Gonal (Follitropin Alpha)

GONAL-F®

Serono

Follitropin alpha (rDNA origin)

Gonadotropin

Action And Clinical Pharmacology: Gonal-F is a gonadotropin preparation of recombinant DNA origin. The active ingredient, recombinant human follicle stimulating hormone (r-hFSH), is a human glycoprotein hormone which consists of 2 noncovalently linked, nonidentical protein components designated as the a- and b-subunits. The physicochemical, immunological, and biological activities of r-hFSH are similar to those of human menopausal urine-derived hFSH, but free of urinary protein and of any LH component.

Gonal-F stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH is the primary hormone responsible for follicular recruitment and development. To complete follicular maturation and effect ovulation in the absence of an endogenous luteinizing hormone (LH) surge, human chorionic gonadotropin (hCG) is given when monitoring of the patient indicates that sufficient follicular development has occurred. There may be a degree of interpatient variability in response to FSH administration, with lack of response to FSH in some patients.

Pharmacokinetics: Following i.v. administration, follitropin alpha (rDNA origin) is distributed to the extracellular fluid space with an initial half-life around 2 hours and eliminated from the body with a terminal half-life of about 1 day. The steady-state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alpha (rDNA origin) dose is excreted in the urine.

Following s.c. or i.m. administration, the absolute bioavailability is about 70%. Following repeated administration, Gonal-F accumulates 3-fold at steady-state within 3 to 4 days. In women whose endogenous gonadotropin secretion is suppressed, Gonal-F has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

Indications And Clinical Uses: For the stimulation of multiple follicular development in ovulatory patients undergoing Assisted Reproductive Technologies (ART) such as in vitro fertilization. To complete follicular maturation in the absence of an endogenous LH surge, hCG is given.

Gonal-F is also indicated for the stimulation of follicular development in patients with hypothalamic-pituitary dysfunction who present either oligomenorrhea or amenorrhea (WHO Group II). To complete follicular maturation and effect ovulation, hCG is given.

Selection of Patients: Before treatment with Gonal-F is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy.

Primary ovarian failure should be excluded by the determination of gonadotropin levels.

Pregnancy: Appropriate evaluation should be performed to exclude pregnancy.

Patients in late 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 husband’s fertility potential should be included in the initial evaluation.

Contra-Indications: Women who exhibit: High levels of FSH indicating primary ovarian failure. Uncontrolled thyroid or adrenal dysfunction. An organic intracranial lesion such as a pituitary tumor. The presence of any cause of infertility other than anovulation, as stated in the Indications unless the women are candidates for Assisted Reproductive Technologies. Abnormal uterine bleeding (see Indications, Selection of Patients). Ovarian cyst or enlargement of undetermined origin (see Indications, Selection of Patients). Sex hormone dependent tumors of the reproductive organs and breasts. Pregnancy/lactation. History of previous allergic reaction to any component of Gonal-F.

Manufacturers’ Warnings In Clinical States: Gonal-F 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 mild to severe adverse reactions. 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 requires monitoring of ovarian response with ultrasound, alone or in combination with measurement of serum estradiol levels, on a regular basis.

Overstimulation of the Ovary During FSH Therapy: Ovarian Enlargement: Use of FSH therapy to stimulate follicular development may result in the recruitment of a number of follicles. This may result in mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain. This degree of enlargement has been reported to occur in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within 2 or 3 weeks.

To minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with Gonal-F therapy, the lowest dose consistent with the expectation of good results should be used. Careful monitoring of ovarian response can further minimize the risk of ovarian enlargement.

If there is clinical evidence of excessive ovarian response (see Precautions, Laboratory Tests), treatment should be discontinued and hCG should not be administered. This will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.

Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement. 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 an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities. 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 distention, severe ovarian enlargement, weight gain, dyspnea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhea. 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 the OHSS.

Severe OHSS occurred in approximately 6% of patients treated with urofollitropin therapy in the initial clinical trials, in patients treated for anovulation due to polycystic ovarian syndrome. In these studies, prospective monitoring of ovarian response using serum estradiol determination or ultrasonographic visualizations was not routinely employed. In the clinical trials in oligo-anovulatory infertile women treated with Gonal-F in which both estradiol and ultrasound measurements were utilized to monitor follicular development, the incidence of severe OHSS was 1 in 513 treatment cycles (0.2%). In the clinical trials in ovulatory infertile women treated with Gonal-F for induction of multiple follicular induction for IVF/ET in which both estradiol and ultrasound measurements were utilized to monitor follicular development, there was no incident of severe OHSS. OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed for at least 2 weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about 7 to 10 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 should 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: The following paragraph describes serious medical events reported following gonadotropin therapy. 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 treatment. The risk of multiple births in patients undergoing ART procedures is related to the number of embryos replaced. In other patients, the incidence of multiple births may be increased by Gonal-F, as has been observed with other gonadotropin preparations. The patient and her husband should be advised of the potential risk of multiple births before starting treatment.

