CLINICAL PHARMACOLOGY
The physicochemical, immunological, and biological
activities of recombinant hCG are comparable to those of placental and human
pregnancy urine-derived hCG. Choriogonadotropin alfa stimulates late follicular
maturation and resumption of oocyte meiosis, and initiates rupture of the
pre-ovulatory ovarian follicle. Choriogonadotropin alfa, the active component
of Ovidrel® PreFilled Syringe , is an analogue of Luteinizing Hormone (LH) and
binds to the LH/hCG receptor of the granulosa and theca cells of the ovary to
effect these changes in the absence of an endogenous LH surge. In pregnancy, hCG,
secreted by the placenta, maintains the viability of the corpus luteum to
provide the continued secretion of estrogen and progesterone necessary to
support the first trimester of pregnancy. Ovidrel® PreFilled Syringe is
administered when monitoring of the patient indicates that sufficient
follicular development has occurred in response to FSH treatment for ovulation
induction.
Pharmacokinetics
When given by intravenous administration, the
pharmacokinetic profile of Ovidrel® followed a biexponential model and was
linear over a range of 25 μg to 1000 μg. Pharmacokinetic parameter estimates
following SC administration of Ovidrel® 250 μg to females are presented in
Table 1.
Table 1: Pharmacokinetic Parameters (mean ± SD) of
r-hCG after Single-Dose Adminis tration of Ovidrel® in Healthy Female
Volunteers
|
Ovidrel® 250 pg SC |
Cmax (IU/L) |
121 ± 44 |
tmax (h)* |
24 (12-24) |
AUC (h•IU/L) |
7701±2101 |
t½(h) |
29 ± 6 |
F |
0.4 ± 0.1 |
Cmax : peak concentration (above baseline), t max: time
of Cmax, AUC: total area under the curve, t ½ :elimination half-life, F:
bioavailability
*median (range) |
Absorption
Following subcutaneous administration of Ovidrel® 250
μg, maximum serum concentration (121 ± 44 IU/L) is reached after
approximately 12 to 24 hours. The mean absolute bioavailability of Ovidrel® following
a single subcutaneous injection to healthy female volunteers is about 40%.
Distribution
Following intravenous administration of Ovidrel® 250
μg to healthy down-regulated female volunteers, the serum profile of hCG
is described by a two-compartment model with an initial half-life of 4.5 ± 0.5 hours.
The volume of the central compartment is 3.0 ± 0.5 L and the steady state
volume of distribution is 5.9 ± 1.0 L.
Metabolism/Excretion
Following subcutaneous administration of Ovidrel® , hCG
is eliminated from the body with a mean terminal half-life of about 29 ± 6
hours. After intravenous administration of Ovidrel® 250 μg to healthy down-regulated
females, the mean terminal half-life is 26.5 ± 2.5 hours and the total body
clearance is 0.29 ± 0.04 L/h. One-tenth of the dose is excreted in the urine.
Pharmacodynamics
In female subjects on oral contraception after an initial
latency period, Ovidrel® induced a clear increase in androstenedione serum
levels by 24 hours after dosing. Pharmacodynamic studies in females determined
that the relationship of Ovidrel® pharmacokinetics to pharmacologic effect of Ovidrel®
are complex and vary with the pharmacodynamic marker examined. In general pharmacologic
effects are not proportional to exposure and in some cases appear to be near
maximal at a 250 μg dose.
Population Pharmacokinetics And Pharmacodynamics
In patients undergoing in-vitro fertilization/embryo
transfer given Ovidrel® subcutaneously to trigger ovulation, the results of a
population PK/PD analysis generally supported the data obtained in healthy subjects.
Pharmacokinetic parameters for Ovidrel® include a median elimination half-life
of 29.2 hours, median apparent clearance (Cl/F) of 0.51 L/hr and median
apparent volume of distribution (V/F) of 21.4 L.
Bioequivalence Of Formulations
Ovidrel® PreFilled Syringe (choriogonadotropin alfa
injection) has been determined to be bioequivalent to Ovidrel®
(choriogonadotropin alfa for injection) based on the statistical evaluation of AUC
and Cmax. A summary of the Ovidrel® PreFilled Syringe pharmacokinetic
parameters is presented in Table 2.
Table 2: Summary of Ovidrel® PreFilled Syringe
Pharmacokinetic Parameters
Parameter |
Cmax (mIU/mL) |
AUClast (mIU•h/mL) |
AUC (mIU•h/mL) |
AUC extrapolated (%) |
tmax (h) |
Mean (Min-Max) |
125 (68.0-294) |
10050 (5646- 14850) |
10350 (5800- 15100) |
2.85 (1.08-6.27) |
20.0 (9.00- 48.0) |
Abbreviations are: Cmax: peak concentration (above
baseline); tmax: time of Cmax |
Special Populations
Safety, efficacy, and pharmacokinetics of Ovidrel®
PreFilled Syringe in patients with renal or hepatic insufficiency have not been
established.
Drug-Drug Interactions
No drug-drug interaction studies have been conducted.
Administration of Ovidrel® PreFilled Syringe may interfere with the
interpretation of pregnancy tests. (see PRECAUTIONS.)
Clinical Studies
The safety and efficacy of Ovidrel® have been examined in
three well-controlled studies in women; two studies for assisted reproductive
technologies (ART) and one study for ovulation induction (OI).
Assisted Reproductive Technologies (ART)
The safety and efficacy of Ovidrel® 250 μg and Ovidrel®
500 μg administered subcutaneously versus 10,000 USP Units of an approved
urinary-derived hCG product administered intramuscularly were assessed in a
randomized, open-label, multicenter study in infertile women undergoing in
vitro fertilization and embryo transfer (Study 7927). The study was conducted
in 20 U.S. centers.
