GONAL-F RFF - follitropin alfa
EMD Serono, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GONAL-F RFF® safely and effectively. See full prescribing information for GONAL-F RFF® (follitropin alfa for injection) for subcutaneous use
Initial U.S. Approval: 1997
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
GONAL-F RFF is a gonadotropin indicated for:
DOSAGE AND ADMINISTRATION
Induction of Ovulation (2.2)
Development of Multiple Follicles in Assisted Reproductive Technology (ART) (2.3)
DOSAGE FORMS AND STRENGTHS
GONAL-F RFF is contraindicated in women who exhibit (4):
WARNINGS AND PRECAUTIONS
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.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
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
2.4 Dosing for Multiple Follicle Development as part of an Assisted Reproductive Technology (ART) Cycle
Gonal-F RFF is indicated for:
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.
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.
The dosing scheme follows a stepwise approach and is individualized for each woman:
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 is contraindicated in women who exhibit:
Ovarian Hyperstimulation Syndrome (OHSS) is a medical event distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a 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 the development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement [see Warnings and Precautions (5.5)], weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions [See Warnings and Precautions (5.3)]. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy, have been reported in association with OHSS.
OHSS occurs after gonadotropin treatment has been discontinued and it can develop rapidly, reaching its maximum 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 Dosage and Administration (2.3, 2.4)], withhold hCG. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, assess women for the development of OHSS for at least two weeks after hCG administration.
OHSS occurred in 6 of 83 (7.2%) GONAL-F RFF treated women in an induction of ovulation trial; none were classified as severe. In an ART trial, OHSS occurred in 11 of 237 (4.6%) GONAL-F RFF treated women and 1 (0.42%) was classified as severe.
Multi-fetal gestation and births have been reported with all gonadotropin therapy, including therapy with GONAL-F RFF. In a trial of induction of ovulation, 20% of live births were multiple births in women receiving GONAL-F RFF over three treatment cycles.
In an ART trial, 35.1% of live births were multiple births in women receiving GONAL-F RFF. The rate of multiple births is dependent on the number of embryos transferred. Advise the woman and her partner of the potential risk of multi-fetal gestation and birth before beginning therapy with GONAL-F RFF.
In most instances, treatment of women with GONAL-F RFF results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given to trigger ovulation 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 concentrations. The combination of both ultrasound and serum estradiol measurement are useful for monitoring follicular growth and maturation, timing of the ovulatory trigger, detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation.
The clinical confirmation of ovulation is obtained by direct or indirect indices of progesterone production, as well as sonographic evidence of ovulation.
Direct or indirect indices of progesterone production:
Sonographic evidence of ovulation:
The following serious adverse reactions are discussed elsewhere in the labeling:
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.
|System Organ Class/Adverse Reactions||GONAL-F RFF
[N=83* (176 treatment cycles†)]
|Central and Peripheral Nervous System|
|Abdominal Pain||10 (12.0%)|
|Ovarian Hyperstimulation||6 (7.2%)|
|Ovarian Cyst||3 (3.6%)|
|Injection Site Pain||4 (4.8%)|
|Injection Site Inflammation||2 (2.4%)|
Development of Multiple Follicles as part of 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.
|System Organ Class/Adverse Reactions||GONAL-F RFF
|Abdominal Pain||55 (23.2%)|
|Body as a Whole- General|
|Abdomen Enlarged||33 (13.9%)|
|Central and Peripheral Nervous System|
|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%)|
|Ovarian Hyperstimulation||11 (4.6%)|
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
GONAL-F RFF is not indicated in pregnant women.
The incidence of congenital malformations after some Assisted Reproductive Technology [(ART), specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)], may be slightly higher than that after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics) and to a higher incidence of multi-fetal gestations after IVF or ICSI. There is no human data that the use of gonadotropins (including GONAL-F RFF), 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) 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 in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data on a limited number of GONAL-F RFF- or GONAL-F-exposed pregnancies indicate no adverse reactions of gonadotropins on pregnancy, embryonal or fetal development, parturition or postnatal development following controlled ovarian stimulation.
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 International Units 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 International Units 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 International Units based on body surface area.
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.
GONAL-F RFF (follitropin alpha for injection) is a gonadotropin [human follicle stimulating hormone (FSH)], a glycoprotein hormone manufactured by recombinant DNA technology. The active drug substance, follitropin alfa, has a dimeric structure consisting 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 human 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 protein content is assessed by size exclusion high pressure liquid chromatography. 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 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 is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.
Each GONAL-F RFF single-dose vial is filled with 82 International Units (6 µg) follitropin alfa to deliver 75 International Units (5.5 mcg) 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.
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.
The pharmacodynamics of GONAL-F RFF have not been fully characterized. There is inter-woman variability in response to follitropin alfa administration.
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.
The mean (%CV) elimination half-life of follitropin alfa is 53 hrs (52%) and is dependent on the absorption rate.
