April 27, 2017
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Gonal-F

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Gonal-F




CLINICAL PHARMACOLOGY

Gonal-f® (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Gonal-f® is the primary hormone responsible for follicular recruitment and development. In order to effect final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Gonal-f® when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration. The physico-chemical, immunological, and biological activities of recombinant FSH (r-hFSH) are comparable to those of pituitary and human menopausal urine-derived FSH. Gonal-f® (follitropin alfa for injection), when administered with hCG, stimulates spermatogenesis in men with hypogonadotropic hypogonadism. FSH, the active component of Gonal-f® , is the primary hormone responsible for spermatogenesis.

Pharmacokinetics

Single dose pharmacokinetics of follitropin alfa were determined following intravenous, subcutaneous and intramuscular administration of 150 IU Gonal-f® to 12 healthy, down-regulated female volunteers. Steady-state pharmacokinetics were also determined in 12 healthy down-regulated female volunteers who were administered a single daily dose of 150 IU for seven days. These pharmacokinetics were confirmed in pituitary down-regulated women undergoing in vitro fertilization and embryo transfer (IVF/ET), treated with FSH doses of up to 450 IU per day. Additionally, single dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 225 IU Gonal-f® to 12 healthy adult male volunteers in a cross-over design. Steady state pharmacokinetics were also determined in 6 healthy adult male volunteers who were administered a single daily dose of 225 IU Gonal-f® for 7 days. No significant difference in pharmacokinetics is expected in males versus females when administered Gonal-f® subcutaneously. The pharmacokinetic parameters from these studies are included in Table 1.

Table 1: Pharmacokinetic parameters (mean ± SD) of FSH following administration of Gonal-f®

Population Female   Male
Healthy Female Volunteers IVF/ET
Patients
Healthy Male Volunteers
Dose (IU) Single Dose
IM
(150 IU)
Single Dose
SC
(150 IU)
Multiple
Dose
SC
(7 × 150 IU)
Multiple
Dose
SC
(5 × 225IU)*
Single Dose
SC
(225IU)
Multiple
Dose
SC
(7 × 225 IU)
AUC (IU-hr/L) 206 ± 66 176 ± 87 187 ± 61 - 220 ± 109 186 ± 23
Cmax(IU/L) 3 ± 1 3 ± 1 9 ± 3 - 2.5 ± 0.8 8.3 ± 0.9
tmax(hr) 25 ± 10 16 ± 10 8 ± 6 - 20 ± 14 10.7 ± 6.7
t1/2terminal (hr) 50 ± 27 24 ± 11 24 ± 8 - 41 ± 14 32 ± 4
CL/F (L/hr) - - - 32 0.86 ± 0.48 0.90 ± 0.12
V/F (L) - - - 0.7 ± 0.2 - -
F (%) 76 ± 30 66 ± 39 - 10 ± 3 - -
Abbreviations are: IVF/ET: in vitro fertilization/embryo transfer;
Cmax: peak concentration (above baseline);
tmax: time of Cmax;
CL/F: apparent clearance;
V/F: apparent volume of distribution; calculated using a one-compartment model.
t1/2: absorption half-life;
F: bioavailability compared to IV
*First five days of fixed regimen followed by adjustment of the dose depending on response
Steady-state AUC (After the 144-168 7th daily SC dose)
increases with body mass index

Absorption

The absorption rate of Gonal-f® following subcutaneous or intramuscular administration was found to be slower than the elimination rate. Hence the pharmacokinetics of Gonal-f® are absorption rate-limited.

Distribution

Human tissue or organ distribution of FSH has not been determined for Gonal-f® . After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two compartment open model with a distribution half-life of about 2-2.5 hours. Steady-state serum levels were reached after 4 to 5 days of daily administration.

Metabolism/Excretion

FSH metabolism following administration of Gonal-f® has not been studied in humans. Total clearance after IV administration in healthy females was 0.6 L/hr; mean residence time was 17-20 hours. FSH renal clearance was 0.07 L/hr after intravenous administration representing approximately 1/8 of total clearance.

