GONAL-F RFF

GONAL-F RFF — follitropin alfa
EMD Serono, Inc.

1 INDICATIONS AND USAGE

Gonal-F RFF is indicated for:

1.1 Induction of ovulation and pregnancy in oligo-anovulatory infertile women for whom the cause of infertility is functional and not due to primary ovarian failure

1.2 Development of multiple follicles in ovulatory infertile women as part of an assisted reproductive technology (ART) cycle

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

Only physicians who are experienced in infertility treatment, should treat women with GONAL-F RFF. GONAL-F RFF is a gonadotropins product capable of causing in women, Ovarian Hyperstimulation Syndrome (OHSS) with or without pulmonary or vascular complications [see Warnings and Precautions (5.2, 5.3,)] and multiple births [see Warnings and Precautions (5.6)]. Gonadotropin therapy requires the availability of appropriate monitoring facilities [see Warnings and Precautions (5.11)]. Use the lowest effective dose of GONAL-F 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.

3 DOSAGE FORMS AND STRENGTHS

For injection: 82.5 International Units of follitropin alpha as a lyophilized powder in a single dose vial for reconstitution, including a 1 mL pre-filled syringe of Sterile Water for Injection, USP for reconstitution to deliver 75 International Units of follitropin alfa.

4 CONTRAINDICATIONS

GONAL-F RFF is contraindicated in women who exhibit:

• ​ Prior hypersensitivity to recombinant FSH products or one of their excipients. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].
• High levels of FSH indicating primary gonadal failure
• The presence of uncontrolled non-gonadal endocrinopathies (for example, thyroid, adrenal, or pituitary disorders)
• Sex hormone dependent tumors of the reproductive tract and accessory organs
• Tumors of the pituitary gland or hypothalamus
• Abnormal uterine bleeding of undetermined origin
• Ovarian cyst or enlargement of undetermined origin