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Follistim (Follitropin Beta) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Follistim® (follitropin beta for injection) contains human follicle-stimulating hormone (hFSH), a glycoprotein hormone which is manufactured by recombinant DNA (rDNA) technology. Follitropin beta has a dimeric structure containing two glycoprotein subunits (alpha and beta). Both the 92 amino acid alpha-chain and the 111 amino acid beta-chain have complex heterogeneous structures arising from two N-linked oligosaccharide chains. Follitropin beta is synthesized in a Chinese hamster ovary (CHO) cell line that has been transfected with a plasmid containing the two subunit DNA sequences encoding for hFSH. The purification process results in a highly purified preparation with a consistent hFSH isoform profile and high specific activity. The biological activity is determined by measuring the increase in ovary weight in female rats. The intrinsic luteinizing hormone (LH) activity in follitropin beta is less than 1 IU per 40,000 IU FSH. The compound is considered to contain no LH activity.

The amino acid sequence and tertiary structure of the product are indistinguishable from that of human follicle-stimulating hormone (hFSH) of urinary source. Also, based on available data derived from physio-chemical tests and bioassay, follitropin beta and follitropin alfa, another recombinant follicle-stimulating hormone product, are indistinguishable.

Follistim® is presented as a sterile, freeze-dried cake, intended for SUBCUTANEOUS or INTRAMUSCULAR administration after reconstitution with Sterile Water for Injection, USP. Each vial of Follistim® contains 75 IU of FSH activity plus 25.0 mg sucrose, NF; 7.35 mg sodium citrate dihydrate, USP; 0.10 mg polysorbate 20, NF, and hydrochloric acid, NF and/or sodium hydroxide, NF to adjust the pH in a sterile, lyophilized form. The pH of the reconstituted preparation is approximately 7.0. The recombinant protein in Follistim® has been standardized for FSH in vivo bioactivity in terms of the First International Reference Preparation for human menopausal gonadotropins (code 70/45), issued by the World Health Organization Expert Committee on Biological Standardization (1982). Under current storage conditions, Follistim® may contain up to 20% of oxidized follitropin beta.

In clinical trials with Follistim®, serum antibodies to FSH or anti-CHO cell derived proteins were not detected in any of the treated patients after exposure to Follistim® for up to three cycles.

Therapeutic Class: Infertility.

[As determined by the Ph. Eur. test for FSH in vivo bioactivity and on the basis of the molar extinction coefficient at 277 nm (εs:mg-1cm-1) = 1.066.]

CLINICAL PHARMACOLOGY

Follistim® (follitropin beta for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Follistim®, is required for normal follicular growth, maturation, and gonadal steroid production. In the female, the level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. In order to effect the final phase of follicle maturation, resumption of meiosis and rupture of the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Follistim® when patient monitoring indicates that appropriate follicular development parameters have been reached.

Pharmacokinetics

Absorption

The bioavailability of Follistim® following subcutaneous and intramuscular administration was investigated in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. After subcutaneous or intramuscular injection the apparent dose absorbed was 77.8% and 76.4%, respectively.

The subcutaneous (455.6 ± 141.4 IU*h/L) and intramuscular (445.7 ± 135.7 IU*h/L) routes of administration were equivalent with respect to area under the curve (AUC) in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. However, equivalence could not be established for Cmax between the subcutaneous (5.41 ± 0.72 IU/L) and intramuscular (6.86 ± 2.90 IU/L) routes of administration.

The pharmacokinetics and pharmacodynamics of a single, intramuscular dose (300 IU) of Follistim® were also investigated in a group of gonadotropin-deficient, but otherwise healthy women. Peak (Cmax) serum FSH levels in these women were 4.3 ± 1.7 IU/L (mean ± SD) and it occurred approximately 27 hours after intramuscular administration.

A multiple, dose proportionality, pharmacokinetic study of Follistim® was completed in healthy, pituitary-suppressed, female subjects given intramuscular doses of 75 IU, 150 IU or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached with all doses after 4 days of treatment based on the minimum concentrations of FSH just prior to dosing (Cmin). Peak blood concentrations with the 75 IU, 150 IU, and 225 IU dose were 4.65 ± 1.49 IU/L, 9.46 ± 2.57 IU/L and 11.30 ± 1.77 IU/L, respectively.

A multiple, dose proportionality, pharmacokinetic study of Follistim® was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75 IU, 150 IU, or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached with all doses after 5 days of treatment based on the minimum concentrations of FSH just prior to dosing (C min). Peak blood concentrations with the 75 IU, 150 IU, and 225 IU dose were 4.30 ± 0.60 IU/L, 8.51 ± 1.16 IU/L and 13.92 ± 1.81 IU/L, respectively.

Distribution

The volume of distribution of Follistim® in healthy, pituitary-suppressed, female subjects following intravenous administration of a 300 IU dose was approximately 8 L.

Metabolism

The recombinant FSH in Follistim® is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.

Elimination

The elimination half-life following a single intramuscular dose (300 IU) of Follistim® in female subjects was 43.9 ± 14.1 hours (mean ± SD). The elimination half-life following a 7-day intramuscular treatment with 75 IU, 150 IU or 225 IU was 26.9 ± 7.8 hours (mean ± SD), 30.1 ± 6.2 and 28.9 ± 6.5, respectively.

