ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. (see WARNINGS)The safety of Ovidrel(R) was examined in four clinical studies that treated 752 patients of whom 335 received Ovidrel(R) 250 ug following follicular recruitment with gonadotropins. When patients enrolled in four clinical studies (3 in ART and one in OI) were injected subcutaneously with either Ovidrel(R) or an approved urinary-derived hCG, 14.6 (49 of 335 patients) in the Ovidrel(R) 250 ug group experienced application site disorders compared to 28% (92 of 328 patients) in the approved u-hCG group. Adverse events reported for Ovidrel(R) 250 ug occurring in at least 2% of patients (regardless of causality) are listed in Table for the ART studies and in Table 10 for the single OI study.Table 9: Incidence of Adverse Events of r-hCG in ART (Studies 7648, 7927, 9073)Body SystemOvidrel(R) 250 ug(n=236)Preferred TermIncidence Rate% (n)At Least One Adverse Event33.1% (78)Application Site Disorders14.0% (33)Injection Site Pain7.6% (18)Injection Site Bruising4.7% (11)Gastro-Intestinal System Disorders8.5% (20)Abdominal Pain4.2% (10)Nausea3.4% 8)Vomiting2.5% 6)Secondary Terms (Post-Operative Pain)4.7% (11)Post-Operative Pain4.7% (11)Adverse events not listed in Table that occurred in less than 2% of patients treated with Ovidrel(R) 250 ug whether or not considered causally related to Ovidrel(R), included: injection site inflammation and reaction, flatulence, diarrhea, hiccup, ectopic pregnancy, breast pain, intermenstrual bleeding, vaginal hemorrhage, cervical lesion, leukorrhea, ovarian hyperstimulation, uterine disorders, vaginitis, vaginal discomfort, body pain, back pain, fever, dizziness, headache, hot flashes, malaise, paraesthesias, rash, emotional lability, insomnia, upper respiratory tract infection, cough, dysuria, urinary tract infection, urinary incontinence, albuminuria, cardiac arrhythmia, genital moniliasis, genital herpes, leukocytosis, heart murmur and cervical carcinoma.Table 10: Incidence of Adverse Events of r-hCG in Ovulation Induction (Study 8209)Body SystemOvidrel(R) 250 ug(n=99)Preferred TermIncidence Rate% (n)At Least One Adverse Event26.2% (26)Application Site Disorders16.2% (16) Injection site pain8.1% (8) Injection site inflammation2.0% (2) Injection site bruising3.0% (3) Injection site reaction3.0% (3)Reproductive Disorders, Female7.1% (7) Ovarian cyst3.0% (3) Ovarian hyperstimulation3.0% (3)Gastro-Intestinal System Disorders4.0% (4) Abdominal pain3.0% (3)Additional adverse events not listed in Table 10 that occurred in less than 2% of patients treated with Ovidrel(R) 250 ug, whether or not considered causally related to Ovidrel(R), included: breast pain, flatulence, abdominal enlargement, pharyngitis, upper respiratory tract infection, hyperglycemia and pruritis.The following medical events have been reported subsequent to pregnancies resulting from hCG therapy in controlled clinical studies:Spontaneous AbortionEctopic PregnancyPremature LaborPostpartum FeverCongenital AbnormalitiesOf 125 clinical pregnancies reported following treatment with FSH and Ovidrel(R) 250 ug or 500 ug, three were associated with congenital anomaly of the fetus or newborn. Among patients receiving Ovidrel(R) 250 ug, cranial malformation was detected in the fetus of one woman and chromosomal abnormality (47, XXX) in another. These events were judged by the investigators to be of unlikely or unknown relation to treatment. These three events represent an incidence of major congenital malformations of 2.4%, which is consistent with the reported rate for pregnancies resulting from natural or assisted conception. In woman who received Ovidrel(R) 500 ug, one birth in set of triplets was associated with Downs syndrome and atrial septal defect. This event was considered to be unrelated to the study drug.The following adverse reactions have been previously reported during menotropin therapy:Pulmonary and vascular complications (see Warnings)Adnexal torsion (as complication of ovarian enlargement)Mild to moderate ovarian enlargementHemoperitoneumThere have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, causal relationship has not been established.. Spontaneous Abortion. Ectopic Pregnancy. Premature Labor. Postpartum Fever. Congenital Abnormalities. Pulmonary and vascular complications (see Warnings). Adnexal torsion (as complication of ovarian enlargement). Mild to moderate ovarian enlargement. Hemoperitoneum. Post-Marketing Experience. In addition to adverse events reported from clinical trials, the following events have been reported during post-marketing use of Ovidrel(R). Therefore, these events were reported from population of uncertain size, the frequency or causal relationship to Ovidrel(R) cannot be reliably determined.Cases of allergic reactions, including anaphylactic reactions and mild reversible skin rashes have been reported in patients treated with Ovidrel(R) since market introduction. The causal relationship is unknown.Thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome (see WARNINGS). Cases of allergic reactions, including anaphylactic reactions and mild reversible skin rashes have been reported in patients treated with Ovidrel(R) since market introduction. The causal relationship is unknown.. Thromboembolic events both in association with, and separate from, the Ovarian Hyperstimulation Syndrome (see WARNINGS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies to evaluate the carcinogenic potential of Ovidrel(R) in animals have not been performed. In vitro genotoxicity testing of Ovidrel(R) in bacteria and mammalian cell lines, chromosome aberration assay in human lymphocytes and in-vivo mouse micronucleus have shown no indication of genetic defects.

