Gonal-F

The dose of GONAL-f 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 GONAL-f therapy, the lowest dose consistent with the expectation of good results should be used. GONAL-f should be administered subcutaneously or intramuscularly until adequate follicular development is indicated by ultrasound alone or in combination with measurement of serum estradiol levels.

The dosage recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing preparations. However, when these doses were used in a clinical study comparing GONAL-f and urinary FSH, GONAL-f was more effective than urinary FSH in terms of a lower total dose and a shorter treatment period needed to achieve pre-ovulatory conditions.

Over the course of treatment, doses may range between 75 to 450 IU (5.5 to 33 μg) 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.

GONAL-f is intended for subcutaneous or intramuscular administration.

For patients who miss a dose, it is not recommended to double the next dose. The patient should be reminded to contact the physician monitoring their treatment.

The majority of patients who require ovulation induction are patients with Polycystic Ovarian Syndrome (PCO). Patients with 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 (5.5 μg) GONAL-f per day, administered subcutaneously or intramuscularly. An incremental adjustment in dose of up to 37.5 IU (2.8 μg) 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 estradiol rise indicates imminent follicular development. Once adequate follicular development is evident, hCG (5000 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 three 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 two more courses before increasing the dose of GONAL-f to 150 IU (11 μg) per day for 7 to 12 days. As before, this dose should be followed by the administration of hCG (5000 to 10 000 USP units) when adequate follicular development is evident. If evidence of ovulation is present but pregnancy does not ensue, repeat the same dose for two more courses. Doses larger than this are not routinely recommended.

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 (11 μg) per day, administered subcutaneously or intramuscularly. 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 five days of treatment; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 37.5-150 IU (2.8-11 μg) additionally at each adjustment. Treatment should be continued until adequate follicular development is indicated. Once adequate follicular development is evident, hCG (5000 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 (16.5 μg) per day, administered subcutaneously or intramuscularly. 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 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 37.5-150 IU (2.8-11 μg) additionally at each adjustment. Doses greater than 450 IU (33 μg) per day are not generally recommended. As before, once adequate follicular development is evident, hCG (5000 to 10 000 USP units) should be administered to induce final follicular maturation in preparation for oocyte retrieval.

Treatment with GONAL-f (follitropin alpha for injection) should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

GONAL-f [37.5 IU (2.8 μg), 75 IU (5.5 μg), 150 IU (11 μg)] should be administered subcutaneously or intramuscularly immediately after reconstitution with Sterile Water for Injection, Ph.Eur./USP. One or more vials of GONAL-f may be dissolved in 0.5-1 mL of Sterile Water for Injection, Ph.Eur./USP (concentration should not exceed 225 IU (16.5 μg)/0.5 mL). 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.

If prescribed GONAL-f 450 IU (33 μg) or 1050 IU (77 μg) Multi-Dose preparations, the injection can be administered subcutaneously and/or intramuscularly after reconstitution of the vial with the solvent in the pre-filled syringe. Patients should be instructed to use the accompanying syringes, calibrated in FSH units, for injection of the reconstituted GONAL-f 450 IU (33 μg) or 1050 IU (77 μg) Multi-Dose.

The 27-gauge injection syringe has unit dose markings from 37.5-600 IU FSH (2.8- 44 μg) for use with GONAL-f 450 IU (33 μg) or 1050 IU (77 μg) Multi-Dose.

Patients should be instructed to take a specific dose of GONAL-f 450 IU (33 μg) or 1050 IU (77 μg) Multi-Dose. The doctor, nurse, or pharmacist should show the patient how to locate the syringe marking that corresponds to the prescribed dose.

The 450 IU (33 μg) and 1050 IU (77 μg) reconstituted solutions can be kept for 28 days, when stored at room temperature (at or below 25°C).

acute pulmonary distress.

thromboembolism.

abdominal pain, nausea, vomiting, diarrhea, abdominal cramps, bloating.

mild to severe injection site reaction (e.g. pain, redness, bruising, swelling and/or irritation at the site of injection).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

severe OHSS, complications of severe OHSS (adnexal torsion, hemoperitoneum).

Safety data on GONAL-f (follitropin alpha for injection) stem from clinical studies, as well as 10 years of post-marketing surveillance.

The most commonly reported adverse reactions with GONAL-f in clinical studies were ovarian cysts, injection site reaction of any severity, headache, mild to moderate OHSS manifesting with symptoms such as abdominal swelling and pain, ovarian enlargement, as well as gastrointestinal symptoms such as nausea, vomiting, and diarrhoea.

