Bravelle - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
Россия
  • Россия
  • Украина

Bravelle - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: United States
Condition: Female Infertility, Follicle Stimulation
Class: Gonadotropins
Form: Liquid solution, Subcutaneous (SC), Intramuscular (IM)
Ingredients: follicle stimulating hormone (FSH), corresponding, lactose monohydrate, polysorbate 20 (tween 20), sodium phosphate buffer (sodium phosphate dibasic, heptahydrate and phosphoric acid)

Pharmaceutical Information

Drug Substance

Proper Name: Purified urofollitropin
Chemical Name: Human follicle stimulating hormone
Structural Formula: Purified urofollitropin is a heterodimer consisting of α and β subunits,
combined by non-covalent bonds
Molecular Weight: Between 45,000 and 52,000 daltons
Physical Form: Off-white, amorphous powder cake
Solubility: Very soluble in water and in high concentration salt-water-ethanol solutions

Clinical Trials

Efficacy results from three randomized, active controlled, multi-center studies are summarized in Tables 1 and 2. Two studies were conducted for In Vitro Fertilization (IVF) and one study for Ovulation Induction (OI).

Assisted Reproductive Technologies (ART)/ In Vitro Fertilization

Two randomized, controlled IVF studies were conducted. Patients underwent pituitary suppression with GnRH agonist before being randomized to BRAVELLE SC, BRAVELLE IM or a commercial recombinant FSH product administered SC. A total of 297 were randomized of whom 179 received BRAVELLE starting at a dose of 225 IU daily for 5 days. This was followed by individual titration of the dose from 75 to 450 IU daily based on ultrasound and estradiol (E2) levels. The total duration of dosing did not exceed 12 days. Results are summarized in Table 2 for the intent-to-treat population.

Study 1

BRAVELLE administered SC and IM in terms of the primary efficacy variable of oocytes retrieved per patient showed no statistically significant differences in either the intent-to-treat or primary efficacy responder (received hCG) populations when compared to the recombinant FSH. A strong numerical trend in favor of BRAVELLE SC compared to recombinant FSH SC for chemical, clinical and continuing pregnancies was demonstrated in both intent-to-treat and primary efficacy responder analyses. BRAVELLE IM required slightly higher doses, but this did not correlate with a different safety profile

or a clinically significant longer duration of treatment. Pregnancy rates with BRAVELLE SC and IM treatment groups for one cycle therapy were excellent compared to historical and published data for various follitropins. BRAVELLE SC and IM showed superior local tolerance at the injection site compared to recombinant FSH.

Study 2

BRAVELLE SC showed no statistically significant differences in either the intent-to-treat or primary efficacy responder (received hCG) in terms of the primary efficacy variable of oocytes retrieved per patient when compared to recombinant FSH SC. BRAVELLE SC showed similar numerical results for chemical, clinical and continuing pregnancies in both the intent-to-treat and primary responder patient populations compared to recombinant FSH. BRAVELLE SC showed superior local tolerance at the injection site compared to recombinant FSH SC.

TABLE 2
EFFICACY OUTCOME BY TREATMENT GROUP FOR IVF STUDIES
(one cycle of treatment)
Parameter Study 1 Study 2
BRAVELLE
SC
n=60
BRAVELLE
IM
n=59
Recombinant
FSH
n=58
BRAVELLE
SC
n=60
Recombinant FSH
SC
n=60
Total oocytes retrieved
per patient (SD)
13.3 (7.9) 12.2 (7.8) 13.1 (8.7) 11.8 (6.3) 11.9 (6.9)
Mature oocytes retrieved
per patient (SD)
9.9 (5.7) 8.7 (5.5) 9.5 (5.6) 9.0 (5.7) 9.2 (6.0)
Patients with oocyte
retrieval (%)
56 (93.3) 55 (93.2) 56 (96.6) 57 (95.0) 59 (98.3)
Patients with embryo
transfer (%)
54 (90.0) 51 (86.4) 55 (94.8) 57 (95.0) 58 (96.7)
Patients with chemical
pregnancy (%)
30 (50.0) 23 (39.0) 20 (34.5) 28 (46.6) 30 (50.0)
Patients with clinical
pregnancy (%)
26 (43.3) 19 (32.2) 18 (31.0) 25 (41.7) 27 (45.0)
Patients with continuing
pregnancy (%)
25 (41.7) 19 (32.2) 17 (29.3) 23 (38.3) 27 (45.0)

