Source: FDA, National Drug Code (US) Revision Year: 2020
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.
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 Administration of Ovidrel in Healthy Female Volunteers:
| Ovidrel 250 µg 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), tmax: time of Cmax, AUC: total area under the curve, t½: elimination half-life, F: bioavailability
* median (range)
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%.
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.
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.
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.
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.
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) | AUCextrapolated (%) | tmax (h) |
|---|---|---|---|---|---|
| Mean | 125 | 10050 | 10350 | 2.85 | 20.0 |
| (Min-Max) | (68.0-294) | (5646-14850) | (5800-15100) | (1.08-6.27) | (9.00-48.0) |
Abbreviations are: Cmax: peak concentration (above baseline); tmax : time of Cmax
Safety, efficacy, and pharmacokinetics of Ovidrel PreFilled Syringe in patients with renal or hepatic insufficiency have not been established.
No drug-drug interaction studies have been conducted. Administration of Ovidrel PreFilled Syringe may interfere with the interpretation of pregnancy tests. (see PRECAUTIONS.)
Long-term studies to evaluate the carcinogenic potential of Ovidrel in animals have not been performed. In vitro genotoxicity testing of Ovidrel in bacteria and mammalian cell lines, chromosome aberration assay in human lymphocytes and in-vivo mouse micronucleus have shown no indication of genetic defects.
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).
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 urinary-derived 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 35-42 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 250 µg (n=32) |
|---|---|
| Clinical Pregnancies not reaching term | 6 (18.8%) |
| Live births | 26 (81.2%) |
| Singleton | 18 (69.2%) |
| Multiple birth | 8 (30.8%) |
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%) |
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