CLINICAL PHARMACOLOGY SECTION.

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(R) 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(R) 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(R) followed biexponential model and was linear over range of 25 ug to 1000 ug. Pharmacokinetic parameter estimates following SC administration of Ovidrel(R) 250 ug to females are presented in Table 1.Table 1: Pharmacokinetic Parameters (mean +- SD) of r-hCG after Single-Dose Administration of Ovidrel(R) in Healthy Female VolunteersOvidrel(R) 250 ug SCCmax: peak concentration (above baseline), tmax: time of Cmax, AUC: total area under the curve, 1/2 elimination half-life, F: bioavailabilityCmax (IU/L)121 +- 44tmax (h)median (range) 24 (12-24)AUC (hIU/L)7701 +- 2101t 1/2 (h)29 +- 6F0.4 +- 0.1. Absorption. Following subcutaneous administration of Ovidrel(R) 250 ug, maximum serum concentration (121 +- 44 IU/L) is reached after approximately 12 to 24 hours. The mean absolute bioavailability of Ovidrel(R) following single subcutaneous injection to healthy female volunteers is about 40%.. Distribution. Following intravenous administration of Ovidrel(R) 250 ug to healthy down-regulated female volunteers, the serum profile of hCG is described by 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 and the steady state volume of distribution is 5.9 +- 1.0 L.. Metabolism/Excretion. Following subcutaneous administration of Ovidrel(R), hCG is eliminated from the body with mean terminal half-life of about 29 +- hours. After intravenous administration of Ovidrel(R) 250 ug 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(R) induced clear increase in androstenedione serum levels by 24 hours after dosing. Pharmacodynamic studies in females determined that the relationship of Ovidrel(R) pharmacokinetics to pharmacologic effect of Ovidrel(R) 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 250 ug dose.. Population pharmacokinetics and pharmacodynamics. In patients undergoing in-vitro fertilization/embryo transfer given Ovidrel(R) subcutaneously to trigger ovulation, the results of population PK/PD analysis generally supported the data obtained in healthy subjects. Pharmacokinetic parameters for Ovidrel(R) include 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(R) PreFilled Syringe (choriogonadotropin alfa injection) has been determined to be bioequivalent to Ovidrel(R) (choriogonadotropin alfa for injection) based on the statistical evaluation of AUC and Cmax. summary of the Ovidrel(R) PreFilled Syringe pharmacokinetic parameters is presented in Table 2.Table 2: Summary of Ovidrel(R) PreFilled Syringe Pharmacokinetic ParametersParameterCmax (mIU/mL)AUClast (mIUh/mL)AUC(mIUh/mL)AUCextrapolated (%)tmax (h)Abbreviations are: Cmax: peak concentration (above baseline); tmax time of Cmax Mean12510050103502.8520.0(Min-Max)(68.0-294)(5646-14850)(5800-15100)(1.08-6.27)(9.00-48.0). Special populations. Safety, efficacy, and pharmacokinetics of Ovidrel(R) 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(R) PreFilled Syringe may interfere with the interpretation of pregnancy tests. (see PRECAUTIONS.).

