Gonal-f RFF

Patient Information

GONAL-F^® RFF
(gon-AL-eff ar-eff-eff)
(follitropin alfa injection) for subcutaneous use

What is GONAL-F RFF?

GONAL-F RFF is a prescription medicine containing follicle-stimulating hormone (FSH).

GONAL-F RFF is used in:

infertile women to:

• help healthy ovaries develop (mature) and release an egg to help you get pregnant
• cause your ovaries to make multiple (more than 1) eggs as part of an Assisted Reproductive Technology (ART) program

Do not use GONAL-F RFF if you:

• are allergic to recombinant human FSH or any of the ingredients in GONAL-F RFF. See the end of this leaflet for a complete list of ingredients in GONAL-F RFF.
• have high levels of FSH in your blood that show your ovaries do not work at all.
• have uncontrolled thyroid, adrenal, or pituitary problems.
• have a tumor in your female organs, including your ovaries, uterus or breast that may get worse with high levels of estrogen.
• have a tumor in your brain, such as a tumor in your pituitary gland or hypothalamus.
• 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.

INSTRUCTIONS FOR USE

GONAL-F^® RFF
(follitropin alfa injection)
for subcutaneous use

 

Important

• Read these instructions completely before you begin.
• GONAL-F RFF is for use under the skin only (subcutaneous).
• Only use GONAL-F RFF if your healthcare provider trains you on how to use it correctly.

Warning:

• Do not reuse needles.
• Do not share your GONAL-F RFF needles or syringes with another person. You may get a serious infection from other people or other people may get a serious infection from you.
• The syringes and needles that come with your GONAL-F RFF are meant for use with GONAL-F RFF only. Do not use GONAL-F RFF syringes to inject other medicines or hormones.
• The GONAL-F RFF^® vial comes in only 75 International Units (IU)

Supplies needed to give your GONAL-F RFF injection.

• a clean flat surface like a table
• 1 GONAL-F RFF 75 IU vial
• 1 Prefilled Syringe of Sterile Water for Injection, USP
• (1) 18 G 1 ½” Mixing Needle
• (1) 29 G ½” Injection Needle
• 1 FDA-cleared sharps container
• 2 alcohol pads
• 1 gauze or cotton ball

Gather your supplies.

• Prepare a clean, flat surface, such as a table or countertop, in a well-lit area.

Step 1 Mixing (reconstituting)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

• Wash your hands with soap and water.
• Using your thumb, flip off the plastic cap of the GONAL-F RFF vial.
• Wipe the top of the vial stopper with an alcohol swab.
• Carefully twist and pull off the protective cap of the prefilled syringe of Sterile Water. Do not touch the needle or allow it to touch any surface.
• Remove the safety seal cover of the 18 G 1 ½ ” pink needle. Twist the needle onto the prefilled syringe until it is tightened, being careful to keep the protective needle cap in place. Carefully remove the protective needle cap. Do not touch or allow the needle to touch any surface.
• Hold the GONAL-F RFF vial firmly on a flat surface.
• Position the prefilled syringe of Sterile Water in a straight, upright position over the marked center circle of the rubber stopper on the vial of the GONAL-F RFF powder.
• Insert the needle through the center circle of the rubber stopper on the vial of the GONAL-F RFF powder while keeping it in a straight, upright position.
• Slowly inject the Sterile Water into the vial of GONAL-F RFF powder by pressing down on the syringe plunger.
• Gently, rotate the vial between your fingers until the powder is dissolved. Do not shake.
• While keeping the needle in the vial of GONAL-F RFF, lift and turn the vial upside down.
• With the needle tip in the liquid, slowly pull back the 18 G 1 ½ ” pink needle as far as needed until you withdraw the entire contents of the vial. Remove the needle from the vial.
• Gently pull the plunger back to allow a small air space. Recap the needle.
• Twist off the 18 G 1 ½ ” pink needle from the syringe and immediately throw away (dispose of) the needle in an FDA-cleared sharps disposal container (See Step 4: How to throw away used needles and syringes) unless you need to mix more vials to get your prescribed dose.
• Do not use this needle to give your injection.

