Cycle 3 92% 45% 14.2 Assisted Reproductive Technology (ART) The efficacy of Gonal-f ® RFF was evaluated in a randomized, assessor-blind, multinational, multicenter, active controlled study in healthy normal 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. Randomization was stratified by insemination technique, (IVF vs. ICSI). All women received pituitary down-regulation with a GnRH agonist before stimulation with recombinant FSH. Efficacy was assessed using 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 maximum dose given for both age groups was 450 International Units per day. Treatment outcomes for Gonal-f ® RFF are summarized in Table 5. Table 5: Treatment Outcomes in ART Study Outcome value (n) Mean number of 2PN oocytes per woman 6.3 (237) Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis. Mean number of 2PN oocytes per subject receiving IVF 6.1 (88) Subgroup analyses. The study was not powered to demonstrate differences in subgroups. Mean number of 2PN oocytes per subject 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 33.5% (218) Secondary efficacy outcomes. The study was not powered to demonstrate differences in these outcomes. Clinical pregnancy rate per embryo transfer 35.8% (204) Mean treatment duration in days (range) 9.7 [3-21] (230)

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

8.1 Pregnancy Risk Summary Gonal-f ® RFF Redi-ject ® is not indicated in pregnant women. The incidence of congenital malformations after some Assisted Reproductive Technology (ART), procedures, 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 a higher incidence of multi-fetal gestations after IVF or ICSI. There is no human data that the use of gonadotropins (including Gonal-f ® RFF Redi-ject ® ), 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 (including Gonal-f ® RFF Redi-ject ® ) 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 US general population, the estimated background risk of major birth defects and miscarriage after spontaneous 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 IU 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 IU 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 IU based on body surface area.

8 USE IN SPECIFIC POPULATIONS Do not use Gonal-f ® RFF Redi-ject ® in pregnant women ( 4 , 8.1 ), Nursing Mothers: It is not known whether this drug is excreted in human milk. ( 8.3 ) Pediatric Use: Safety and efficacy not established. ( 8.4 ) Renal and Hepatic Insufficiency: Safety, efficacy, and pharmacokinetics of Gonal-f ® RFF Redi-ject ® in women with renal or hepatic insufficiency have not been established. ( 8.6 ) 8.1 Pregnancy Risk Summary Gonal-f ® RFF Redi-ject ® is not indicated in pregnant women. The incidence of congenital malformations after some Assisted Reproductive Technology (ART), procedures, 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 a higher incidence of multi-fetal gestations after IVF or ICSI. There is no human data that the use of gonadotropins (including Gonal-f ® RFF Redi-ject ® ), 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 (including Gonal-f ® RFF Redi-ject ® ) 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 US general population, the estimated background risk of major birth defects and miscarriage after spontaneous 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 IU 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 IU 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 IU 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 Redi-ject ® . 8.3 Females and Males of Reproductive Potential Since Gonal-f ® RFF Redi-ject ® is not indicated in pregnant women, verify a negative pregnancy test before administering Gonal-f ® RFF Redi-ject ® to a woman [see Dosage and Administration (2.2 , 2.3) ]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.6 Renal and Hepatic Insufficiency Safety, efficacy, and pharmacokinetics of Gonal-f ® RFF Redi-ject ® in women with renal or hepatic insufficiency have not been established.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Gonal-f ® RFF Redi-ject ® (follitropin alfa) injection is a disposable, prefilled single-patient-use pen containing a clear and colorless to slightly yellow solution. Each Redi-ject ® is supplied in a carton containing 29G × 1/2 inch disposable needles to be used for administration. The following package presentations are available: NDC 44087-1115-1 - One Gonal-f ® RFF Redi-ject ® delivers 300 International Units per 0.48 mL and 5 single-use disposable 29G × ½" needles NDC 44087-1116-1 - One Gonal-f ® RFF Redi-ject ® delivers 450 International Units per 0.72 mL and 7 single-use disposable 29G × ½" needles NDC 44087-1117-1 - One Gonal-f ® RFF Redi-ject ® delivers 900 International Units per 1.44 mL and 14 single-use disposable 29G × ½" needles 16.2 Storage and Handling Pharmacy Storage: Refrigerate at 2°C to 8°C (36°F to 46°F) until dispensed. Patient Storage: Refrigerate at 2°C to 8°C (36°F to 46°F) until the expiration date, or store at room temperature at 20° to 25°C (68°F to 77°F) for up to three months or until the expiration date, whichever occurs first. Store pen in the original carton to protect from light. After the first injection, store refrigerated at 2°C to 8°C (36°F to 46°F) or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 28 days. Keep the cap on the pen to protect from light. Do not freeze. Discard unused material after 28 days.

16.2 Storage and Handling Pharmacy Storage: Refrigerate at 2°C to 8°C (36°F to 46°F) until dispensed. Patient Storage: Refrigerate at 2°C to 8°C (36°F to 46°F) until the expiration date, or store at room temperature at 20° to 25°C (68°F to 77°F) for up to three months or until the expiration date, whichever occurs first. Store pen in the original carton to protect from light. After the first injection, store refrigerated at 2°C to 8°C (36°F to 46°F) or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 28 days. Keep the cap on the pen to protect from light. Do not freeze. Discard unused material after 28 days.