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 (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.
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.
|Cycle||GONAL-F RFF (n=83)|
|Cumulative* Percent Ovulation||Cumulative* Clinical Pregnancy† Rate|
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.
|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)|
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
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 (2.2)].
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.
Advise women to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Hypersensitivity Reactions and Anaphylaxis
Advise women to discontinue Gonal-F RFF and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur [see Warnings and Precautions (5.1)].
Ovarian Hyperstimulation Syndrome
Inform women regarding the risks of OHSS [see Warnings and Precautions (5.2)] and OHSS-associated conditions including pulmonary and vascular complications [see Warnings and Precautions (5.3)], and ovarian torsion [see Warnings and Precautions (5.4)] with the use of GONAL-F RFF. Advise women to seek medical attention if any of these conditions occur.
Abnormal Ovarian Enlargement
Inform women regarding the hazards associated with abnormal ovarian enlargement that may occur with GONAL-F RFF therapy. If the ovaries are abnormally enlarged on the last day of GONAL-F RFF therapy, inform women not to administer hCG and to avoid intercourse [see Warnings and Precautions (5.5)].
Multi-fetal Gestation and Birth
Advise the woman and her partner of the potential risk of multi-fetal gestation and birth before beginning therapy with GONAL-F RFF [see Warnings and Precautions (5.6)].
Inform women that the incidence of congenital malformations (birth defects) after some Assisted Reproductive Technology [(ART) specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)] may be slightly higher than after spontaneous conception [see Warnings and Precautions (5.7)].
Inform women undergoing ART that the incidence of ectopic pregnancy may be increased with these procedures, particularly for women with tubal abnormalities. Advise women who become pregnant and have: abdominal/pelvic pain (particularly on one side); shoulder, neck or rectal pain; and nausea and vomiting to seek immediate medical attention [see Warnings and Precautions (5.8)].
Inform women that the risk of spontaneous abortion (miscarriage) is increased with gonadotropin products (including GONAL-F RFF). However, causality has not been established. The increased risk may be a factor of the underlying infertility [see Warnings and Precautions (5.9)].
Advise women not to breastfeed because the secretion of prolactin during lactation can result in inadequate response to ovarian stimulation with Gonal-F RFF [see Use in Specific Populations (8.2)].
Dosing and Use of GONAL-F RFF single-use vials
Instruct women on the correct usage and dosing of GONAL-F RFF [see Dosage and Administration (2.3, 2.4)]. Instruct women to reconstitute one or more vials of GONAL-F RFF using 1 mL sterile diluent and the 18G 1-1/2" pink mixing needle provided. Instruct women to safely remove mixing needle and replace with 29G ½" needle for injection. Caution women not to change the dosage or the schedule of administration unless she is told to do so by her healthcare provider.
Duration and Necessary Monitoring in Women Undergoing Therapy with GONAL-F RFF
Prior to beginning therapy with GONAL-F RFF, inform women about the time commitment and monitoring procedures necessary for treatment [see Dosage and Administration (2.3, 2.4) and Warnings and Precautions (5.11)].
Instructions Regarding a Missed Dose
Inform the woman that if she misses or forgets to take a dose of GONAL-F RFF, she should not double the next dose and should call her healthcare provider for further dosing instructions [see Dosage and Administration (2.5)].
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:
|Do not use GONAL-F RFF if you:
|Before you start using GONAL-F RFF tell your healthcare provider about all of your medical conditions, including if you:
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?
|What are the possible side effects of GONAL-F RFF?
GONAL-F RFF may cause serious side effects, including:
|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?
|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
(follitropin alfa injection)
for subcutaneous use
Supplies needed to give your GONAL-F RFF injection.
Gather your supplies.
Step 1 Mixing (reconstituting)
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
Step 3 Injecting the dose
Warning: Do not throw away loose needles and pens in your household trash.
For more information, go to http:/www.fda.gov/safesharpsdisposal.
Step 5 How to store your GONAL-F RFF vials
EMD Serono, Inc
Rockland, MA 02370
EMD Serono, Inc. is an affiliate of Merck: KGaA, Darmstadt, Germany
©2017 EMD Serono, Inc.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
GONAL-f® RFF 75 IU
(follitropin alfa for injection)
contains 82 IU to deliver 75 IU
Use immediately after reconstitution. Discard unused material.
Sterile Water for
For Reconstitution Only
Not for Injection
Store at 15°-25°C (59°-77°F)
Manufactured for :
EMD Serono, Inc., Rockland, MA 02370
GONAL- f® RFF 75 IU
(follitropin alfa for injection)
For subcutaneous use
10 vials Gonal-f® RFF
10 pre-filled syringes Sterile Water for Injection, USP
10 18-gauge needles for reconstitution
10 29-gauge needles for administration
* revised formulation female
follitropin alfa kit
|Labeler - EMD Serono, Inc. (088514898)|