DailyMed Label: Ovidrel

DailyMed Label: Ovidrel

2023

DailyMed Prescription

Ovidrel

choriogonadotropin alfa

EMD Serono, Inc.

NDC: 44087-1150

NDC: 44087-1150

Ovidrel ® PreFilled Syringe (choriogonadotropin alfa injection) is a sterile liquid preparation of choriogonadotropin alfa (recombinant human Chorionic Gonadotropin, r-hCG). Choriogonadotropin alfa is a water soluble glycoprotein consisting of two non-covalently linked subunits - designated α and β - consisting of 92 and 145 amino acid residues, respectively, with carbohydrate moieties linked to ASN-52 and ASN-78 (on alpha subunit) and ASN-13, ASN-30, SER-121, SER-127, SER-132 and SER-138 (on beta subunit). The primary structure of the α - chain of r-hCG is identical to that of the α - chain of hCG, FSH and LH. The glycoform pattern of the α - subunit of r-hCG is closely comparable to urinary derived hCG (u-hCG), the differences mainly being due to the branching and sialylation extent of the oligosaccharides. The β - chain has both O- and N-glycosylation sites and its structure and glycosylation pattern are also very similar to that of u-hCG. The production process involves expansion of genetically modified Chinese Hamster Ovary (CHO) cells from an extensively characterized cell bank into large scale cell culture processing. Choriogonadotropin alfa is secreted by the CHO cells directly into the cell culture medium that is then purified using a series of chromatographic steps. This process yields a product with a high level of purity and consistent product characteristics including glycoforms and biological activity. The biological activity of choriogonadotropin alfa is determined using the seminal vesicle weight gain test in male rats described in the "Chorionic Gonadotrophins" monograph of the European Pharmacopoeia. The in vivo biological activity of choriogonadotropin alfa has been calibrated against the third international reference preparation IS75/587 for chorionic gonadotropin. Ovidrel ® PreFilled Syringe is a sterile, liquid intended for subcutaneous (SC) injection. Each Ovidrel ® PreFilled Syringe is filled with 0.515 mL containing 257.5 µg of choriogonadotropin alfa, 28.1 mg mannitol, 505 µg 85% O-phosphoric acid, 103 µg L-methionine, 51.5 µg Poloxamer 188, Sodium Hydroxide (for pH adjustment), and Water for Injection to deliver 250 µg of choriogonadotropin alfa in 0.5 mL. The pH of the solution is 6.5 to 7.5. Therapeutic Class: Infertility

Ovidrel ® PreFilled Syringe (choriogonadotropin alfa injection) is indicated for the induction of final follicular maturation and early luteinization in infertile women who have undergone pituitary desensitization and who have been appropriately pretreated with follicle stimulating hormones as part of an Assisted Reproductive Technology (ART) program such as in vitro fertilization and embryo transfer. Ovidrel ® PreFilled Syringe is also indicated for the induction of ovulation (OI) and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure. 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. Primary ovarian failure should be excluded by the determination of gonadotropin levels. Appropriate evaluation should be performed to exclude pregnancy. 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. Evaluation of the partner's fertility potential should be included in the initial evaluation.

For Subcutaneous Use Only 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. 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. 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. Figure 1 Figure 2

Ovidrel ® PreFilled Syringe (choriogonadotropin alfa injection) is contraindicated in women who exhibit: Prior hypersensitivity to hCG preparations or one of their excipients. Primary ovarian failure. Uncontrolled thyroid or adrenal dysfunction. An uncontrolled organic intracranial lesion such as a pituitary tumor. Abnormal uterine bleeding of undetermined origin (see " Selection of Patients " ). Ovarian cyst or enlargement of undetermined origin (see " Selection of Patients " ). Sex hormone dependent tumors of the reproductive tract and accessory organs. Pregnancy.

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. 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. 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: A rise in basal body temperature Increase in serum progesterone and 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: Fluid in the cul-de-sac Ovarian stigmata Collapsed follicle Secretory endometrium Accurate interpretation of the indices of ovulation require a physician who is experienced in the interpretation of these tests. 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. 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. 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. Safety and effectiveness in pediatric patients has not been established. Safety and effectiveness in geriatric patients has not been established.

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Ovidrel ® PreFilled Syringe (choriogonadotropin alfa injection) is supplied in a sterile, liquid single dose pre-filled 1 mL syringe. Each Ovidrel ® PreFilled Syringe is filled with 0.515 mL containing 257.5 µg of choriogonadotropin alfa, 28.1 mg mannitol, 505 µg 85% O-phosphoric acid, 103 µg L-methionine, 51.5 µg Poloxamer 188, Sodium Hydroxide (for pH adjustment), and Water for Injection to deliver 250 µg of choriogonadotropin alfa in 0.5 mL. The following package combination is available: 1 pre-filled syringe containing 250 μg Ovidrel ® PreFilled Syringe NDC 44087-1150-1 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.

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 C max : peak concentration (above baseline), t max : time of C max , AUC: total area under the curve, t ½ : elimination half-life, F: bioavailability C max (IU/L) 121 ± 44 t max (h) median (range) 24 (12-24) AUC (h∙IU/L) 7701 ± 2101 t ½ (h) 29 ± 6 F 0.4 ± 0.1 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 C max . A summary of the Ovidrel ® PreFilled Syringe pharmacokinetic parameters is presented in Table 2. Table 2: Summary of Ovidrel ® PreFilled Syringe Pharmacokinetic Parameters Parameter C max (mIU/mL) AUCl ast (mIU∙h/mL) AUC (mIU∙h/mL) AUC extrapolated (%) t max (h) Abbreviations are: C max : peak concentration (above baseline); t max : time of C max 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) 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 .)

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 nmol/L ÷ 3.18 = ng/mL ) 423 Clinical pregnancy rate per initiated treatment cycle (%) 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) 35.1 Clinical pregnancy rate per transfer (%) 36.3 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) nmol/L ÷ 3.18 = ng/mL 394 Clinical pregnancy rate per initiated treatment cycle (%) 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) 33 Clinical pregnancy rate per transfer (%) 37.6 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 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. 22 (22%) 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%)

OVIDREL ® PreFilled Syringe 250 µg/0.5 mL choriogonadotropin alfa injection NDC 44087-1150-1 For subcutaneous injection Rx Only 1 Ovidrel ® PreFilled Syringe EMD SERONO PRINCIPAL DISPLAY PANEL - 250 µg/0.5 mL Syringe Carton