 

 

Note: If your dose requires more than 1 vial of GONAL-F RFF 75 IU, use the same 18 G 1 ½ ” pink needle and syringe containing the mixture to mix (reconstitute) additional vials. Follow Step 1.

Step 2 Preparing the dose

 

 

 

 

• Check that the GONAL-F RFF liquid solution is clear. Do not use if the liquid is discolored or contains any particles. If this happens, throw it away and call your healthcare provider or pharmacist right away.
• Allow the liquid solution to come to room temperature before giving your injection.Caution: Do not use a microwave or other heating element to warm up the reconstituted liquid.
• Remove the safety seal cover of the 29 G 1 ½ ” red needle. Twist the needle onto the prefilled syringe until it is tightened, being careful to keep the protective needle cap in place. Carefully remove the protective needle cap. Do not touch or allow the needle to touch any surface
• With the syringe pointing upward, gently tap on the syringe and slowly push the plunger until all air bubbles are gone and a drop of liquid appears on the tip of the needle.
• Recap the needle and set on a clean, flat surface. The syringe is now ready for giving your prescribed dose of GONAL-F RFF.

Step 3 Injecting the dose

 

 

 

 

• Your healthcare provider should show you how to set the prescribed dose and use the syringe.
• Change your injection site each day to decrease discomfort. GONAL-F RFF is injected under the skin (subcutaneously) of your stomach area, upper arm, or upper leg.
• Uncap the syringe and inject the dose as directed by your healthcare provider.
• Lightly press a cotton ball or gauze on the site if needed.

Step 4 How to throw away used needles and syringes

• Put used needles and syringes in an 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 an 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.

Step 5 How to store your GONAL-F RFF vials

• Store all vials of GONAL-F RFF powder away from light.
• Store the powder vials 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) until the expiration date.
• Keep the GONAL-F RFF vials and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Description

Gonal-f® RFF (follitropin alfa for injection) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the α- and β-subunits. The α- and β-subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structure are indistinguishable from those of human follicle stimulating hormone. Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors. Purification by immunochromatography using an antibody specifically binding FSH results in a highly purified preparation with a consistent FSH isoform profile, and a high specific activity. The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats. The in vivo biological activity of follitropin alfa has been calibrated against the first International Standard for recombinant human follicle stimulating hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization. Gonal-f® RFF (follitropin alfa injection) contains no luteinizing hormone (LH) activity. Based on available data derived from physico-chemical tests and bioassays, follitropin alfa and follitropin beta, another recombinant follicle stimulating hormone product, are indistinguishable.

Gonal-f® RFF (follitropin alfa injection) is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.

Each Gonal-f® RFF single-dose vial is filled with 82 IU (6 µg)follitropin alfa to deliver 75 IU (5.5 µg) follitropin alfa and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate, 0.45 mg monobasic sodium phosphate monohydrate, 0.1 mg methionine, and 0.05 mg polysorbate 20. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials are reconstituted with Sterile Water for Injection, USP.

Under current storage conditions, Gonal-f® RFF may contain up to 10% of oxidized follitropin alfa.

Therapeutic Class: Infertility

Gonal-F RFF is indicated for:

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

Development Of Multiple Follicles In Ovulatory Infertile Women As Part Of An Assisted Reproductive Technology (ART) Cycle

Dosage And Administration

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 and multiple births [see WARNINGS AND PRECAUTIONS]. Gonadotropin therapy requires the availability of appropriate monitoring facilities [see WARNINGS AND PRECAUTIONS]. 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 Dosing for Induction of Ovulation , Dosing For Multiple Follicle Development As Part Of An Assisted Reproductive Technology (ART) Cycle ].

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.

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]. 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].
  • Discourage intercourse when the risk for OHSS is increased [see WARNINGS AND PRECAUTIONS].
• 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.

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:

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.

• 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.
• 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].
• Do not use doses greater than 450 International Units per day.

Missed Dose

Do not double the next dose if the woman misses or forgets to take a dose of GONAL-F RFF.

How Supplied

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.

GONAL-F RFF (follitropin alfa for injection) is supplied in a sterile, lyophilized white powder in single-dose vials containing 82 International Units with diluent (Sterile Water for Injection, USP) in a pre-filled syringe. Following reconstitution with the diluent as described, upon administration each vial will deliver a dose of 75 International Units.

