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Generic Name: follitropin alfa
Dosage Form: Injection
Gonal-f® (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 Stimulation Hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization. Gonal-f® 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® is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.
Each Gonal-f® Multi-Dose vial is filled with 600 IU (44 μg) follitropin alfa to deliver 450 IU (33 μg) follitropin alfa and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate and 0.45 mg monobasic sodium phosphate monohydrate. O-phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Multiple Dose vials are reconstituted with Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP.
Under current storage conditions, Gonal-f® may contain up to 10% of oxidized follitropin alfa.
Therapeutic Class: Infertility
Gonal-f - Clinical Pharmacology
Gonal-f® (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Gonal-f® 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® when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration. The physico-chemical, immunological, and biological activities of recombinant FSH (r-hFSH) are comparable to those of pituitary and human menopausal urine-derived FSH. Gonal-f® (follitropin alfa for injection), when administered with hCG, stimulates spermatogenesis in men with hypogonadotropic hypogonadism. FSH, the active component of Gonal-f®, is the primary hormone responsible for spermatogenesis.
Single dose pharmacokinetics of follitropin alfa were determined following intravenous, subcutaneous and intramuscular administration of 150 IU Gonal-f® to 12 healthy, down-regulated female volunteers. Steady-state pharmacokinetics were also determined in 12 healthy down-regulated female volunteers who were administered a single daily dose of 150 IU for seven days. These pharmacokinetics were confirmed in pituitary down-regulated women undergoing in vitro fertilization and embryo transfer (IVF/ET), treated with FSH doses of up to 450 IU per day. Additionally, single dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 225 IU Gonal-f® to 12 healthy adult male volunteers in a cross-over design. Steady state pharmacokinetics were also determined in 6 healthy adult male volunteers who were administered a single daily dose of 225 IU Gonal-f® for 7 days. No significant difference in pharmacokinetics is expected in males versus females when administered Gonal-f® subcutaneously. The pharmacokinetic parameters from these studies are included in Table 1.
The absorption rate of Gonal-f® following subcutaneous or intramuscular administration was found to be slower than the elimination rate. Hence the pharmacokinetics of Gonal-f® are absorption rate-limited.Distribution
Human tissue or organ distribution of FSH has not been determined for Gonal-f®.
After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two compartment open model with a distribution half-life of about 2-2.5 hours. Steady-state serum levels were reached after 4 to 5 days of daily administration.Metabolism/Excretion
FSH metabolism following administration of Gonal-f® has not been studied in humans. Total clearance after IV administration in healthy females was 0.6 L/hr; mean residence time was 17-20 hours. FSH renal clearance was 0.07 L/hr after intravenous administration representing approximately 1/8 of total clearance.Pharmacodynamics
Following daily subcutaneous administration of 150 IU of Gonal-f® for 7 days in healthy female volunteers, serum inhibin and estradiol, and total follicular volume responded as a function of time, with pronounced inter-individual variability. Pharmacodynamic effect lagged behind FSH serum concentration. Of the three pharmacodynamic parameters, serum inhibin levels responded with the least delay and declined rapidly after discontinuation of Gonal-f®. Follicular growth was most delayed and continued even after discontinuation of Gonal-f® administration, and after serum FSH levels had declined. Maximum follicular volume was better correlated with either inhibin or estradiol peak levels than with FSH concentration. Inhibin rise was an early index of follicular development. In healthy male volunteers, despite high interindividual variation and the absence of down-regulation, daily administration of 225 IU Gonal-f® was shown to increase the levels of inhibin to reach a plateau during the whole administration period and then return to baseline.Population pharmacokinetics and pharmacodynamics
To establish the pharmacokinetics and pharmacodynamics of FSH in a target population, measurements performed during a clinical study of in vitro fertilization/embryo transfer were used in conjunction with pharmacokinetic data from studies in healthy female volunteers. The apparent clearance was comparable to that in healthy volunteers. The absorption rate was found to be influenced by the body mass index (BMI), suggesting that the higher the BMI, the lower the rate of absorption. However, FSH serum levels following fixed (during the first five days) and then adjusted doses of Gonal-f® were found to be poor predictors of follicular growth rate. High pre-treatment serum FSH levels may predict lower follicular growth rates.
Special populations: Safety, efficacy, and pharmacokinetics of Gonal-f® 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® have been examined in four clinical studies, two studies for ovulation induction and two studies for assisted reproductive technologies (ART). In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.
1. Ovulation Induction:
The safety and efficacy of Gonal-f® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy (Study 5642).