The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of GONAL-f, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) was severe OHSS and its associated complications, such as adnexal torsion, thromboembolic events, haemoperitoneum and acute pulmonary distress (see Warnings and Precautions).

Severe OHSS was also the most frequently reported serious adverse reaction (see Warnings and Precautions). Complications of severe OHSS have been reported both in clinical studies and from spontaneous sources.

More than 1000 patients were exposed to r-hFSH during the clinical development programme of GONAL-f. In addition to the clinical trial patient population, it is estimated that 580 000 to 1 700 000 patients have been exposed to r-hFSH during the post-marketing phase. The following summary presents the adverse drug reactions that have been reported with the use of r-hFSH during clinical trials and during post-market use. These data provide a comprehensive description of the safety profile of GONAL-f.

mild systemic allergic reactions (e.g. erythema, rash or facial swelling), anaphylactic-like reactions, which can manifest by one or more of the following signs/symptoms: urticaria, diffuse edema and erythema, facial swelling, difficulty in breathing.

The common and very common ADRs have been reported from clinical studies, as well as in post-marketing surveillance. Severe OHSS has been reported from clinical studies, as well as in post-marketing surveillance. However, the rare and very rare ADRs, such as complications of severe OHSS and allergic reactions, have generally been reported from post-marketing sources.

The following adverse reactions reported during gonadotropin therapy are listed in decreasing order of potential severity: pulmonary and vascular complications (see Warnings and Precautions); ovarian hyperstimulation syndrome (see Warnings and Precautions); 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; 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 labour, 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 four birth defects have been reported following urofollitropin-hCG or urofollitropin, Pergonal (menotropins for injection, USP)-hCG therapy in clinical trials for stimulation prior to in vitro fertilization. The aborted pregnancies included one Trisomy 13, one Trisomy 18, and one fetus with multiple congenital anomalies (hydrocephaly, omphalocele, and meningocele). One meningocele, one external ear defect, one dislocated hip and ankle, and one 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.

GONAL-f multi-dose was examined in twenty-five healthy volunteers who received 300 IU (22 μg) each of GONAL-f from single-dose ampoules 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.

Before treatment with GONAL-f is instituted, a thorough gynaecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy.

Each single dose vial of sterile, lyophilized powder, intended for s.c. or i.m. injection after reconstitution, contains: FSH activity 75 IU. Diluent provided for reconstitution is Sterile Water for Injection USP. Nonmedicinal ingredients: disodium phosphate dehydrate, methionine, polysorbate 20, sodium dihydrogen phosphate monohydrate and sucrose. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Single dose vials of 3 mL (nominal capacity). Packages of 1 vial accompanied by 1 glass vial (2 mL) Sterile Water for Injection USP or 1 mL pre-filled syringe WFI, Ph.Eur., 1×27-gauge injection needle and 1 mixing needle.

Each multidose vial of sterile, lyophilized powder contains: FSH activity 1050 IU. Diluent provided for reconstitution is Bacteriostatic Water for Injection USP (0.9% benzyl alcohol). Nonmedicinal ingredients: disodium phosphate dihyrate, sodium dihydrogen phosphate monohydrate and sucrose. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Multidose vials of 3 mL (nominal capacity). Packages of 1 vial accompanied by 2 mL pre-filled BWFI syringe, 15 injection syringes with attached 27G×0.5 inch needle and calibrated in FSH units (IU FSH).

Each single dose vial of sterile, lyophilized powder, intended for s.c. or i.m. injection after reconstitution, contains: FSH activity 150 IU. Diluent provided for reconstitution is Sterile Water for Injection USP. Nonmedicinal ingredients: disodium phosphate dehydrate, methionine, polysorbate 20, sodium dihydrogen phosphate monohydrate and sucrose O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Single dose vials of 3 mL (nominal capacity). Packages of 1 vial accompanied by 1 glass vial (2 mL) Sterile Water for Injection USP or 1 mL pre-filled syringe WFI, Ph.Eur., 1×27-gauge injection needle and 1 mixing needle.

Each multidose vial of sterile, lyophilized powder contains: FSH activity 450 IU. Diluent provided for reconstitution is Bacteriostatic Water for Injection USP (0.9% benzyl alcohol). Nonmedicinal ingredients: disodium phosphate dihyrate, sodium dihydrogen phosphate monohydrate and sucrose. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Multidose vials of 3 mL (nominal capacity). Packages of 1 vial accompanied by 1 mL pre-filled BWFI syringe, 6 injection syringes with attached 27G×0.5 inch needle and calibrated in FSH units (IU FSH).

