Gonal-f Dailymed

 

Prior to initiation of treatment with GONAL-F: Perform a complete gynecologic and endocrinologic evaluation Exclude primary ovarian failure Exclude the possibility of pregnancy Demonstrate tubal patency Evaluate the fertility status of the male partner The dosing scheme is stepwise and is individualized for each woman [see Clinical Studies (14.1)]. Administer a starting dose of 75 International Units of GONAL-F subcutaneously daily for 14 days in the first cycle of use. In subsequent cycles of treatment, determine the starting dose (and dosage adjustments) of GONAL-F based on the woman's history of the ovarian response to GONAL-F. If indicated by the ovarian response after the initial 14 days, make an incremental adjustment in dose of up to 37.5 International Units. If indicated by the ovarian response, make additional incremental adjustments in the dose, up to 37.5 International Units, every 7 days. Continue treatment until follicular growth and/or serum estradiol levels indicate an adequate ovarian response. Consider the following when planning the woman's individualized dose: Use the lowest dose of Gonal-F consistent with the expectation of good results. Use appropriate GONAL-F dose adjustment(s) to prevent multiple follicular growth and cycle cancellation. The maximum, individualized, daily dose of GONAL-F is 300 International Units per day. In general, do not exceed 35 days of treatment, unless an estradiol rise indicates imminent follicular development. When pre-ovulatory conditions are reached, administer human chorionic gonadotropin (hCG) to induce final oocyte maturation and ovulation. Human chorionic gonadotropin, hCG, (5,000 USP units) should be given 1 day after the last dose of GONAL-F. Encourage the woman and her partner to have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent. Withhold hCG in cases where the ovarian monitoring suggests an increased risk of ovarian hyperstimulation syndrome (OHSS) on the last day of GONAL-F therapy (for example estradiol greater than 2,000 pg per mL) [see Warnings and Precautions (5.2, 5.3, 5.5, 5.11)]. Discourage intercourse when the risk for OHSS is increased [see Warnings and Precautions (5.2, 5.5)]. Schedule a follow-up visit in the luteal phase. Individualize the initial dose administered in subsequent cycles based on the woman's response in the preceding cycle. As in the initial cycle, do not administer doses larger than 300 International Units of FSH per day. Administer 5,000 USP units of hCG 1 day after the last dose of GONAL-F to complete follicular development and induce ovulation. Follow the above recommendations to minimize the chance of development of OHSS.

Prior to initiation of treatment with GONAL-F: Perform a complete gynecologic and endocrinologic evaluation, and diagnose the cause of infertility Exclude the possibility of pregnancy Evaluate the fertility status of the male partner The dosing scheme follows a stepwise approach and is individualized for each woman. Beginning on cycle day 2 or 3, administer subcutaneously a starting dose of 150 International Units of GONAL-F daily until sufficient follicular development, as determined by ultrasound in combination with measurement of serum estradiol levels, is attained. In most cases, therapy should not exceed ten days. In women whose endogenous gonadotropin levels are suppressed, initiate GONAL-F administration at a dose of 225 International Units per day. Adjust the dose after 5 days based on the woman's ovarian response, as determined by ultrasound evaluation of follicular growth and serum estradiol levels. Do not make additional dosage adjustments more frequently than every 3-5 days or by more than 75-150 International Units at each adjustment. Continue treatment until adequate follicular development is evident, and then administer hCG (5,000 to 10,000 USP units) to induce final follicular maturation in preparation for oocyte retrieval. Withhold hCG administration in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of GONAL-F therapy [see Warnings and Precautions (5.2, 5.3, 5.4, 5.11)]. Do not use doses greater than 450 International Units per day.

Ovarian Hyperstimulation Syndrome (OHSS) is a medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a 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. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement [see Warnings and Precautions (5.6)], weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions [see Warnings and Precautions (5.4)]. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy, have been reported in association with OHSS. OHSS occurs after gonadotropin treatment has been discontinued and it can develop rapidly, reaching its maximum 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 Dosage and Administration (2.2, 2.3)], withhold hCG. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, assess women for the development of OHSS for at least two weeks after hCG administration. If serious OHSS occurs, stop gonadotropins, including GONAL-F and hCG, and consider whether the woman needs to be hospitalized. Treatment is primarily symptomatic and overall consists of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, avoid diuretics except in the late phase of resolution as described below. The management of OHSS is divided into three phases as follows: Acute Phase:Management is directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Thoroughly assess daily or more often, based on the clinical need, fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth. Treatment, consisting of limited intravenous fluids, electrolytes, human serum albumin, is intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Chronic Phase:After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction. Resolution Phase:As third space fluid returns to the intravascular compartment, a fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if necessary, to combat pulmonary edema. Do not remove ascitic, pleural, and pericardial fluid, unless there is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. OHSS increases the risk of injury to the ovary. Avoid pelvic examination or intercourse, as these may cause rupture of an ovarian cyst, which may result in hemoperitoneum. If bleeding occurs and requires surgical intervention, control the bleeding and retain as much ovarian tissue as possible. 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 (for example, atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported in women treated with gonadotropins, including GONAL-F. In addition, thromboembolic events both in association with, and separate from OHSS have been reported in women treated with gonadotropins, including GONAL-F. Intravascular thrombosis and embolism, which may originate in venous or arterial vessels, can result in reduced blood flow to critical organs or the extremities. Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarctions. In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of ovulation induction and Assisted Reproductive Technology (ART) need to be weighed against the risks. It should be noted that pregnancy also carries an increased risk of thrombosis.