The primary efficacy parameter was the ovulation rate. Two hundred and twenty-two patients entered into the first cycle of treatment, of whom 110 received Gonal-f® and 112 received urofollitropin. Ovulation rates were similar between Gonal-f® and urofollitropin treatment groups. The study results for the 222 patients who received treatment in at least one cycle are summarized in Table 2.
For the 90 patients who had a clinical pregnancy (39 in Gonal-f® group; 51 in urofollitropin group), the outcome of the pregnancy was:
A second randomized, comparative, open-label, multicenter study was conducted in 23 U.S. centers (Study 5727). The primary efficacy parameter was ovulation rate. Ovulation rates were similar between Gonal-f® and urofollitropin treatment groups. Two hundred and thirty-two patients with oligo-anovulatory infertility received treatment with up to three cycles of Gonal-f® administered subcutaneously (118 patients) or urofollitropin administered intramuscularly (114 patients).
The cumulative patient ovulation rate and clinical pregnancy rates by cycle are presented for the 232 patients who received treatment in at least one cycle.
For the 85 patients who had a clinical pregnancy (44 in Gonal-f® group; 41 in urofollitropin group), the outcome of the pregnancy is shown in Table 5.
2. Assisted Reproductive Technologies (ART):
The safety and efficacy of Gonal-f® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for In Vitro Fertilization and Embryo Transfer (IVF/ET) after pituitary down-regulation with a GnRH agonist (Study 5503). The purpose of the study was to demonstrate that Gonal-f®, administered subcutaneously, was clinically not different in terms of safety and efficacy from urofollitropin, administered intramuscularly. The initial and maximal doses of Gonal-f® were 225 and 450 IU, respectively. The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration. One hundred and twenty-three patients were randomized and received either Gonal-f® (60 patients) or urofollitropin (63 patients).
The results summarized in Table 6 are mean data with Gonal-f® and urofollitropin administered to ovulatory infertile women undergoing multiple follicular development for IVF/ET.
For the 22 patients who had a clinical pregnancy (12 in Gonal-f® group; 10 in urofollitropin group), the outcome of the pregnancy is shown in Table 7.
A second randomized, comparative, open-label, multicenter study was conducted in 7 U.S. centers (Study 5533). One hundred and fourteen patients with ovulatory infertility undergoing IVF/ET were randomized and received either Gonal-f® by subcutaneous administration (56 patients) or urofollitropin by intramuscular administration (58 patients) following pituitary down-regulation with a GnRH agonist. The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration. Results are summarized in Table 8.
For the 25 patients who had a clinical pregnancy (12 in Gonal-f® group; 13 in urofollitropin group), the outcome of the pregnancy is shown in Table 9.
The safety and efficacy of Gonal-f® administered concomitantly with hCG have been examined in three open-label clinical studies for induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism.
The three multicenter studies involved three to six months of pretreatment with chorionic gonadotropin for injection (Profasi®) to normalize serum testosterone levels, followed by 18 months of treatment with Gonal-f® and hCG. The objective of each study was induction of spermatogenesis (a sperm density of ≥ 1.5 x 106/mL).
Study 5844 enrolled 32 patients in six centers in the United Kingdom, France and Germany. The second trial, Study 6410, was conducted in Australia and enrolled 10 patients in two centers. Study 6793, conducted in 7 centers in the United States, was planned to enroll 32 patients. The interim data for the US study includes 30 of the planned 32 patients. For all 3 studies, a total of 72 patients were enrolled and received hCG and 56 of those patients entered the Gonal-f® treatment phase of the trials.
The populations enrolled in the three studies were similar: Study 5844 studied a naïve population who had had no prior treatment with gonadotropins; mean age was 25.9 (range 16 to 48) years, mean (± SD) testis volume was 2.0 ± 1.2 mL, and 12 of the 32 patients (37.5%) were anosmic. Thirty-one of the patients were Caucasian and one was Asian. In Study 6410, mean age was 36 (range 26 to 48) years, 6 and 1 of the 10 patients had previously been treated with gonadotropins and GnRH, respectively; mean testis volume was 4.5 ± 2.9 mL; and 2 of the 10 patients (20%) were anosmic. Seven patients were Caucasian and three were Asian. In the 30 patients reported in the interim analysis of Study 6793, the mean age was 30.1 (range 22 to 44) years; 4 and 3 of the 30 patients had been treated with gonadotropins and GnRH, respectively, in the past; mean testis volume was 4.4 ± 1.3 mL; and 10 of the 30 patients (33.3%) were anosmic. Twenty five of the patients were Caucasian, three were Asian, and one each of Moroccan and Indian ancestry.