The following package combinations are available:

1 vial GONAL-F RFF 75 International Units and 1 pre-filled syringe Sterile Water for Injection, USP, 1 mL, 1 reconstitution needle (18 gauge), 1 administration needle (29 gauge), NDC 44087-9005-1

10 vials GONAL-F RFF 75 International Units and 10 pre-filled syringes Sterile Water for Injection, USP, 1 mL, 10 reconstitution needles (18 gauge), 10 administration needles (29 gauge), NDC 44087-9005-6

Storage And Handling

Lyophilized vials may be stored refrigerated or at room temperature (2°-25°C/36°-77°F). Protect from light. Use immediately after reconstitution [see DOSAGE AND ADMINISTRATION].

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.

Manufactured for : EMD Serono, Inc., Rockland, MA 02370. Revised: Dec 2020.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Hypersensitivity Reactions and Anaphylaxis [see WARNINGS AND PRECAUTIONS]
• Ovarian Hyperstimulation Syndrome [see WARNINGS AND PRECAUTIONS]
• Pulmonary and Vascular Complications [see WARNINGS AND PRECAUTIONS]
• Ovarian Torsion [see WARNINGS AND PRECAUTIONS]
• Abnormal Ovarian Enlargement [see WARNINGS AND PRECAUTIONS]
• Multi-fetal Gestation and Birth [see WARNINGS AND PRECAUTIONS]
• Embryofetal Toxicity [see WARNINGS AND PRECAUTIONS]
• Ectopic Pregnancy [see WARNINGS AND PRECAUTIONS]
• Spontaneous Abortion [see WARNINGS AND PRECAUTIONS]
• Ovarian Neoplasms [see WARNINGS AND PRECAUTIONS]

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 Triale

System Organ Class/Adverse Reactions	GONAL-F RFF [N=83 *(176 treatment cycles†)] n‡ (%)
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%)
* total number of women treated with GONAL-F RFF † up to 3 treatment cycles per woman ‡number of women with the adverse reaction

 

Development Of Multiple Follicles As Part Pf 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*) n† (%)
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%)
* total number of women treated with GONAL-F RFF † number of women with the adverse reaction

 

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

Drug Interactions

No Information Provided

Gonal-f® RFF (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonal-f® RFF (follitropin alfa injection) is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see “Precautions/Laboratory Tests”). Safe and effective use of Gonal-f® RFF (follitropin alfa injection) in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis. The lowest effective dose should be used.

Overstimulation of the Ovary During FSH Therapy

Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain occurs in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within two or three weeks. Careful monitoring of ovarian response can further minimize the risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Gonal-f® RFF (follitropin alfa injection) therapy, hCG should not be administered in this course of therapy. This will reduce the chances of development of Ovarian Hyperstimulation Syndrome.

Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an apparent 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 development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see “Pulmonary and Vascular Complications”). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).

OHSS occurred in 6 of 83 (7.2%) Gonal-f® RFF (follitropin alfa injection) treated women in Study 22240 (ovulation induction); none were classified as severe. In Study 21884 (ART), OHSS occurred in 11 of 237 (4.6%) Gonal-f® RFF (follitropin alfa injection) treated women and 1 (0.42%) was classified as severe. OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at 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 “Precautions / Laboratory Tests”), the hCG must be withheld.

If severe OHSS occurs, treatment must be stopped and the patient should be hospitalized.

A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.

Pulmonary and Vascular Complications

Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported. In addition, thromboembolic events both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported. Intravascular thrombosis and embolism can result in reduced blood flow to critical organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death.

Multiple Births

Reports of multiple births have been associated with Gonal-f® RFF (follitropin alfa injection) treatment. In Study 22240 for women receiving Gonal-f® RFF (follitropin alfa injection) over three treatment cycles, 20% of live births were multiple births. In Study 21884, 35.1% of live births were multiple births in women receiving Gonal-f® RFF (follitropin alfa injection) . The rate of multiple births is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.