Ovarian torsion has been reported after treatment with gonadotropins, including GONAL-F. This may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries. Early diagnosis and immediate detorsion limit damage to the ovary due to reduced blood supply.

Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased in women who become pregnant as a result of ART. Advise women who become pregnant following ART and have: abdominal/pelvic pain (particularly on one side); shoulder, neck or rectal pain; and nausea and vomiting to seek immediate medical attention. Confirm the presence of an intrauterine pregnancy early by β-hCG testing and transvaginal ultrasound.



Risk Summary GONAL-F is not indicated in pregnant women The incidence of congenital malformations after some Assisted Reproductive Technology, specifically in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)], may be slightly higher than that after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, maternal and paternal genetic background, sperm characteristics) and to a higher incidence of multi-fetal gestations after IVF or ICSI. There is no human data that the use of gonadotropins (including GONAL-F) alone or as part of IVF or ICSI cycles, increases the risk of congenital malformations. The risk of spontaneous abortion (miscarriage) is increased in women who have used gonadotropins products (including GONAL-F) to achieve pregnancy. In animal studies, the continuous administration of recombinant human FSH during pregnancy resulted in a decrease in the number of viable fetuses and difficult and prolonged delivery. No teratogenic effect has been observed. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Human Data Data on a limited number of exposed pregnancies indicate no adverse reactions of gonadotropins on pregnancy, embryonal or fetal development, parturition or postnatal development following controlled ovarian stimulation.

Because GONAL-F is not indicated in pregnant women, verify a negative pregnancy test before administering GONAL-F to a woman

Because GONAL-F is not indicated in pregnant women, verify a negative pregnancy test before administering GONAL-F to a woman [see Dosage and Administration (2.3, 2.4)].

The safety and efficacy of GONAL-F were examined in a randomized, open-label, multicenter, active-controlled trial conducted in the U.S in oligo-anovulatory infertile women. Women were randomized to GONAL-F , administered subcutaneously, or a comparator urofollitropin product, administered intramuscularly. The primary efficacy parameter was the ovulation rate. Two hundred and thirty-two women received treatment for up to three cycles with GONAL-F (118 women ) or urofollitropin (114 women). Ovulation results for women who received treatment with GONAL-F in at least one cycle are summarized in Table 5. Table 5: Cumulative Ovulation and Clinical Pregnancy Rates in Induction of Ovulation Trial Cycle Gonal-F (n=118) CumulativeCumulative rates were determined per woman over cycles 1, 2, and 3 Percent Ovulation Cumulative Clinical PregnancyClinical pregnancy was defined as a pregnancy for which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration Rate Cycle 1   58%Non-inferior to comparator recombinant human FSH based on a two-sided 95% confidence interval, intent-to-treat analysis.   13%Secondary efficacy outcomes. The trial was not powered to demonstrate differences in these outcomes. Cycle 2   72%   25% Cycle 3   81%   37 For the 44 woman in the GONAL-F group who achieved clinical pregnancy, 22.7 % did not reach a term pregnancy, 63.6% had singleton births and 13.7% had multiple births. An additional randomized, open-label, multinational, multicenter trial, active-comparator trial was conducted in oligo-anovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy. Results for the primary efficacy outcome of cumulative percent ovulation at Cycle 1 were similar to those presented in Table 5 for the U.S. ovulation induction trial.

The efficacy of GONAL-F in ART, was evaluated in a randomized,open-label, multicenter, active-controlled trial conducted ith the U.S, in ovulatory, infertile women undergoing stimulation of multiple follicles for In Vitro Fertilization (IVF) and Embryo Transfer (ET). All women received a gonadotrophin releasing hormone (GnRH) agonist for pituitary down-regulation before randomization and administration of GONAL-F (n=56) or a comparator urofollitropin product (n=58). The primary efficacy endpoint was the number of mature pre-ovulatory follicles on the day of hCG administration. The trial was not powered to demonstrate differences in secondary outcomes. Treatment outcomes for a single IVF cycle with controlled stimulation with GONAL-F are summarized in Table 6. Table 6: Treatment Outcomes with GONAL-F in an In Vitro Fertilization Trial in Ovulatory Women Gonal-F (n=56) Mean number of follicles ≥ 14mm diameter on day of hCGPrimary efficacy outcome (n=50) 7.2 Mean number of oocytes recovered per patientSecondary efficacy outcomes. The trial was not powered to demonstrate differences in these outcomes. (n=49) 9.3 Mean Serum E2 (pg/mL) on day of hCG (n=46) 1221 Mean treatment duration in days (range) (n=56) 10.1 (5-15) Clinical pregnancyClinical pregnancy was defined as a pregnancy for which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.rate per attempt (n=56) 20% Clinical pregnancy rate per embryo transfer (n=47) 23% For the 11 woman in the GONAL-F group who achieved clinical pregnancy, 36.3% did not reach a term pregnancy, 36.3% had singleton births and 27.3% had multiple births. An additional randomized, open-label, multinational, multicenter study in ovulatory infertile women was conducted in non-U.S. countries. Women were randomized to receive either GONAL-F by subcutaneous administration (60 women) or urofollitropin by intramuscular administration (63 women) after down-regulation of the pituitary with a GnRH agonist. The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration. Results over a single IVF cycle for the primary efficacy outcome of mature pre-ovulatory follicles on the day of hCG administration were similar to the primary efficacy results presented in Table 6 for the U.S.ART trial.

