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Follistim AQ (Follitropin Beta Subcutaneous) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Follistim® AQ Cartridge (follitropin beta injection) contains human follicle-stimulating hormone (hFSH), a glycoprotein hormone which is manufactured by recombinant DNA (rDNA) technology. The active drug substance, 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. [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.] 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 follitropin beta are indistinguishable from that of human follicle-stimulating hormone (hFSH) of urinary source. Also, based on available data derived from physiochemical tests and bioassay, follitropin beta and follitropin alfa, another recombinant follicle-stimulating hormone product, are indistinguishable.

Follistim® AQ Cartridge is a ready-for-use, prefilled with solution, disposable cartridge containing either 175 IU of follitropin beta in 0.210 mL (833 IU/mL), 350 IU in 0.420 mL (833 IU/mL), 650 IU in 0.780 mL (833 IU/mL) or 975 IU in 1.170 mL (833 IU/mL) of aqueous solution for multiple dose use, with a maximal deliverable dose of either 150 IU, 300 IU, 600 IU or 900 IU, respectively. Inactive ingredients in the cartridges include: benzyl alcohol, NF 10 mg/mL; L-methionine, USP 0.5 mg/mL; polysorbate 20, NF 0.2 mg/mL; sodium citrate (dihydrate), USP 14.7 mg/mL; sucrose, NF 50 mg/mL; and water for injection, USP. Hydrochloric acid, NF and/or sodium hydroxide, NF are used to adjust the pH to 7.

Follistim® AQ Cartridge is for use only with the Follistim Pen®, which features an adjustable dosing system for administering the drug in a microvolume of solution. The Follistim Pen® with Follistim® AQ Cartridge is intended for SUBCUTANEOUS USE ONLY. The recombinant protein in Follistim® AQ Cartridge 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® AQ Cartridge may contain up to 11% of oxidized follitropin beta.

In clinical trials with Follistim® (follitropin beta for injection), 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

CLINICAL PHARMACOLOGY

Follicle stimulating hormone (FSH), the active component in Follistim® AQ Cartridge (follitropin beta injection), is required for normal follicular growth, maturation, and gonadal steroid production. In women, 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. Follistim® AQ Cartridge stimulates ovarian follicular growth in women who do not have primary ovarian failure. 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 treatment with Follistim® AQ Cartridge when patient monitoring indicates appropriate follicular development parameters have been reached.

Pharmacokinetics

The pharmacokinetics of Follistim® AQ Cartridge (follitropin beta injection) were evaluated in an open-labeled, single-center, randomized study in 20 healthy female subjects. A single subcutaneous injection of lyophilized Follistim® (follitropin beta for injection) which was reconstituted and administered by conventional syringe was compared to a single subcutaneous injection of Follistim® AQ Cartridge administered using the Follistim Pen®. The precision of the Follistim Pen® resulted in more efficient delivery of the ready-for-use solution contained in the Follistim® AQ Cartridge and an 18% increase in AUC0–∞ and Cmax. The 18% difference found between serum FSH concentrations in subjects administered the two formulations was due to differences between the anticipated and actual volume delivered with the conventional syringe. The pharmacokinetic parameters for Follistim® AQ Cartridge are as follows:

TABLE 1: Mean (SD) Pharmacokinetic Parameters of a Single Subcutaneous Injection of 150 IU of Follistim® AQ Cartridge (n=20)
AUC0-∞
(IU/L*h)
Cmax
(IU/L)
tmax
(h)
t1/2
(h)
CLapp
(L/h/kg)
AUC0-∞Area under the curve
CmaxMaximum Concentration
tmaxTime to maximum concentration
t1/2Elimination half-life
CLappClearance
Follistim® AQ Cartridge215.1
(45.8)
3.4
(0.7)
12.9
(6.2)
33.4
(4.2)
0.01
(0.003)

Absorption

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

In healthy, pituitary-suppressed, female subjects following a subcutaneous administration of 300 IU of Follistim®, the AUC was 455.6±141.4 IU/L*h and Cmax was 5.41±0.72 IU/L. A multiple, dose proportionality, pharmacokinetic study of Follistim® was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75, 150, or 225 IU for seven days. Steady-state blood concentrations of FSH were reached with all doses after five days of treatment based on the minimum concentrations of FSH just prior to dosing (Cmin). Peak blood concentrations with the 75, 150, and 225 IU dose were 4.30±0.60, 8.51±1.16, 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® AQ Cartridge is biochemically similar to natural FSH, and it is therefore anticipated that it is metabolized in the same manner.

Elimination

The elimination half-life (t1/2) following a single subcutaneous injection of 150 IU of Follistim® AQ Cartridge in female patients was 33.4 (4.2) hours. The clearance was 0.01 (0.003) L/h/kg.

Special Populations

The pharmacokinetics of Follistim® AQ Cartridge (follitropin beta injection) have not been determined in special populations such as geriatric, pediatric, renally impaired, and hepatically impaired patients.

Drug-Drug Interactions

Formal drug-drug interaction studies have not been conducted (see PRECAUTIONS).

CLINICAL STUDIES

The efficacy, tolerance, and ease of use of Follistim® AQ Cartridge (follitropin beta injection) administered using the Follistim Pen® were established in two US clinical studies [one study for Assisted Reproductive Technologies (ART) and one study for Ovulation Induction (OI)].

Assisted Reproductive Technologies (ART)

Results from an open-label, non-controlled, multicenter study in 60 women undergoing Controlled Ovarian Hyperstimulation (COH) for IVF or ICSI with Follistim® AQ Cartridge are summarized in Table 2.

TABLE 2: Results From an Open-label, Non-controlled, Multicenter Study in 60 Women Undergoing COH for IVF or ICSI With Follistim® AQ Cartridge Self-administered With the Follistim Pen®.
ParameterFollistim® AQ Cartridge
n=60
Mean (SD) number of oocytes recovered13.9 (10.3)
Mean (SD) total number of embryos obtained7.2 (5.5)
Median serum estradiol on the day of hCG (pg/mL)1423.0
Range (469.5-4874.0)
Mean (SD) treatment duration (days)9.0 (1.6)
Biochemical pregnancy rate/attempt (%)56.7
Biochemical pregnancy rate/transfer (%)61.8

Ovulation Induction (OI)

Results from an open-label, non-controlled, multicenter study in 43 clomiphene-resistant women with chronic anovulation (WHO group II) who were treated with Follistim® AQ Cartridge for induction of ovulation are summarized in Table 3.

TABLE 3: Results From an Open-label, Non-controlled, Multicenter Study in 43 Clomiphene-resistant Women With Chronic Anovulation (WHO group II) Undergoing Ovulation Induction With Follistim® AQ Cartridge Self-administered With the Follistim Pen®.
Follistim® AQ Cartridge
(n=43)
n
Ovulation rate95.3%41
Biochemical pregnancy per attempt34.9%15

Ease of Use

In an observer questionnaire, designed to assess the “Ease of Use” of Follistim® AQ Cartridge with the Follistim Pen®, subjects rated their experience with the pen injector device. Subjects undergoing ART and OI rated their injection experience in two separate studies. On Day 6 in the ART group, more subjects rated the overall experience as “very good” as compared to Day 2, 54 subjects (90%) versus 49 subjects (81.8%), respectively, and only one subject (1.7%) had a “neutral” response. In the Ovulation Induction group, the experience rating of “very good” increased from 90.7% on Day 2 to 95.2% on Day 8.

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