Pharmacodynamics

Following daily subcutaneous administration of 150 IU of Gonal-f® for 7 days in healthy female volunteers, serum inhibin and estradiol, and total follicular volume responded as a function of time, with pronounced inter-individual variability. Pharmacodynamic effect lagged behind FSH serum concentration. Of the three pharmacodynamic parameters, serum inhibin levels responded with the least delay and declined rapidly after discontinuation of Gonal-f® . Follicular growth was most delayed and continued even after discontinuation of Gonal-f® administration, and after serum FSH levels had declined. Maximum follicular volume was better correlated with either inhibin or estradiol peak levels than with FSH concentration. Inhibin rise was an early index of follicular development. In healthy male volunteers, despite high interindividual variation and the absence of down-regulation, daily administration of 225 IU Gonal-f® was shown to increase the levels of inhibin to reach a plateau during the whole administration period and then return to baseline.

Population Pharmacokinetics And Pharmacodynamics

To establish the pharmacokinetics and pharmacodynamics of FSH in a target population, measurements performed during a clinical study of in vitro fertilization/embryo transfer were used in conjunction with pharmacokinetic data from studies in healthy female volunteers. The apparent clearance was comparable to that in healthy volunteers. The absorption rate was found to be influenced by the body mass index (BMI), suggesting that the higher the BMI, the lower the rate of absorption. However, FSH serum levels following fixed (during the first five days) and then adjusted doses of Gonal-f® were found to be poor predictors of follicular growth rate. High pre-treatment serum FSH levels may predict lower follicular growth rates.

Special Populations

Safety, efficacy, and pharmacokinetics of Gonal-f® in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions

No drug-drug interaction studies have been conducted (see PRECAUTIONS).

Clinical Studies

Women

The safety and efficacy of Gonal-f® have been examined in four clinical studies, two studies for ovulation induction and two studies for assisted reproductive technologies (ART). In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.

Ovulation Induction

The safety and efficacy of Gonal-f® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy (Study 5642).

The primary efficacy parameter was the ovulation rate. Two hundred and twenty-two patients entered into the first cycle of treatment, of whom 110 received Gonal-f® and 112 received urofollitropin. Ovulation rates were similar between Gonal-f® and urofollitropin treatment groups. The study results for the 222 patients who received treatment in at least one cycle are summarized in Table 2.

Table 2: Cumulative Patient Ovulation and Clinical Pregnancy Rates by Treatment Group in Ovulation Induction

Study 5642 Gonal-f® (n=110) Urofollitropin
(n=112)
Cumulative Ovulation Rate
  Cycle 1 64% 59%
  Cycle 2 78% 82%
  Cycle 3 84% 91%
Cumulative Clinical Pregnancy* Rate
  Cycle 1 21% 21%
  Cycle 2 28% 38%
  Cycle 3 35% 46%
*A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34 -36 after hCG administration.

For the 90 patients who had a clinical pregnancy (39 in Gonal-f® group; 51 in urofollitropin group), the outcome of the pregnancy was:

Table 3: Pregnancy Outcome by Treatment Group in Ovulation Induction

Study 5642 Gonal-f® (n=39) Urofollitropin
(n=51)
Pregnancies not reaching term 20.5% 13.7%
Single births 74.4% 74.5%
Multiple births 5.1% 11.8%

A second randomized, comparative, open-label, multicenter study was conducted in 23 U.S. centers (Study 5727). The primary efficacy parameter was ovulation rate. Ovulation rates were similar between Gonal-f® and urofollitropin treatment groups. Two hundred and thirty-two patients with oligoanovulatory infertility received treatment with up to three cycles of Gonal-f® administered subcutaneously (118 patients) or urofollitropin administered intramuscularly (114 patients).

The cumulative patient ovulation rate and clinical pregnancy rates by cycle are presented for the 232 patients who received treatment in at least one cycle.

Table 4: Cumulative Patient Ovulation and Clinical Pregnancy Rates by Treatment Group in Ovulation Induction

Study 5727 Gonal-f® (n=118) Urofollitropin
(n=114)
Cumulative Ovulation Rate
  Cycle 1 58% 68%
  Cycle 2 72% 86%
  Cycle 3 81% 93%
Cumulative Clinical Pregnancy* Rate
  Cycle 1 13% 14%
  Cycle 2 25% 25%
  Cycle 3 37% 36%
*A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34 -36 after hCG administration.