The primary efficacy endpoint of all three studies was the achievement of a sperm density ≥ 1.5 x 106/mL. The study results for the patients treated with Gonal-f® and hCG are summarized in Table 10.
The time to achievement of the primary efficacy endpoint is summarized in Table 11.
Of the 56 patients who received Gonal-f® in Studies 5844, 6410, and 6793, 12 pregnancies were achieved in 10 partners of the 37 patients who were seeking pregnancy and who currently had a partner during the studies. Thus, pregnancy (clinical and chemical) was documented to have been achieved by 27% of the patients’ partners seeking pregnancy during the exposure period to Gonal-f® in the 3 trials. Eight pregnancies continued to term, and 8 healthy babies were born to 7 couples as a result of those studies.
INDICATIONS & USAGE
Women: Gonal-f® (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-f® is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.
Selection of Patients:
Men: Gonal-f® (follitropin alfa for injection) is indicated for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure.
Selection of Patients:
Before treatment with Gonal-f® is instituted for azoospermia, a thorough medical and endocrinologic evaluation must be performed.
Hypogonadotropic hypogonadism should be confirmed, and primary testicular failure should be excluded by the determination of gonadotropin levels.
Prior to Gonal-f® therapy for azoospermia in patients with hypogonadotropic hypogonadism, serum testosterone levels should be normalized.
Gonal-f® (follitropin alfa for injection) is contraindicated in women and men who exhibit:
Gonal-f® (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.
Gonal-f® 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® 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® 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 9 of 228 (3.9%) Gonal-f® treated women during ovulation induction clinical trials and of this number, 1 of 228 (0.4%) was classified as severe. In ART clinical studies, OHSS occurred in 0 of 116 (0.0%) Gonal-f® treated women. 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.
Reports of multiple births have been associated with Gonal-f® treatment. In ovulation induction clinical trials, 12.3% of live births were multiple births in women receiving Gonal-f® and 14.5% of live births were multiple births in women receiving urofollitropin. In IVF/ET clinical trials, 44.0% of live births were multiple births in women receiving Gonal-f® and 41.0% of live births were multiple births in women receiving urofollitropin and is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.
INFORMATION FOR PATIENTS
Prior to therapy with Gonal-f®, 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® Multi-Dose.
In most instances, treatment of women with Gonal-f® 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.
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®. 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 Category X. See CONTRAINDICATIONS.
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®, 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.
Safety and effectiveness in pediatric patients have not been established.
The safety of Gonal-f® was examined in four clinical studies that enrolled 691 patients into two studies for ovulation induction (454 patients) and two studies for ART (237 patients).
Adverse events occurring in more than 10% of patients were headache, ovarian cyst, nausea, and upper respiratory tract infection in the U.S. ovulation induction study and headache in the U.S. ART study. Adverse events (without regard to causality assessment) occurring in at least 2% of patients are listed in Table 13 and Table 14.
Additional adverse events not listed in Table 13 that occurred in 1 to 2% of Gonal-f® treated patients in the US ovulation induction study included the following: leukorrhea, vaginal hemorrhage, migraine, fatigue, asthma, nervousness, somnolence, and hypotension.
Additional adverse events not listed in Table 14 that occurred in 1 to 2% of Gonal-f® treated patients in the U.S. Assisted Reproductive Technology (ART) study included the following: D&C following delivery or abortion, dysmenorrhea, vaginal hemorrhage, diarrhea, tooth disorder, vomiting, dizziness, paraesthesia, abdomen enlarged, chest pain, fatigue, dyspnea, anorexia, anxiety, somnolence, injection site inflammation, injection site reaction, pruritus, pruritus genital, myalgia, thirst, and palpitation.
Two additional clinical studies (for ovulation induction and ART, respectively) were conducted in Europe. The safety profiles from these two studies were comparable to that of the data presented above.
Gonal-f® Multi-Dose was examined in twenty-five healthy volunteers who received 300 IU each of Gonal-f® from single-dose ampules and multi-dose vials. Overall, both presentations were well tolerated and local tolerability between the two groups was comparable. Injection site inspections revealed very rare local reactions (mild redness in one patient after single-dose injection and mild bruising in two subjects after multi-dose injection). Subjective assessments indicated minimal or mild transient pain in two and five subjects who received Gonal-f® single-dose and Gonal-f&