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. The safety and efficacy of Ovidrel(R) 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(R) 250 ug and Ovidrel(R) 500 ug administered subcutaneously versus 10,000 USP Units of an approved urinary-derived hCG product administered intramuscularly were assessed in 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(R) 250 ug. The number of oocytes retrieved was similar for the Ovidrel(R) and urinary-derived hCG (10,000 USP Units) treatment groups. The efficacy of Ovidrel(R) 250 ug and Ovidrel(R) 500 ug 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(R) 250 ug are summarized in Table 3.Table 3: Efficacy Outcomes of r-hCG in ART (Study 7927)ParameterOvidrel(R) 250 ug(n 94)Mean number of oocytes retrieved per patient13.60Mean number of mature oocytes retrieved per patient7.6Mean number of PN fertilized oocytes per patient7.2Mean number of PN or cleaved embryos per patient7.6Implantation rate per embryo transferred (%)18.7Mean mid-luteal serum progesterone levels (nmol/Lnmol/L 3.18 ng/mL)423Clinical pregnancy rate per initiated treatment cycle (%)Clinical pregnancy was defined as pregnancy during which fetal sac (with or without heartbeat activity) was detected by ultrasound on day 35-42 after hCG administration) 35.1Clinical pregnancy rate per transfer (%) 36.3For the 33 patients who achieved clinical pregnancy with Ovidrel(R) 250 ug, the outcomes of the pregnancies are presented in Table 4.Table 4: Pregnancy Outcomes of r-hCG in ART (Study 7927)ParameterOvidrel(R) 250 ug(n 33)Clinical pregnancies not reaching term4 (12.1%)Live births29 (87.9%)Singleton20 (69.0%)Multiple birth9 (31.0%)The safety and efficacy of Ovidrel(R) 250 ug administered subcutaneously versus 5,000 IU of an approved urinary-derived hCG product administered subcutaneously were assessed in 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(R) 250 ug. The efficacy of Ovidrel(R) 250 ug 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(R) 250 ug are summarized in Table 5.Table 5: Efficacy Outcomes of r-hCG in ART (Study 7648)ParameterOvidrel(R) 250 ug(n 97)Mean number of oocytes retrieved per patient10.6Mean number of mature oocytes retrieved per patient10.1Mean number of PN fertilized oocytes per patient5.7Mean number of PN or cleaved embryos per patient5.1Implantation rate per embryo transferred (%)17.4Mean mid-luteal serum progesterone levels (nmol/L)nmol/L 3.18 ng/mL 394Clinical pregnancy rate per initiated treatment cycle (%)Clinical pregnancy was defined as pregnancy during which fetal sac (with or without heartbeat activity) was detected by ultrasound on day 35-42 after hCG administration) 33Clinical pregnancy rate per transfer (%) 37.6For the 32 patients who achieved clinical pregnancy with Ovidrel(R) 250 ug, the outcomes of the pregnancies are presented in Table 6.Table 6: Pregnancy Outcomes of r-hCG in ART (Study 7648)ParameterOvidrel(R) 250 ug(n 32)Clinical Pregnancies not reaching term6 (18.8%)Live births26 (81.2%)Singleton18 (69.2%)Multiple birth8 (30.8%). Ovulation Induction (OI). The safety and efficacy of Ovidrel(R) 250 ug administered subcutaneously versus 5,000 IU of an approved urinary-derived hCG product administered intramuscularly were assessed in 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(R) 250 ug. The efficacy of Ovidrel(R) 250 ug 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(R) 250 ug are summarized in Table 7.Table 7: Efficacy Outcomes of r-hCG in OI (Study 8209)ParameterOvidrel(R) 250 ug(n 99)Ovulation Rate91 (91.9%)Clinical Pregnancy RateClinical pregnancy was defined as pregnancy during which 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 clinical pregnancy with Ovidrel(R) 250 ug, the outcome of the pregnancy is presented in Table 8.Table 8: Pregnancy Outcomes of r-hCG in OI (Study 8209)ParameterOvidrel(R) 250 ug(n 22)Clinical Pregnancies not reaching term7 (31.8%)Live births15 (68.2%)Singleton13 (86.7%)Multiple birth2 (13.3%).