Special Populations

The effect of body weight on the pharmacokinetics of Follistim® was evaluated in a group of European and Japanese women who were significantly different in terms of body weight. The European subjects had a body weight of (mean ± SD) 67.4 ± 13.5 kg and the Japanese subjects were 46.8 ± 11.6 kg. Following a single intramuscular dose of 300 IU of Follistim®, the AUC (IU*h/L) was significantly smaller in European subjects (339 ± 105) than in Japanese subjects (544 ± 201). However, clearance per kg of body weight was essentially the same for the respective groups (0.014 and 0.013 1*h-1kg-1).

Clinical Studies

The efficacy of Follistim® was established in four controlled, clinical studies [three studies for Assisted Reproductive Technologies (ART) and one study for Ovulation Induction], three of which are described below. In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.

Assisted Reproductive Technologies (ART)

Results from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® (Protocol 37608) in 981 infertile women treated for one cycle with in vitro fertilization with Follistim® or Metrodin® after pituitary suppression with a GnRH agonist are summarized in Table I.

Table I. Results From a Randomized, Assessor-blind, Group Comparative, Multicenter Safety and Efficacy Study of Follistim® (Protocol 37608) in Infertile Women Treated With In Vitro Fertilization With Follistim® or Metrodin® After Pituitary Suppression With a GnRH Agonist 1
Parameter Follistim ®
(n=585)
Metrodin ®
(n=396)
Total number of oocytes recovered10.99.0
Number of mature oocytes recovered9.17.3
Maximum serum estradiol before
hCG (pmol/L) 2
66375692
Treatment duration (days)11.0
(range 1-29)
11.6
(range 1-21)
Ongoing 3 pregnancy rate/attempt22.2%18.2%
Ongoingpregnanvy rate/transfer 4 26.0%22.0%

1 All values are means
2 Conversion factor to pg/mL is 3.671
3 A single vital or multiple vital pregnancy was termed ongoing when a pregnancy, at least 12 weeks after embryo transfer (ET), was confirmed by the investigator
4 Transfers were limited to a maximum of three embryos

Metrodin® is a registered trademark of Serono Laboratories, Inc., Randolph, MA 02368.

The outcomes of the 286 clinical pregnancies (179 in Follistim® and 107 in Metrodin®) are shown in Table II:

Table II. Outcome for All Clinical 1 Pregnancies
Follistim ®
(n=179)
Metrodin ®
(n=107)
Did not result in live birth50 (28%)35 (33%)
Single birth87 (49%)43 (40%)
Multiple birth42 (23%)29 (27%)

1 Clinical pregnancies included ongoing pregnancies as well as miscarriages with or without proof of a vital fetus

Results from a randomized, assessor-blind, group comparative, single center safety and efficacy study of Follistim® (Protocol 37604) in 89 infertile women treated with in vitro fertilization with Follistim® or Humegon® without pituitary suppression with a GnRH agonist are summarized in Table III.

Table III. Results From a Randomized, Assessor-blind, Group Comparative, Single Center Safety and Efficacy Study of Follistim (Protocol 37604) in Infertile Women Treated With In Vitro Fertilization With Follistim or Humegon Without Pituitary Suppression With a GnRH Agonist 1
ParameterFollistim®
(n=54)
Humegon®
(n=35)
Total number of oocytes recovered9.97.6
Number of mature oocytes recovered9.46.9
Maximum serum estradiol before hCG (pmol/L) 2 37913087
Treatment duration (days)5.8
(range 1-9)
6.0
(range 2-10)
Ongoing 3 pregnancy rate/attempt22.2%17.1%
Ongoing pregnancy rate/transfer 4 30.8%22.2%

1 All values are means
2 Conversion factor to pg/mL is 3.671
3 A single vital or multiple vital pregnancy was termed ongoing when a pregnancy, at least 12 weeks after embryo transfer (ET), was confirmed by the investigator
4 Transfers were limited to a maximum of three embryos

The outcomes of the 22 clinical pregnancies (14 in Follistim® and 8 in Humegon®) are shown in Table IV:

Table IV. Outcome for all Clinical 1 Pregnancies
Follistim ®
(n=14)
Humegon ®
(n=8)
Did not result in live birth2 (14%)2 (25%)
Single birth7 (50%)4 (50%)
Multiple birth5 (36%)2 (25%)

1 Clinical pregnancies included ongoing pregnancies as well as miscarriages with or without proof of a vital fetus

Ovulation Induction

Results from a randomized, assessor-blind, group comparative, multicenter safety and efficacy study of Follistim® (Protocol 37609) in 172 chronic anovulatory women who failed to ovulate and/or conceive during clomiphene citrate treatment are summarized in Tables V, VI, and VII.

Table V. Cumulative Ovulation Rates from Protocol 37609
Follistim ®
(n=105)
Metrodin ®
(n=67)
First treatment cycle72%63%
Second treatment cycle82%79%
Third treatment cycle85%82%
Table VI. Cumulative Ongoing 1 Pregnancy Rates from Protocol 37609
Follistim ®
(n=105)
Metrodin ®
(n=67)
First treatment cycle14%10%
Second treatment cycle19%18%
Third treatment cycle23%19%

1 All ongoing pregnancies were confirmed after at least 12 weeks after the hCG injection

The outcomes of the 56 clinical pregnancies (35 in Follistim® and 21 in Metrodin®) are shown in Table VII:

Table VII. Outcome for all Clinical 1 Pregnancies
Follistim ®
(n=35)
Metrodin ®
(n=21)
Did not result in live birth11 (31%)8 (38%)
Single birth22 (63%)12 (57%)
Multiple birth2 (6%)1 (5%)

1 Clinical pregnancies included ongoing pregnancies as well as miscarriages with or without proof of a vital fetus

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