General

Careful attention should be given to the diagnosis of infertility in candidates for Gonal-f® RFF (follitropin alfa for injection) therapy (see “Indications and Usage/ Selection of Patients”).

Information for Patients

Prior to therapy with Gonal-f® RFF (follitropin alfa injection) , patients should be informed of the duration of treatment and monitoring of their condition that will be required. The risks of ovarian hyperstimulation syndrome and multiple births in women (see WARNINGS) and other possible adverse reactions (see “Adverse Reactions“) should also be discussed.

See “DOSAGE AND ADMINISTRATION” for “PATIENT INSTRUCTIONS FOR USE OF GONAL-F® RFF (follitropin alfa injection) “.

Laboratory Tests

In most instances, treatment of women with Gonal-f® RFF (follitropin alfa injection) results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given 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 levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma estrogens do not give an indication of the size or number of follicles.

The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:

1. A rise in basal body temperature;
2. Increase in serum progesterone; and
3. Menstruation following a shift in basal body temperature.

When used in conjunction with the indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:

1. Fluid in the cul-de-sac;
2. Ovarian stigmata;
3. Collapsed follicle; and
4. Secretory endometrium.

Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f® RFF. 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 (≥40 IU/kg/day) for extended periods, through reduced fecundity.

Pregnancy

Pregnancy Category X. (See CONTRAINDICATIONS).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Gonal-f® RFF (follitropin alfa injection) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Ovarian hyperstimulation syndrome (OHHS) and multiple gestations have been observed with GONAL-F RFF overdosage [see WARNINGS AND PRECAUTIONS].

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].
• 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

Mechanism Of Action

GONAL-F RFF stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to bring about final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given, following the administration of GONAL-F RFF, when monitoring of the patient indicates that sufficient follicular development is achieved.

Pharmacodynamics

The pharmacodynamics of GONAL-F RFF have not been fully characterized. There is inter-woman variability in response to follitropin alfa administration.

Pharmacokinetics

The pharmacokinetics of GONAL-F RFF have not been fully characterized. Follitropin alfa mean (%CV) AUClast is 884 International Units hr/L (20%) and Cmax is 9.83 International Units/L (23%) following a single subcutaneous dose of 300 International Units of GONAL-F RFF to 21 pre-menopausal healthy female volunteers who had previously received a GnRH agonist for pituitary down-regulation.

Absorption

The mean (%CV) time to Cmax 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.

Clinical Studies

Induction Of Ovulation (OI)

Induction of Ovulation was evaluated in a randomized, assessor-blind, multinational, multicenter, active-controlled trial in oligo-anovulatory infertile women. Women were randomized to either GONAL-F RFF (n=83), administered subcutaneously, or a comparator recombinant human FSH product. The use of insulin-sensitizing agents was allowed during the trial. The trial was designed to evaluate and compare mean ovulation rates in the first cycle of treatment. Results for GONAL-F RFF are presented in Table 3. Also presented in this table are secondary outcome results from cycle 1 through 3. The trial was not powered to demonstrate differences in any of the secondary outcomes.

Table 3: Cumulative Ovulation and Clinical Pregnancy Rates in Induction of Ovulation

Cycle	GONAL-F RFF (n=83)
	Cumulative* Percent Ovulation	Cumulative* Clinical Pregnancy† Rate
Cycle 1	72%‡	28%§
Cycle 2	89%§	41%§
Cycle 3	92%§	45%§
* Cumulative rates were determined per woman over cycles 1, 2, and 3. † 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. ‡ Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis. § Secondary efficacy outcomes. The trial was not powered to demonstrate differences in these outcomes.

 

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*	6.3 (237)
Mean number of 2PN oocytes per woman receiving IVF†	6.1 (88)
Mean number of 2PN oocytes per woman receiving ICSI†	6.5 (132)
Clinical pregnancy‡rate per attempt§	33.5% (218)
Clinical pregnancy ‡rate per embryo transfer§	35.8% (204)
Mean treatment duration in days (range)§	9.7 [3-21] (230)
* Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis. † Subgroup analyses. The trial was not powered to demonstrate differences in subgroups. ‡ 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. § Secondary efficacy outcomes. The trial was not powered to demonstrate differences in these outcomes.