The primary efficacy parameter in this single-cycle study
was the number of oocytes retrieved. 297 patients entered the study, of whom 94
were randomized to receive Ovidrel® 250 μg. The number of oocytes
retrieved was similar for the Ovidrel® and urinary-derived hCG (10,000 USP
Units) treatment groups. The efficacy of Ovidrel® 250 μg and Ovidrel® 500
μg were both found to be clinically and statistically equivalent to that
of the approved urinary-derived hCG product and to each other. The efficacy
results for the patients who received Ovidrel® 250 μg are summarized in
Table 3.
Table 3: Efficacy Outcomes of r-hCG in ART (Study
7927)
Parameter |
Ovidrel® 250 μg
(n = 94) |
Mean number of oocytes retrieved per patient |
13.60 |
Mean number of mature oocytes retrieved per patient |
7.6 |
Mean number of 2 PN fertilized oocytes per patient |
7.2 |
Mean number of 2 PN or cleaved embryos per patient |
7.6 |
Implantation rate per embryo transferred (%) |
18.7 |
Mean mid-luteal serum progesterone levels (nmol/L*) |
423 |
Clinical pregnancy rate per initiated treatment cycle (%)† |
35.1 |
Clinical pregnancy rate per transfer (%)† |
36.3 |
*nmol/L ÷ 3.18 = ng/mL
†Clinical pregnancy was defined as a pregnancy during which a fetal sac
(with or without heartbeat activity) was detected by ultrasound on day 35-4 2
after Hcg administration) |
For the 33 patients who achieved a clinical pregnancy
with Ovidrel® 250 μg, the outcomes of the pregnancies are presented in
Table 4.
Table 4: Pregnancy Outcomes of r-hCG in ART (Study 7927)
Parameter |
Ovidrel® 250 μg
(n = 33) |
Clinical pregnancies not reaching term |
4 (12.1%) |
Live births |
29 (87.9%) |
Singleton |
20 (69.0%) |
Multiple birth |
9 (31.0%) |
The safety and efficacy of Ovidrel® 250 μg
administered subcutaneously versus 5,000 IU of an approved urinary-derived hCG
product administered subcutaneously were assessed in a second, randomized,
multicenter study in infertile women undergoing in vitro fertilization and
embryo transfer (Study 7648). This double-blinded study was conducted in nine
centers in Europe and Israel.
The primary efficacy parameter in this single-cycle study
was the number of oocytes retrieved per patient. 205 patients entered the
study, of whom 97 received Ovidrel® 250 μg. The efficacy of Ovidrel® 250
μg was found to be clinically and statistically equivalent to that of the
approved urinaryderived hCG product. The results for the 97 patients who
received Ovidrel® 250 μg are summarized in Table 5.
Table 5: Efficacy Outcomes of r-hCG in ART (Study 7648)
Parameter |
Ovidrel® 250 μg
(n = 97) |
Mean number of oocytes retrieved per patient |
10.6 |
Mean number of mature oocytes retrieved per patient |
10.1 |
Mean number of 2 PN fertilized oocytes per patient |
5.7 |
Mean number of 2 PN or cleaved embryos per patient |
5.1 |
Implantation rate per embryo transferred (%) |
17.4 |
Mean mid-luteal serum progesterone levels (nmol/L)* |
394 |
Clinical pregnancy rate per initiated treatment cycle (%)† |
33 |
Clinical pregnancy rate per transfer (%)† |
37.6 |
*nmol/L ÷ 3.18 = ng/mL
†Clinical pregnancy was defined as a pregnancy during which a fetal sac (with
or without heartbeat activity) was detected by ultrasound on day 35-4 2 after
hCG administration) |
For the 32 patients who achieved a clinical pregnancy
with Ovidrel® 250 μg, the outcomes of the pregnancies are presented in
Table 6.
Table 6: Pregnancy Outcomes of r-hCG in ART (Study 7648)
Parameter |
Ovidrel® 250μg
(n = 32) |
Clinical Pregnancies not reaching term |
6 (18.8%) |
Live births |
26 (81.2%) |
Singleton |
18 (69.2%) |
Multiple birth |
8 (30.8%) |
Ovulation Induction (OI)
The safety and efficacy of Ovidrel® 250 μg
administered subcutaneously versus 5,000 IU of an approved urinary-derived hCG
product administered intramuscularly were assessed in a double-blind, randomized,
multicenter study in anovulatory infertile women (Study 8209) which was
conducted in 19 centers in Australia, Canada, Europe and Israel.
The primary efficacy parameter in this single-cycle study
was the patient ovulation rate. 242 patients entered the study, of whom 99
received Ovidrel® 250 μg. The efficacy of Ovidrel® 250 μg was found to
be clinically and statistically equivalent to that of the approved
urinary-derived hCG product. The results of those patients who received Ovidrel®
250 μg are summarized in Table 7.
Table 7: Efficacy Outcomes of r-hCG in OI (Study 8209)
Parameter |
Ovidrel® 250 μg
(n = 99) |
Ovulation Rate |
91 (91.9%) |
Clinical Pregnancy Rate* |
22 (22%) |
*Clinical pregnancy was defined as a pregnancy during which
a fetal sac (with or without heartbeat activity) was detected by ultrasound on
day 35-4 2 after hCG administration. |
For the 22 patients who had a clinical pregnancy with Ovidrel® 250 μg, the outcome of the pregnancy is presented in Table 8.
Table 8: Pregnancy Outcomes of r-hCG in OI (Study 8209)
Parameter |
Ovidrel® 250 μg
(n = 22) |
Clinical Pregnancies not reaching term |
7 (31.8%) |
Live births |
15 (68.2%) |
Singleton |
13 (86.7%) |
Multiple birth |
2 (13.3%) |