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.

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.

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.

For the 33 patients who achieved a clinical pregnancy with Ovidrel® 250 µg, the outcomes of the pregnancies are presented in Table 4.

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.

For the 32 patients who achieved a clinical pregnancy with Ovidrel® 250 µg, the outcomes of the pregnancies are presented in Table 6.

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.

For the 22 patients who had a clinical pregnancy with Ovidrel® 250 µg, the outcome of the pregnancy is presented in Table 8.

Selection of Patients

1. Before treatment with gonadotropins is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Ovidrel® PreFilled Syringe only if enrolled in an in vitro fertilization program.
2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.
3. Appropriate evaluation should be performed to exclude pregnancy.
4. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting FSH and Ovidrel® PreFilled Syringe therapy.
5. Evaluation of the partner's fertility potential should be included in the initial evaluation.

Overstimulation of the Ovary Following hCG Therapy

General

Careful attention should be given to the diagnosis of infertility in candidates for hCG therapy. (see "Indications and Usage/ Selection of Patients"). After the exclusion of pre-existing conditions, elevations in ALT were found in 10 (3%) of 335 patients receiving Ovidrel® 250 µg, 9 (10%) of 89 patients receiving Ovidrel® 500 µg and in 16 (4.8%) of 328 patients receiving urinary-derived hCG. The elevations ranged up to 1.2 times the upper limit of normal. The clinical significance of these findings is not known.

Information for Patients

Prior to therapy with hCG, patients should be informed of the duration of treatment and monitoring of their condition that will be required. The risks of ovarian hyperstimulation syndrome and multiple births in women (see WARNINGS) and other possible adverse reactions (see "Adverse Reactions") should also be discussed.

Laboratory Tests

In most instances, treatment of women with FSH results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because serum estrogens do not give an indication of the size or number of follicles.

Human chorionic gonadotropins can crossreact in the radioimmunoassay of gonadotropins, especially luteinizing hormone. Each individual laboratory should establish the degree of crossreactivity with their gonadotropin assay. Physicians should make the laboratory aware of patients on hCG if gonadotropin levels are requested.

The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:

1. A rise in basal body temperature
2. Increase in serum progesterone and
3. Menstruation following a shift in basal body temperature

When used in conjunction with the indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:

1. Fluid in the cul-de-sac
2. Ovarian stigmata
3. Collapsed follicle
4. Secretory endometrium

Accurate interpretation of the indices of ovulation require a physician who is experienced in the interpretation of these tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy

Intrauterine death and impaired parturition were observed in pregnant rats given a dose of urinary-hCG (500 IU) equivalent to three times the maximum human dose of 10,000 USP, based on body surface area.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if hCG is administered to a nursing woman.

Pediatric Patients

Safety and effectiveness in pediatric patients has not been established.

Geriatric Patients

Safety and effectiveness in geriatric patients has not been established.

Post-Marketing Experience

In addition to adverse events reported from clinical trials, the following events have been reported during post-marketing use of Ovidrel®. Therefore, these events were reported from a population of uncertain size, the frequency or causal relationship to Ovidrel® cannot be reliably determined.

• Cases of allergic reactions, including anaphylactic reactions and mild reversible skin rashes have been reported in patients treated with Ovidrel® since market introduction. The causal relationship is unknown.
• Thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome (see "WARNINGS")

Infertile Women Undergoing Assisted Reproductive Technologies (ART)

Ovidrel® PreFilled Syringe 250 µg should be administered one day following the last dose of the follicle stimulating agent. Ovidrel® PreFilled Syringe should not be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. Administration should be withheld in situations where there is an excessive ovarian response, as evidenced by clinically significant ovarian enlargement or excessive estradiol production.

Infertile Women Undergoing Ovulation Induction (OI)

Ovidrel® PreFilled Syringe should not be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography.

Ovidrel® PreFilled Syringe 250 µg should be administered one day following the last dose of the follicle stimulating agent.

Ovidrel® PreFilled Syringe administration should be withheld in situations where there is an excessive ovarian response, as evidenced by multiple follicular development, clinically significant ovarian enlargement or excessive estradiol production.

Directions for Administration of Ovidrel® Prefilled Syringe

Ovidrel® PreFilled Syringe is intended for a single subcutaneous injection. Any unused material should be discarded.

Ovidrel® PreFilled Syringe may be self-administered by the patient. Follow the directions below for injecting Ovidrel® PreFilled Syringe.

Step 1: Wash your hands thoroughly with soap and water.

Step 2: Carefully clean the injection site.

Make yourself comfortable by sitting or lying down. Carefully clean the injection site on the stomach with an alcohol wipe and allow it to air-dry.

Step 3: Administer your injection.

Carefully remove the needle cap from the syringe. Do not touch the needle or allow the needle to touch any surface. Inject the prescribed dose as directed by your doctor, nurse or pharmacist.

Step 4: Gently withdraw the needle.

Discard the needle and syringe into your safety container. Place gauze over the injection site. If any bleeding occurs, apply gentle pressure. If bleeding does not stop within a few minutes, place a clean piece of gauze over the injection site and cover it with an adhesive bandage.

Step 5: Storage and clean up.

Remember that your injection materials must be kept sterile and cannot be reused.

Storage

The Ovidrel® PreFilled Syringe must be stored refrigerated between 2-8°C (36-46°F) before being dispensed to the patient. Patients should store the pre-filled syringe refrigerated to allow the product to be used until the expiry date shown on the syringe or carton. The Ovidrel® PreFilled Syringe may be stored by the patient for no more than 30 days at room temperature (up to 25°C (77°F) but must be used within those 30 days.

Protect from light.

Store in original package. Discard unused material.