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Gonal-f
Overview
What is Gonal-f?
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 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 mcg) or 1200 IU (87 mcg) follitropin alfa to deliver 450 IU (33 mcg) or 1050 IU (77 mcg) follitropin alfa, respectively, 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
What does Gonal-f look like?
What are the available doses of Gonal-f?
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What should I talk to my health care provider before I take Gonal-f?
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How should I use Gonal-f?
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.
Each Gonal-f Multi-Dose Vial delivers 450 IU or 1050 IU follitropin alfa, respectively.
What interacts with Gonal-f?
- Gonal-f (follitropin alfa for injection) is contraindicated in women and men who exhibit:
- Prior hypersensitivity to recombinant FSH preparations or one of their excipients.
- High levels of FSH indicating primary gonadal failure.
- Uncontrolled thyroid or adrenal dysfunction.
- Sex hormone dependent tumors of the reproductive tract and accessory organs.
- An organic intracranial lesion such as a pituitary tumor. And in women who exhibit:
- Abnormal uterine bleeding of undetermined origin (see "").
- Ovarian cyst or enlargement of undetermined origin (see "").
- Pregnancy.
What are the warnings of Gonal-f?
8. OATP1B1 substrates – Gemfibrozil is an inhibitor of organic anion-transporter polyprotein (OATP) 1B1 and may increase exposure of drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly (see ). Combination therapy of gemfibrozil with simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated (see ).
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 ""). 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
Ovarian Hyperstimulation Syndrome (OHSS)
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 with gonadotropins including Gonal-f. 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 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.
What are the precautions of Gonal-f?
General
Careful attention should be given to the diagnosis of infertility in candidates for Gonal-f (follitropin alfa for injection) therapy (see "").
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 "") and other possible adverse reactions (see "") should also be discussed.
A 'Patient's Information Leaflet' is provided for patients prescribed Gonal-f Multi-Dose.
Laboratory Tests
- A rise in basal body temperature;
- Increase in serum progesterone; and
- Menstruation following a shift in basal body temperature.
- Fluid in the cul-de-sac;
- Ovarian stigmata;
- Collapsed follicle; and
- Secretory endometrium.
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.
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. 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
See
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, 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.
What are the side effects of Gonal-f?
Women
- Spontaneous Abortion
- Ectopic Pregnancy
- Premature Labor
- Postpartum Fever
- Congenital Abnormalities
- Pulmonary and vascular complications (see ""),
- Adnexal torsion (as a complication of ovarian enlargement),
- Mild to moderate ovarian enlargement,
- Hemoperitoneum
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 multi-dose, respectively.
The following medical events have been reported subsequent to pregnancies resulting from gonadotropins in controlled clinical studies:
Two incidents of congenital cardiac malformations have been reported in children born following pregnancies resulting from treatment with Gonal-f and hCG in Gonal-f clinical studies 5642 and 5727. In addition, a pregnancy occurring in study 5533 following treatment with Gonal-f and hCG was complicated by apparent failure of intrauterine growth and terminated for a suspected syndrome of congenital abnormalities. No specific diagnosis was made. The incidence does not exceed that found in the general population.
The following adverse reactions have been previously reported during menotropin 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.
| Body System Preferred Term | Gonal-f Patients (%) Experiencing EventsTreatment cycles = 288 n=118 | UrofollitropinPatients (%) Experiencing EventsTreatment cycles = 277 n= 114 |
|---|---|---|
| Reproductive, Female | ||
| Intermenstrual Bleeding | 9.3% | 4.4% |
| Breast Pain Female | 4.2% | 6.1% |
| Ovarian Hyperstimulation | 6.8% | 3.5% |
| Dysmenorrhea | 2.5% | 6.1% |
| Ovarian Disorder | 1.7% | 2.6% |
| Cervix Lesion | 2.5% | 0.9% |
| Menstrual Disorder | 2.5% | 0.9% |
| Gastro-intestinal System | ||
| Abdominal Pain | 9.3% | 12.3% |
| Nausea | 13.6% | 3.5% |
| Flatulence | 6.8% | 8.8% |
| Diarrhea | 7.6% | 3.5% |
| Vomiting | 2.5% | 2.6% |
| Dyspepsia | 1.7% | 3.5% |
| Headache | 22.0% | 20.2% |
| Dizziness | 2.5% | 0.0% |
| Neoplasm | ||
| Ovarian Cyst | 15.3% | 28.9% |
| Body as a Whole- General | ||
| Pain | 5.9% | 6.1% |
| Back Pain | 5.1% | 1.8% |
| Influenza-like Symptoms | 4.2% | 2.6% |
| Fever | 4.2% | 1.8% |
| Respiratory System | ||
| Upper Respiratory Tract Infection | 11.9% | 7.9% |
| Sinusitis | 5.1% | 5.3% |
| Pharyngitis | 2.5% | 3.5% |
| Coughing | 1.7% | 2.6% |
| Rhinitis | 0.8% | 2.6% |
| Skin and Appendages | ||
| Acne | 4.2% | 2.6% |
| Psychiatric | ||
| Emotional Lability | 5.1% | 2.6% |
| Urinary System | ||
| Urinary Tract Infection | 1.7% | 4.4% |
| Resistance Mechanism | ||
| Moniliasis Genital | 2.5% | 0.9% |
| Application Site | ||
| Injection Site Pain | 2.5% | 0.9% | Body System Preferred Term | Gonal-f Patients (%) Experiencing Eventsn=59 | UrofollitropinPatients (%) Experiencing Eventsn= 61 |
| Reproductive, Female | ||
| Intermenstrual Bleeding | 3.6% | 5.2% |
| Leukorrhea | 1.7% | 3.4% |
| Vaginal Hemorrhage | 3.6% | 3.4% |
| Gastro-intestinal System | ||
| Nausea | 5.4% | 1.7% |
| Flatulence | 3.6% | 0.0% |
| Central and Peripheral Nervous System | ||
| Headache | 12.5% | 3.4% |
| Body as a Whole- General | ||
| Abdominal Pain | 8.9% | 3.4% |
| Pelvic Pain Female | 7.1% | 1.7% |
| Respiratory System | ||
| Upper Respiratory Tract Infection | 3.6% | 1.7% |
| Metabolic and Nutritional | ||
| Weight Increase | 3.6% | 0.0% |
Men
The safety of Gonal-f was examined in 3 clinical studies that enrolled 72 patients for induction of spermatogenesis and fertility of whom 56 patients received Gonal-f. One hundred and twenty-three adverse events, including 7 serious events, were reported in 34 of the 56 patients during Gonal-f treatment.
