Gonal-f
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Questions & Answers
Side Effects & Adverse Reactions
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.
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.
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.
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.
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
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.
- Before treatment with Gonal-f® is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Gonal-f® only if enrolled in an in vitro fertilization program.
- Primary ovarian failure should be excluded by the determination of gonadotropin levels.
- Appropriate evaluation should be performed to exclude pregnancy.
- Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Gonal-f® therapy.
- Evaluation of the partner's fertility potential should be included in the initial evaluation.
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.
- 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.
History
There is currently no drug history available for this drug.
Other Information
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 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
Sources
Gonal-f Manufacturers
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Emd Serono, Inc.
![Gonal-f (Follitropin Alfa) Kit [Emd Serono, Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Gonal-f | Emd Serono, Inc.
Each Gonal-f® Multi-Dose Vial delivers 450 IU or 1050 IU follitropin alfa, respectively.
Dosage Infertile Patients with oligo-anovulationThe dose of Gonal-f® (follitropin alfa for 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® may range up to 300 IU per day depending on the individual patient response. Gonal-f® 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® 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, (5,000 USP units) should be given 1 day after the last dose of Gonal-f®. 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® 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, 5,000 USP units of hCG must be given 1 day after the last dose of Gonal-f® 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®.
Assisted Reproductive TechnologiesAs in the treatment of patients with oligo-anovulatory infertility, the dose of Gonal-f® to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with Gonal-f® should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day, until sufficient follicular development is attained. In most cases, therapy should not exceed ten days.
In patients undergoing ART, whose endogenous gonadotropin levels are suppressed, Gonal-f® 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 (5,000 to 10,000 USP units) 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.
Male Patients with Hypogonadotropic HypogonadismThe dose of Gonal-f® (follitropin alfa for injection) to induce spermatogenesis must be individualized for each patient. Gonal-f® must be given in conjunction with hCG. Prior to concomitant therapy with Gonal-f® and hCG, pretreatment with hCG alone (1,000 to 2,250 USP units two to three times per week) is required. Treatment should continue for a period sufficient to achieve serum testosterone levels within the normal range. Such pretreatment may require 3 to 6 months and the dose of hCG may need to be increased to achieve normal serum testosterone levels. After normal serum testosterone levels are reached, the recommended dose of Gonal-f® is 150 IU administered subcutaneously three times a week and the recommended dose of hCG is 1,000 USP units (or the dose required to maintain serum testosterone levels within the normal range) three times a week. The lowest dose of Gonal-f® which induces spermatogenesis should be utilized. If azoospermia persists, the dose of Gonal-f® may be increased to a maximum dose of 300 IU three times per week. Gonal-f® may need to be administered for up to 18 months to achieve adequate spermatogenesis.
Administration Multi-Dose 450 IU VialDissolve the contents of one Multi-Dose vial (450 IU) with 1 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP. Resulting concentration will be 600 IU/mL. Following reconstitution as directed, product will deliver the equivalent of six 75 IU doses.
Multi-Dose 1050 IU VialDissolve the contents of one Multi-Dose vial (1050 IU) with 2 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP. Resulting concentration will be 600 IU/mL. Following reconstitution as directed, product will deliver the equivalent of fourteen 75 IU doses.
Patients should be instructed to use the accompanying syringes, calibrated in FSH units (IU FSH) for administration. The 27-gauge injection syringe (see figure below) has unit dose markings from 37.5 IU to 600 IU FSH for use with Gonal-f® Multi-Dose. Patients should be instructed to take a specific dose of Gonal-f® Multi-Dose. The doctor, nurse, or pharmacist should show the patient how to locate the syringe marking that corresponds to the prescribed dose.
Patient Instructions for Use for Gonal-f® Multi-Dose Vial Step 1: Mixing (reconstituting) Gonal-f® Multi-Dose Vial Wash your hands with soap and water. Using your thumb, flip off the plastic cap of the Gonal-f® Multi-Dose vial. Wipe the top of the vial stopper with an alcohol swab. Carefully twist the needle cap off the syringe labeled 'Bacteriostatic Water for Injection, USP'. Do not touch the needle or allow the needle to touch any surface. Position the needle of the syringe of water in a straight, upright position over the marked center circle of the rubber stopper on the vial of Gonal-f® Multi-Dose powder. Keep the needle in a straight, upright position as you insert it through the center circle, or it may be difficult to depress the plunger. Slowly inject the water into the vial by depressing the syringe plunger. When all the water has been injected into the vial, withdraw the needle and safely dispose of it immediately in your needle container. Do not use this needle to inject your dose. Do not shake the vial. If bubbles appear, wait a few moments for the bubbles to settle. The liquid drug should be clear. Step 2: Preparing the Dose Wipe the rubber stopper of the vial of Gonal-f® Multi-Dose liquid with an alcohol wipe. Carefully pull the cap from the needle. Do not touch the needle or allow the needle to touch any surface. Firmly hold the vial of Gonal-f® Multi-Dose liquid on a flat surface, insert the needle through the marked center circle of the rubber stopper. Keeping the needle in the vial, lift the vial and turn it upside down with the needle pointing toward the ceiling. With the needle tip in the liquid, slowly pull back the plunger until the syringe fills to slightly more than the mark for your prescribed dose. Next, keeping the needle in the vial, slowly adjust the plunger to your prescribed dose – this will clear away any air bubbles. Check that you have the plunger set at your prescribed dose. Remove the syringe needle from the vial. Inject the prescribed dose as directed by the doctor.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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