Precautions: General: Careful attention should be given to diagnosis in candidates for Gonal-F therapy (see Indications, Selection of Patients).

Information for the Patient: Prior to therapy with Gonal-F, patients should be informed of the duration of treatment and monitoring of their condition that will be required. Possible adverse reactions (see Adverse Effects) and the risk of multiple births should also be discussed.

Laboratory Tests: In most instances, treatment 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: a rise in basal body temperature; increase in serum progesterone and menstruation following a shift in basal body temperature.

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: fluid in the cul-de-sac; ovarian stigmata; collapsed follicle and secretory endometrium.

Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests.

For patients undergoing extended cycles of treatment, PTT and liver enzymes should be monitored.

Drug Interactions: Clomiphene citrate used with Gonal-F may enhance follicular response, and caution is indicated when using the two together. No other clinically significant drug/drug or drug/food interactions have been reported during Gonal-F therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-F. However, r-hFSH showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosome aberration test and a micronucleus test.

Impaired fertility has been reported in rats exposed to pharmacological doses of r-hFSH (³40 IU/kg/day) for extended periods through reduced fecondity.

Pregnancy: There are no adequate and well-controlled studies in pregnant women.

Given in high doses (>5 IU/kg/day) Gonal-F caused an increase in deaths, fetal effects and dystocia in pregnant rats and rabbits, but without being a teratogen. However, since Gonal-F is not indicated in pregnancy, these data are of limited clinical relevance.

Lactation: It is not known whether this drug is excreted in human milk, although animal studies have shown that r-hFSH is excreted in milk. Therefore, Gonal-F is contraindicated in lactating mothers.

Adverse Reactions: The following adverse reactions reported during gonadotropin therapy are listed in decreasing order of potential severity: pulmonary and vascular complications (see Warnings); Ovarian Hyperstimulation Syndrome (see Warnings); adnexal torsion (as a complication of ovarian enlargement); hemoperitoneum; mild to moderate ovarian enlargement; abdominal pain; ovarian cysts; gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal cramps, bloating); pain, rash, swelling, and/or irritation at the site of injection; breast tenderness; headache and dermatological symptoms (dry skin, body rash, hair loss, hives).

The following medical events have been reported subsequent to pregnancies resulting from Gonal-F therapy in controlled clinical trials: spontaneous abortion, ectopic pregnancy, premature labor, postpartum fever.

Congenital Abnormalities: Two incidents of congenital cardiac malformations have been reported in children born following pregnancies resulting from treatment with Gonal-F and hCG in clinical studies. In addition, a pregnancy occurring in a study following treatment with Gonal-F and hCG was characterized by apparent failure of intrauterine growth and terminated for a suspected syndrome of congenital abnormalities. No specific diagnosis was made.

Three incidents of chromosomal abnormalities and 4 birth defects have been reported following urofollitropin-hCG or urofollitropin, Pergonal (menotropins for injection)-hCG therapy in clinical trials for stimulation prior to in vitro fertilization. The aborted pregnancies included 1 Trisomy 13, 1 Trisomy 18, and 1 fetus with multiple congenital anomalies (hydrocephaly, omphalocele and meningocele). One meningocele, 1 external ear defect, 1 dislocated hip and ankle and 1 dilated cardiomyopathy in presence of maternal Systemic Lupus Erythematosus were reported. None of these events were thought to be drug-related. The incidence does not exceed that found in the general population.

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.

Drug Abuse and Dependence: There have been no reports of abuse or dependence with Gonal-F.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Aside from possible ovarian hyperstimulation and multiple gestations (see Warnings), little is known concerning the consequences of acute overdosage with Gonal-F. Apart from expected ovarian and endometrial effects, no acute toxicity was seen in animals given doses of r-hFSH up to 1 000-fold the human dose.

Dosage And Administration: The dose to stimulate development of the follicle must be individualized for each patient and the particular indication. To minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with therapy, the lowest dose consistent with the expectation of good results should be used. It should be administered s.c. or i.m. until adequate follicular development is indicated by ultrasound alone or in combination with measurement of serum estradiol levels. Over the course of treatment, doses may range between 75 to 450 IU depending on the indication and the individual patient response. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. If the ovaries are abnormally enlarged or significant abdominal pain occurs, Gonal-F treatment should be discontinued, hCG should not be administered, and the patient should be advised to refrain from intercourse until resolution of the cycle; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome and, should spontaneous ovulation occur, reduce the chances of multiple gestation. While individual dosing regimens will differ between patients, typical treatment regimens are presented below.

