- Make sure the Gonal-f ® RFF Pen is at room temperature before using.
- Make sure the liquid in the Pen is clear. Do not use the Gonal-f ® RFF Pen if it contains any particles. Get a replacement from your doctor, nurse or pharmacist.
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Gonal-f ® RFF Pen (follitropin alfa 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 (alpha)- and (beta)-subunits. 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. 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 Pen 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 Pen is a disposable, prefilled drug delivery system intended for the subcutaneous injection of multiple and variable doses of a liquid formulation of follitropin alfa.
Each Gonal-f ® RFF Pen is filled with 415 IU (30 mcg), 568 IU (41 mcg), or 1026 IU (75 mcg) follitropin alfa to deliver at least 300 IU (22 mcg) in 0.5 mL, 450 IU (33 mcg) in 0.75 mL, or 900 IU (66 mcg) in 1.5 mL, respectively. Each Pen also contains 60 mg/mL sucrose, 3.0 mg/mL m-cresol, 1.1 mg/mL di-sodium hydrogen phosphate dihydrate, 0.45 mg/mL sodium dihydrogen phosphate monohydrate, 0.1 mg/mL methionine, 0.1 mg/mL Poloxamer 188. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment.
Under current storage conditions, Gonal-f ® RFF Pen may contain up to 10% of oxidized follitropin alfa.
Therapeutic Class: Infertility
Gonal-f ® RFF Pen (follitropin alfa injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Gonal-f ® RFF Pen is the primary hormone responsible for follicular recruitment and development. In order to effect 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 Pen when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration.
Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 IU Gonal-f ® RFF Pen 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 1.
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Abbreviations are: C max : peak concentration (above baseline); t max : time of C max ; t ½ : elimination half life
The absorption rate of Gonal-f ® RFF Pen following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of Gonal-f ® RFF Pen are absorption rate-limited.
Human tissue or organ distribution of FSH has not been determined for Gonal-f ® RFF Pen.
FSH metabolism and excretion following administration of Gonal-f ® RFF Pen have not been studied in humans.
Special populations: Safety, efficacy, and pharmacokinetics of Gonal-f ® RFF Pen in patients with renal or hepatic insufficiency have not been established.
Drug-Drug Interactions: No drug-drug interaction studies have been conducted (see PRECAUTIONS ).
The safety and efficacy of Gonal-f ® RFF have been examined in two clinical studies: one study (Study 22240) for ovulation induction and one study (Study 21884) for assisted reproductive technologies (ART).
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Gonal-f ® RFF Pen (follitropin alfa injection) is indicated for the induction of ovulation and pregnancy in the oligo-anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-f ® RFF Pen is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.
Gonal-f ® RFF Pen (follitropin alfa injection) is contraindicated in women who exhibit:
Gonal-f ® RFF Pen (follitropin alfa injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.
Gonal-f ® RFF Pen 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 Pen in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis. The lowest effective dose should be used.
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 Pen 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 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 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.
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 treatment. In Study 22240 for women receiving Gonal-f ® RFF 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. 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 Pen (follitropin alfa injection) therapy (see "Indications and Usage/ Selection of Patients").
Information for Patients: Prior to therapy with Gonal-f ® RFF Pen, 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.
A `Patient's Information Leaflet' is provided for patients prescribed Gonal-f ® RFF Pen.
Laboratory Tests: In most instances, treatment of women with Gonal-f ® RFF Pen 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:
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:
Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests.
Drug Interactions: No drug/drug interaction studies have been performed.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f ® RFF Pen. 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 Pen, 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.
The safety of Gonal-f ® RFF was examined in two clinical studies [(one ovulation induction study (n=83) and one study in ART (n=237)].
Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 22240 (ovulation induction) are listed in Table 4.
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Headache occurred in greater than 20% of patients receiving Gonal-f ® RFF in this study.
Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 21884 (ART) are listed in Table 5.
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Headache and abdomen enlargement occurred in more than 10% of patients and abdominal pain occurred in more than 20% of patients. The following medical events have been reported subsequent to pregnancies resulting from Gonal-f ® RFF therapy in controlled clinical studies:
There are no indications that use of gonadotropins during ART is associated with an increased risk of congenital malformations.
The following adverse reactions have been previously reported during Gonal-f ® RFF therapy:
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.
During post-market surveillance, reports of hypersensitivity reactions including anaphylactoid reactions have been reported with the use of Gonal-f ® RFF.
Aside from possible ovarian hyperstimulation and multiple gestations (see " WARNINGS "), there is no information on the consequences of acute overdosage with Gonal-f ® RFF Pen (follitropin alfa injection).
The Gonal-f ® RFF Pen delivery system delivers at least 300 IU, 450 IU, or 900 IU, equivalent to a maximum of four 75 IU injections, six 75 IU injections or twelve 75 IU injections, respectively. The minimum dose that can be set is 37.5 IU; the maximum dose that can be set is 300 IU (for 300 IU delivery system) or 450 IU (for 450 IU and 900 IU delivery system).