For the 85 patients who had a clinical pregnancy (44 in Gonal-f® group; 41 in urofollitropin group), the outcome of the pregnancy is shown in Table 5.

Table 5: Pregnancy Outcome by Treatment Group in Ovulation Induction

Study 5727 Gonal-f®
(n=44)
Urofollitropin (n=41)
Pregnancies not reaching term 22.7% 22.0%
Single births 63.6% 65.9%
Multiple births 13.7% 12.2%

Assisted Reproductive Technologies (ART)

The safety and efficacy of Gonal-f® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for In Vitro Fertilization and Embryo Transfer (IVF/ET) after pituitary down-regulation with a GnRH agonist (Study 5503). The purpose of the study was to demonstrate that Gonal-f® , administered subcutaneously, was clinically not different in terms of safety and efficacy from urofollitropin, administered intramuscularly. The initial and maximal doses of Gonal-f® were 225 and 450 IU, respectively. The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration. One hundred and twenty-three patients were randomized and received either Gonal-f® (60 patients) or urofollitropin (63 patients).

The results summarized in Table 6 are mean data with Gonal-f® and urofollitropin administered to ovulatory infertile women undergoing multiple follicular development for IVF/ET.

Table 6: Treatment Outcomes by Treatment Group in ART

Study 5503 Gonal-f®
(n=60)
Urofollitropin
(n=63)
Mean number of follicles ≥ 14mm
diameter on day of hCG
7.8 9.2
Mean number of oocytes recovered per patient 9.3 10.7
Mean Serum E2 (pg/mL) on day of hCG 1576 2193
Mean treatment duration in days (range) 9.9 (5-20) 9.4 (5-14)
Clinical pregnancy* rate per attempt 20% 16%
Clinical pregnancy* rate per embryo
transfer
24% 19%
*A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34 -36 after hCG administration.

For the 22 patients who had a clinical pregnancy (12 in Gonal-f® group; 10 in urofollitropin group), the outcome of the pregnancy is shown in Table 7.

Table 7: Pregnancy Outcome by Treatment Group in ART

Study 5503 Gonal-f®
(n=12)
Urofollitropin (n=10)
Pregnancies not reaching term 25.0% 20.0%
Single births 41.7% 50.0%
Multiple births 33.3% 30.0%

A second randomized, comparative, open-label, multicenter study was conducted in 7 U.S. centers (Study 5533). One hundred and fourteen patients with ovulatory infertility undergoing IVF/ET were randomized and received either Gonal-f® by subcutaneous administration (56 patients) or urofollitropin by intramuscular administration (58 patients) following pituitary down-regulation with a GnRH agonist. The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration. Results are summarized in Table 8.

Table 8: Treatment Outcomes by Treatment Group in ART

Study 5533 Gonal-f®
(n=56)
urofollitropin
(n=58)
Mean number of follicles ≥ 14mm
diameter on day of hCG
7.2 8.3
Mean number of oocytes recovered per patient 9.3 12.3
Mean Serum E2 (pg/mL) on day of hCG 1236 1513
Mean treatment duration in days (range) 10.1(5-15) 9.0 (5-12)
Clinical pregnancy* rate per attempt 21% 22%
Clinical pregnancy* rate per embryo
transfer
26% 25%
*A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34 -36 after hCG administration.

For the 25 patients who had a clinical pregnancy (12 in Gonal-f® group; 13 in urofollitropin group), the outcome of the pregnancy is shown in Table 9.

Table 9: Pregnancy Outcome by Treatment Group in ART

Study 5533 Gonal-f®
(n=12)
Urofollitropin (n=13)
Pregnancies not reaching term 33.3% 30.8%
Single births 41.7% 38.5%
Multiple births 25.0% 30.8%

Men

The safety and efficacy of Gonal-f® administered concomitantly with hCG have been examined in three open-label clinical studies for induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism.