The efficacy of GONAL-F administered concomitantly with human chorionic gonadotropin (hCG) for induction of spermatogenesis in men with hypogonadotropic hypogonadism was established in three open-label, uncontrolled, non-randomized, multi-center, multi-national, escalating dose clinical trials (Trials 1, 2 and 3) conducted in 78 adult men (aged 16 to 48 years) with primary or secondary hypogonadotropic hypogonadism (defined as serum testosterone <100 ng/mL and low or normal FSH and LH) and azoospermia (sperm concentration <0.1×106/mL). Men were required at study entry to have normal serum cortisol and prolactin levels and be euthyroid. Men less than 21 years of age were required to have either confirmed anosmia or documented bone age >15 years to be eligible for study participation. Enrolled men received three to six months of pretreatment with hCG injection to normalize serum testosterone levels, followed by 18 months of treatment with GONAL-F and hCG. Of the 78 men enrolled in the trials, 63 men were treated with GONAL-F and hCG. Characteristics of the trial populations are shown in Table 7. Table 7. Trial Population Characteristics in Trials 1, 2 and 3 Trial 1 N=32 Trial 2 N=10 Trial 3 N=36 Median age (range) (years) 26 (16-48) 37 (26-48) 30 (20-44) Race n(%) Caucasian 31 (97) 7 (70) 31 (86) Asian 1 (3) 3 (30) 3 (8) African-American 0 0 0 Other 0 0 2 (6) Prior treatment with gonadotropin (FSH) or GnRHGonadotropin releasing hormone (GnRH) agonistProhibited in Trial 1 (%) 0 5 (50) 4 (11) Mean (SD) testis volume (mL)Mean testicular volume was required to be <4 mL in Trial 1 and <6 mL in Trial 3. Testicular size was not considered for enrollment into Trial 2. 2 (1) 5 (3) 4 (1) N(%) with anosmia (i.e. diagnosis of Kallmann's syndrome) 12 (37) 2 (20) 13 (36) The primary efficacy measure in all trials was the proportion of men achieving a sperm density ≥ 1.5 × 106/mL during treatment with Gonal-F. Pregnancy (clinical and chemical) in partners of men desiring fertility was a secondary endpoint. Efficacy results in men who received at least one dose of Gonal-F and had at least one follow-up assessment are summarized in Table 8 and Table 9. Table 8: Proportion of Men Receiving Gonal-F Who Achieved a Sperm Density ≥ 1.5 × 106/mL Trial 1 (n=26) Trial 2 (n=8) Trial 3 (n=29) Sperm Concentration ≥ 1.5 × 106/mL Yes 12 (46.2%) 5 (62.5%) 20 (80%) No 14 (53.8%) 3 (37.5%) 5 (20%) Missing 4 95% Confidence Interval (26.6% - 66.6%) (24.5% - 91.5%) (40.7% - 82.8%) Table 9: Pregnancy Outcome in Partners of Men Desiring Fertility Trial 1 (n=7)N reflects number of partners desiring pregnancy who had a partner at the time of enrollment, as not all enrolled men sought fertility Trial 2 (n=10) Trial 3 (n=26) , Pregnancy 6 (86%) 3 (30%) 5 (19%) Pregnancy not reaching term 1 (14%) 1 (10%) 2 (8%) Single full-term live births 5 (71%) 2 (20%) 3 (11%) The time to achievement of sperm density ≥1.5 × 106/mL is summarized in Table 10. Table 10: Time to Achievement of Sperm Density ≥ 1.5 × 106/ mL in Men Receiving Gonal-F Trial 1 (n=26) Trial 2 (n=8) Trial 3 (n=29) Number (%) of Men Achieving Sperm Concentration 22 (76) n 12 (46) 5 (62) Time (Months) to Sperm Concentration ≥ 1.5 × 106/mL Median 12.4 9.1 9 Range (2.7 – 18.1) (8.8 – 11.7) (2.8 – 18.2)

Ectopic Pregnancy Inform women undergoing ART that the incidence of ectopic pregnancy may be increased with these procedures, particularly for women with tubal abnormalities. Advise women who become pregnant and have: abdominal/pelvic pain (particularly on one side); shoulder, neck or rectal pain; and nausea and vomiting to seek immediate medical attention [see Warnings and Precautions (5.8)].