Ovulation Induction

In the one randomized, controlled ovulation induction study, patients underwent pituitary suppression with GnRH agonist before being randomized to BRAVELLE SC, BRAVELLE IM or commercial recombinant FSH product administered SC. A total of 111 oligo-anovulatory patients were randomized of whom 72 received BRAVELLE starting at a dose of 150 IU BRAVELLE daily for 5 days. This was followed by individual titration of the dose from 75 to 450 IU daily based on ultrasound and estradiol (E2) levels. The total duration of dosing did not exceed 12 days. Results for the intent-to-treat population are summarized in Table 6.

BRAVELLE SC or IM were equal in effectiveness to recombinant FSH for ovulation induction in oligo-anovulatory down-regulated patients in the study. Pregnancy rates were also equivalent. There were a few significant differences favouring recombinant FSH over BRAVELLE SC or IM for the secondary efficacy variables of meeting hCG criteria and receiving hCG, but these pharmacological differences were small and did not translate into differences in clinical outcomes. The mean dose and duration of treatment with BRAVELLE IM were slightly more than those for BRAVELLE SC and recombinant FSH SC. BRAVELLE IM or SC demonstrated excellent and equivalent safety and local tolerance.

TABLE 3
EFFICACY OUTCOME BY TREATMENT GROUP IN OVULATION INDUCTION STUDY
(one cycle of treatment)
Parameter BRAVELLE
SC
n=35
BRAVELLE
IM
n=37
Recombinant FSH
SC
n=38
Ovulation (%) 25 (69.4) 26 (70.3) 30 (78.9)
Received hCG (%) 26 (72.2) 28 (75.7) 35 (92.1)
Peak serum E2 (pg/mL) (SD) 990.9 (696.2) 893.2 (815.2) 1109.0 (788.9)
Patients with chemical
pregnancy (%)
11 (30.6) 8 (21.6) 13 (34.2)
Patients with clinical
pregnancy (%)
9 (25.0) 7 (18.9) 11 (28.9)
Patients with continuing
pregnancy (%)
9 (25.7) 7 (18.9) 10 (26.3)

• Chi-Square Test - significant for BRAVELLE SC vs. Recombinant hFSH SC

Pharmacology

No preclinical pharmacology studies were conducted with BRAVELLE (Urofollitropin for Injection, Purified), since the pharmacologic actions of human gonadotropins are well known. Observations made in two single-dose studies, conducted to assess the overall toxicological effects in female Sprague Dawley CD rats and female Beagles confirmed the pharmacological activity of Purified urofollitropin in showing an increase in the number and size of ovarian follicles following subcutaneous administration of the compound at doses of 4 to 400 IU/kg. In a single-dose toxicity study in Beagle dogs, subcutaneous administration of 4, 40 and 400 IU/kg of Purified urofollitropin did not elicit any effects on cardiovascular parameters such as blood pressure, heart rate or ECG readings.

Toxicology

Two studies were conducted to assess the overall toxicological effects of single doses of Purified urofollitropin administered subcutaneously to female Sprague Dawley CD rats and female Beagle dogs. Another study was conducted in conscious female Beagle dogs to determine whether Purified urofollitropin has any effects on cardiovascular parameters.

Following subcutaneous administration of 4, 40 or 400 IU/kg to Sprague Dawley rats, and 4, 40, or 100 IU/kg to female Beagle dogs, a dose-related increase in the size and number of ovarian follicles was observed. A statistically significant increase in ovarian weight was observed in the highest dose groups of both species (400 IU/kg group in rats and 100 IU/kg group in dogs). No treatment-related adverse effects were observed in either.

In the conscious dog model, no significant cardiovascular (blood pressure, heart rate, mean arterial pressure), physiological or electrophysiological effects were observed at doses up to 100 IU/kg.

Carcinogenesis and Mutagenesis

Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic potential of urofollitropin.