Infertile Patients with Oligo-Anovulation: The dose of Gonal-f ® RFF Pen (follitropin alfa injection) to stimulate development of the follicle must be individualized for each patient.
The lowest dose consistent with the expectation of good results should be used. Over the course of treatment, doses of Gonal-f ® RFF Pen may range up to 300 IU per day depending on the individual patient response. Gonal-f ® RFF Pen should be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5 to 7 days. Subsequent monitoring intervals should be based on individual patient response.
It is recommended that the initial dose of the first cycle be 75 IU of Gonal-f ® RFF Pen per day, administered subcutaneously. An incremental adjustment in dose of up to 37.5 IU may be considered after 14 days. Further dose increases of the same magnitude could be made, if necessary, every seven days. Treatment duration should not exceed 35 days unless an E2 rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, chorionic gonadotropin, hCG, should be given after the last dose of Gonal-f ® RFF Pen. Chorionic gonadotropin should be withheld if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, Gonal-f ® RFF Pen treatment should be discontinued, hCG should not be administered, and the patient should be advised not to have intercourse; this may reduce the chance of development of the Ovarian Hyperstimulation Syndrome and, should spontaneous ovulation occur, reduce the chance of multiple gestation. A follow-up visit should be conducted in the luteal phase.
The initial dose administered in the subsequent cycles should be individualized for each patient based on her response in the preceding cycle. Doses larger than 300 IU of FSH per day are not routinely recommended. As in the initial cycle, hCG must be given after the last dose of Gonal-f ® RFF Pen to complete follicular development and induce ovulation. The precautions described above should be followed to minimize the chance of development of the Ovarian Hyperstimulation Syndrome.
The couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity. Care should be taken to ensure insemination. In light of the indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct the necessary laboratory studies, he/she should not use Gonal-f ® RFF Pen.
Assisted Reproductive Technologies: As in the treatment of patients with oligo-anovulatory infertility, the dose of Gonal-f ® RFF Pen to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with Gonal-f ® RFF Pen should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day administered subcutaneously, until sufficient follicular development is attained. In most cases, therapy should not exceed ten days.
In patients undergoing ART under 35 years old, whose endogenous gonadotropin levels are suppressed, Gonal-f ® RFF Pen should be initiated at a dose of 150 IU per day. In patients 35 years old and older whose endogenous gonadotropin levels are suppressed, Gonal-f ® RFF Pen should be initiated at a dose of 225 IU per day. Treatment should be continued until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after five days based on the patient's response; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 75-150 IU additionally at each adjustment. Doses greater than 450 IU per day are not recommended. Once adequate follicular development is evident, hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of therapy. This should reduce the chance of developing OHSS.
Administer subcutaneously in the abdomen as described in the `Patient's Information Leaflet' provided for patients prescribed Gonal-f ® RFF Pen.
Make sure you have all the supplies listed below before you begin.
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Before you start, wash your hands with soap and water. On a clean surface, layout everything you need.
Preparing the Pen
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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Gonal-f ® RFF Pen (follitropin alfa injection) is a disposable, prefilled multiple-dose delivery system containing a sterile, ready-to-use liquid formulation of follitropin alfa. Each Gonal-f ® RFF Pen is filled with 415 IU, 568 IU, or 1026 IU follitropin alfa to deliver a minimum total of 300 IU in 0.5 mL, 450 IU in 0.75 mL, or 900 IU in 1.5 mL, respectively. Each Pen is supplied in a carton containing 29G × 1/2 inch disposable needles to be used for administration.
The following package combinations are available:
NDC 44087-1113-1 One Gonal-f ® RFF Pen contains 415 IU to deliver a minimum total of 300 IU/0.5 mL and 5 single-use disposable 29G × ½ " needles
NDC 44087-1112-1 One Gonal-f ® RFF Pen contains 568 IU to deliver a minimum total of 450 IU/0.75 mL and 7 single-use disposable 29G × ½ " needles
NDC 44087-1114-1 One Gonal-f ® RFF Pen contains 1026 IU to deliver a minimum total of 900 IU/1.5 mL and 14 single-use disposable 29G × ½ " needles
Store the Gonal-f ® RFF Pen refrigerated (2°-8°C/36°-46°F) until dispensed. Upon dispensing, the patient may store the pen refrigerated (2°-8°C/36°-46°F) until the expiration date, or at room temperature (20°-25°C/68°-77°F) for up to one month or until the expiration date, whichever occurs first. After the first injection, the pen may be stored refrigerated (2°-8°C/36°-46°F) or at room temperature (20°-25°C/68°-77°F) for up to 28 days. Protect from light. Do not freeze. Discard unused material after 28 days.
Rx only
Manufactured for: SERONO, INC., Rockland, MA 02370 U.S.A.
Revised: January 2005