In Study 5844, 21 adverse events, including 4 serious adverse events, were reported by 14 of the 26 patients (53.8%) treated with Gonal-f. Events occurring in more than one patient were varicocele (4) and injection site reactions (4). The 4 serious adverse events were testicular surgery for cryptorchidism, which existed prestudy, hemoptysis, an infected pilonidal cyst, and lymphadenopathy associated with an Epstein-Barr viral infection.
In Study 6410, 3 adverse events were reported in 2 of the 8 patients (24%) treated with Gonal-f. One serious adverse event was reported, surgery for gynecomastia which existed at baseline.
In the interim analysis of Study 6793, 18 of 22 patients (81.8%) reported a total of 99 adverse events during Gonal-f treatment. The most common events of possible, probable, or definite relationship to study drug therapy occurring in more than 2 patients were: acne (25 events in 13 patients; 59% of patients); breast pain (4 events in 3 patients; 13.6% of patients); and fatigue, gynecomastia, and injection site pain (each of which was reported as 2 events by 2 patients; 9.1% of patients). Two serious adverse events (hospitalization for drug abuse and depression) were reported by a single patient in the interim analysis.
A total of 12,026 injections of Gonal-f were administered by the 56 patients who received Gonal-f in Studies 5844, 6410, and 6793 combined. The injections were well-tolerated, with no or mild reactions (redness, swelling, bruising and itching) reported by patients for 93.3% of injections. Moderate and severe reactions, consisting primarily of pain, were reported for 4.8% of injections, and no self-assessment was available for 1.9% of injections.
Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of Gonal-f. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Gonal-f, can not be reliably determined.
Body as a Whole - General:
Respiratory System:
Vascular disorders:
(see
)
What should I look out for while using Gonal-f?
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 ""). 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.
What might happen if I take too much Gonal-f?
Aside from possible ovarian hyperstimulation and multiple gestations (see ""), there is no information on the consequences of acute overdosage with Gonal-f (follitropin alfa for injection).
How should I store and handle Gonal-f?
Dispense in a tight container as defined in the USP with a child-resistant closure.Gonal-f (follitropin alfa for injection) is supplied in a sterile, lyophilized form in multiple dose vials filled with 600 IU or 1200 IU in order to deliver 450 IU and 1050 IU FSH, respectively, after reconstitution with diluent (Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol as a preservative). Each carton contains syringes with mounted 27G × 0.5 inch needle, calibrated in FSH units (IU FSH) which should be used for administration. Lyophilized Multi-Dose vials may be stored refrigerated or at room temperature (2°-25°C/36°-77°F). Following reconstitution, the Multi-Dose vial may be stored refrigerated or at room temperature (2°-25°C/36°-77°F). Protect from light. Discard unused reconstituted solution after 28 days.The following package combinations are available:Gonal-f (follitropin alfa for injection) is supplied in a sterile, lyophilized form in multiple dose vials filled with 600 IU or 1200 IU in order to deliver 450 IU and 1050 IU FSH, respectively, after reconstitution with diluent (Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol as a preservative). Each carton contains syringes with mounted 27G × 0.5 inch needle, calibrated in FSH units (IU FSH) which should be used for administration. Lyophilized Multi-Dose vials may be stored refrigerated or at room temperature (2°-25°C/36°-77°F). Following reconstitution, the Multi-Dose vial may be stored refrigerated or at room temperature (2°-25°C/36°-77°F). Protect from light. Discard unused reconstituted solution after 28 days.The following package combinations are available:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 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.
Non-Clinical Toxicology
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 ""). 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.
No drug/drug interaction studies have been performed.
Careful attention should be given to the diagnosis of infertility in candidates for Gonal-f (follitropin alfa for injection) therapy (see "").
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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