The three multicenter studies involved three to six months of pretreatment with chorionic gonadotropin for injection to normalize serum testosterone levels, followed by 18 months of treatment with Gonal-f® and hCG. The objective of each study was induction of spermatogenesis (a sperm density of ≥ 1.5 × 106/mL).

Study 5844 enrolled 32 patients in six centers in the United Kingdom, France and Germany. The second trial, Study 6410, was conducted in Australia and enrolled 10 patients in two centers. Study 6793, conducted in 7 centers in the United States, was planned to enroll 32 patients. The interim data for the US study includes 30 of the planned 32 patients. For all 3 studies, a total of 72 patients were enrolled and received hCG and 56 of those patients entered the Gonal-f® treatment phase of the trials.

The populations enrolled in the three studies were similar: Study 5844 studied a naïve population who had had no prior treatment with gonadotropins; mean age was 25.9 (range 16 to 48) years, mean (± SD) testis volume was 2.0 ± 1.2 mL, and 12 of the 32 patients (37.5%) were anosmic. Thirty-one of the patients were Caucasian and one was Asian. In Study 6410, mean age was 36 (range 26 to 48) years, 6 and 1 of the 10 patients had previously been treated with gonadotropins and GnRH, respectively; mean testis volume was 4.5 ± 2.9 mL; and 2 of the 10 patients (20%) were anosmic. Seven patients were Caucasian and three were Asian. In the 30 patients reported in the interim analysis of Study 6793, the mean age was 30.1 (range 22 to 44) years; 4 and 3 of the 30 patients had been treated with gonadotropins and GnRH, respectively, in the past; mean testis volume was 4.4 ± 1.3 mL; and 10 of the 30 patients (33.3%) were anosmic. Twenty five of the patients were Caucasian, three were Asian, and one each of Moroccan and Indian ancestry.

The primary efficacy endpoint of all three studies was the achievement of a sperm density ≥ 1.5 × 106/mL. The study results for the patients treated with Gonal-f® and hCG are summarized in Table 10.

Table 10: Number of Men Receiving Gonal-f® Who Achieved a Sperm Density ≥ 1.5 × 106/mL

  Study 5844
(n=26)
Study 6410
(n=8)
Study 6793
(n=22)*
Sperm Concentration ≥ 1.5 × 106/mL      
    Yes 12 (46.2%) 5 (62.5%) 14 (63.6%)
    No 14 (53.8%) 3 (37.5%) 8 (36.4%)
    95% Confidence Interval (26.6% -
66.6%)
(24.5% -
91.5%)
(40.7% -
82.8%)
*Interim data

The time to achievement of the primary efficacy endpoint is summarized in Table 11.

Table 11: Time to Achievement of Sperm Density ≥ 1.5 × 10 / mL in Men Receiving Gonal-f®

  Study 5844
(n=26)
Study 6410
(n=8)
Study 6793
(n=22)*
Number of Men Achieving Sperm Concentration      
    n 12 5 14
Time (Months) to Sperm Concentration ≥ 1.5 × 106/mL 5 (71%) 2 (20%) 1 (5%)
    Median 12.4 9.1 6.8
    Range (2.7 – 18.1) (8.8 – 11.7) (2.8 – 15.7)
*Interim data

Table 12: Pregnancy Outcome in Partners of Men Desiring Fertility

  Study 5844
(n=7)
Study 6410
(n=10)
Study 6793
(n=20)*
Pregnancy 6 (86%) 3 (30%) 3 (15%)
Pregnancy not reaching term 1 (14%) 1 (10%) 2 (10%)
Single births 5 (71%) 2 (20%) 1 (5%)
*Interim data

Of the 56 patients who received Gonal-f® in Studies 5844, 6410, and 6793, 12 pregnancies were achieved in 10 partners of the 37 patients who were seeking pregnancy and who currently had a partner during the studies. Thus, pregnancy (clinical and chemical) was documented to have been achieved by 27% of the patients' partners seeking pregnancy during the exposure period to Gonal-f® in the 3 trials. Eight pregnancies continued to term, and 8 healthy babies were born to 7 couples as a result of those studies.

Last reviewed on RxList: 10/7/2016
This monograph has been modified to include the generic and brand name in many instances.

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