Each single dose vial of sterile, lyophilized powder, intended for s.c. or i.m. injection after reconstitution, contains: FSH activity 37.5 IU. Diluent provided for reconstitution is Sterile Water for Injection PhEur/USP. Nonmedicinal ingredients: disodium phosphate dehydrate, methionine, polysorbate 20, sodium dihydrogen phosphate monohydrate and sucrose. O-phosphoric acid and/or sodium hydroxide may be used for pH adjustment prior to lyophilization. Single dose vials of 3 mL (nominal capacity). Packages of 1 vial accompanied by 1 glass vial (2 mL) of Sterile Water for Injection USP or 1 mL pre-filled syringe WFI, Ph.Eur., 1×27-gauge injection needle and 1 mixing needle.

Not indicated for treatment in the geriatric population.

There have been no reports of abuse or dependence with GONAL-f.

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.

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. The causality of these neoplasms has not been established. Although, to date, the results of recent epidemiological studies do not suggest a causal relationship between the use of gonadotropins in ART and the occurrence of neoplasms, long term follow-up studies are still ongoing.

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.

In women with generally recognized risk factors for thrombo-embolic events, such as personal or family history, treatment with gonadotropins may further increase the risk. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thrombo-embolic events.

Careful attention should be given to diagnosis in candidates for GONAL-f (follitropin alpha for injection) therapy (see Indications and Clinical Use, Selection of Patients).

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 Monitoring and 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.

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 Reactions) and the risk of multiple births should also be discussed.

Before starting treatment, the couple’s infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and pituitary or hypothalamus tumours, and appropriate specific treatment given.

During training of the patient for self-administration, special attention should be given to specific instructions for the use of the multidose and/or monodose preparations.

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 two or three 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 Monitoring and Laboratory Tests), treatment should be discontinued and hCG should not be administered. This will reduce the chances of development of the Ovarian Hyperstimulation Syndrome (OHSS).

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.

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 diarrhoea. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see Cardiovascular and Respiratory). 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 6.0% 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.

To minimize the risk of OHSS or of multiple pregnancy, ultrasound scans, as well as serum oestradiol measurements are recommended.

When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be considered.

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 Monitoring and Laboratory Tests), the hCG should not be administered.

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.

No studies on the effects on the ability to drive and use machines have been performed.

Not indicated for treatment in pediatric population.

In patients undergoing ovarian stimulation, the incidence of multiple pregnancies is increased as compared with natural conception. 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 partner should be advised of the potential risk of multiple births before starting treatment.

Since women with infertility undergoing assisted reproduction, and particularly IVF, often have tubal abnormalities, the incidence of ectopic pregnancies might be increased. The prevalence of ectopic pregnancies after IVF was reported to be 2 to 5%, as compared to 1 to 1.5% in the general population. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

The incidence of pregnancy wastage by miscarriage or abortion may be higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than in the normal population.

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conception. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

Impaired fertility has been reported in rats exposed to pharmacological doses of r-hFSH (40 IU/kg/day) for extended periods through reduced fecundity.

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. To date, no particular malformative effect has been reported. No teratogenic effect has been observed in animal studies.

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. During lactation, the secretion of prolactin can entail a poor response to ovarian stimulation.

No studies have been conducted with special populations and conditions.

GONAL-f (follitropin alpha for injection) 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 LH surge, 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.

One main pharmacodynamics study has been performed in healthy female volunteers down-regulated with a GnRH agonist (Study 5117). The aim of this study was to assess pharmacodynamic characteristics of r-hFSH administered subcutaneously daily for one week. After subcutaneous administration over one week, the first pharmacodynamic marker of ovarian response to FSH was serum inhibin, followed by plasma E2 and follicular growth. When FSH administration was stopped, inhibin levels dropped, while E2 continued to rise for one day and follicle size further increased during four days.

Two thirds of the volunteers developed significant follicular growth followed by corresponding decreasing levels of inhibin and increasing levels of E2 secretion. Moreover, no correlation was found between maximal serum FSH concentrations during administration and the maximal E2 responses, inhibin responses and follicular growth responses.

Following intravenous administration, GONAL-f is distributed to the extracellular fluid space with an initial half-life of approximately 2 hours and eliminated from the body with a terminal half-life of approximately 1 day. The steady-state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the GONAL-f dose is excreted in the urine.

Following subcutaneous or intramuscular administration, the absolute bioavailability is 70%. Following repeated administration, GONAL-f accumulates 3-fold at steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, GONAL-f has been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.