Assisted Reproductive Technologies: In patients undergoing Assisted Reproductive Technologies (ART) whose endogenous gonadotropin levels are not suppressed, Gonal-F should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU/day, administered s.c. or i.m. Treatment should be continued until adequate follicular development is indicated as determined by either ultrasound alone or in combination with measurement of serum estradiol levels. Adjustments to dose, based on the patient’s response, should only be considered after the first 5 days of treatment; subsequently dosage should be adjusted no more frequently than every 3 to 5 days and by no more than 75 to 150 IU additionally at each adjustment. Treatment should be continued until adequate follicular development is indicated. 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.

In patients undergoing ART, whose endogenous gonadotropin levels are suppressed indicating a hypogonadotropic state, Gonal-F should be initiated at a dose of 225 IU/day, administered s.c. or i.m. Treatment should be continued until adequate follicular development is indicated as determined by either ultrasound alone or in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after 5 days based on the patient’s response; subsequently dosage should be adjusted no more frequently than every 3 to 5 days and by no more than 75 to 150 IU additionally at each adjustment. Doses greater than 450 IU/day are not generally recommended. As before, 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.

Polycystic Ovarian Syndrome: Patients with Polycystic Ovarian Syndrome (PCO) tend to show a more rapid and exaggerated response to treatment. Therefore, in this patient population, particular care should be employed to ensure that patients are adequately monitored and that the lowest dose consistent with the expectation of good results is employed.

It is recommended that treatment of any patient be initiated at a dose of 75 IU Gonal-F/day, administered s.c. or i.m., for 7 to 12 days. Administration may exceed 12 days if inadequate follicular development is indicated by ultrasound alone or in combination with measurement of serum estradiol levels. Once adequate follicular development is evident, hCG (5 000 to 10 000 USP units) should be administered to induce final follicular maturation and effect ovulation. The patient should attempt to have intercourse at a consistent frequency of at least 3 times/week from the day prior to administration of hCG until ovulation becomes apparent.

If there is evidence of ovulation but pregnancy does not ensue, this regimen should be repeated for at least 2 more courses before increasing the dose to 150 IU/day for 7 to 12 days. As before, this dose should be followed by the administration of 5 000 to 10 000 USP units of hCG when adequate follicular development is evident. If evidence of ovulation is present but pregnancy does not ensue, repeat the same dose for 2 more courses. Doses larger than this are not routinely recommended.

Administration: Gonal-F should be administered s.c. or i.m. immediately after reconstitution with 0.5 to 1 mL Sterile Water for Injection. To avoid the injection of large volumes, up to 3 ampuls may be dissolved in 1 mL Sterile Water for Injection. Any unused reconstituted material should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstituted Solutions: The Sterile Water for Injection provided with the lyophilized material should be used for reconstituting the product. Volumes used for reconstitution should be between 0.5 and 1 mL; up to 3 ampuls may be dissolved in 1 mL of Sterile Water for Injection. Reconstituted ampuls should be used immediately, and any unused solution should be discarded.

Parenteral Products: The reconstituted product may be administered either i.m. or s.c. Reconstituted ampuls should be visually examined for particulate matter prior to administration.

Availability And Storage: 75 IU: Each single dose ampul of sterile, lyophilized white pellets, intended for s.c. or i.m. injection after reconstitution, contains: FSH activity 75 IU. Diluent provided for reconstitution is Sterile Water for Injection. Nonmedicinal ingredients: dibasic sodium phosphate, monobasic sodium phosphate monohydrate and sucrose. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Single dose ampuls of 3 mL. Packages of 1, 10 and 100 ampuls accompanied by 1, 10 and 100 ampuls (1 mL) Sterile Water for Injection, respectively.

150 IU: Each single dose ampul of sterile, lyophilized white pellets, intended for s.c. or i.m. injection after reconstitution, contains: FSH activity 150 IU. Diluent provided for reconstitution is Sterile Water for Injection. Nonmedicinal ingredients: dibasic sodium phosphate, monobasic sodium phosphate monohydrate and sucrose. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Single dose ampuls of 3 mL. Packages of 1 and 50 ampuls accompanied by 1 and 50 ampuls (1 mL) Sterile Water for Injection, respectively.

Lyophilized ampuls are stable when stored at or below room temperature (25°C) and protected from light. Do not use the product after the expiry date indicated on the label.

GONAL-F® Serono Follitropin alpha (rDNA origin) Gonadotropin

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