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Ovidrel(R) 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 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.. 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 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.

DESCRIPTION SECTION.

DESCRIPTION. Ovidrel(R) PreFilled Syringe (choriogonadotropin alfa injection) is sterile liquid preparation of choriogonadotropin alfa (recombinant human Chorionic Gonadotropin, r-hCG). Choriogonadotropin alfa is water soluble glycoprotein consisting of two non-covalently linked subunits designated and 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 chain of r-hCG is identical to that of the chain of hCG, FSH and LH. The glycoform pattern of the 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 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 series of chromatographic steps. This process yields product with 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(R) PreFilled Syringe is sterile, liquid intended for subcutaneous (SC) injection. Each Ovidrel(R) PreFilled Syringe is filled with 0.515 mL containing 257.5 ug of choriogonadotropin alfa, 28.1 mg mannitol, 505 ug 85% O-phosphoric acid, 103 ug L-methionine, 51.5 ug Poloxamer 188, Sodium Hydroxide (for pH adjustment), and Water for Injection to deliver 250 ug of choriogonadotropin alfa in 0.5 mL. The pH of the solution is 6.5 to 7.5.Therapeutic Class: Infertility.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. For Subcutaneous Use Only. Infertile Women Undergoing Assisted Reproductive Technologies (ART). Ovidrel(R) PreFilled Syringe 250 ug should be administered one day following the last dose of the follicle stimulating agent. Ovidrel(R) 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(R) PreFilled Syringe should not be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography.Ovidrel(R) PreFilled Syringe 250 ug should be administered one day following the last dose of the follicle stimulating agent.Ovidrel(R) 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(R) Prefilled Syringe. Ovidrel(R) PreFilled Syringe is intended for single subcutaneous injection. Any unused material should be discarded.Ovidrel(R) PreFilled Syringe may be self-administered by the patient. Follow the directions below for injecting Ovidrel(R) 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 few minutes, place 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.

GENERAL PRECAUTIONS SECTION.

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(R) 250 ug, (10%) of 89 patients receiving Ovidrel(R) 500 ug 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.

GERIATRIC USE SECTION.

Geriatric Patients. Safety and effectiveness in geriatric patients has not been established.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Ovidrel(R) PreFilled Syringe (choriogonadotropin alfa injection) is supplied in sterile, liquid single dose pre-filled mL syringe. Each Ovidrel(R) PreFilled Syringe is filled with 0.515 mL containing 257.5 ug of choriogonadotropin alfa, 28.1 mg mannitol, 505 ug 85% O-phosphoric acid, 103 ug L-methionine, 51.5 ug Poloxamer 188, Sodium Hydroxide (for pH adjustment), and Water for Injection to deliver 250 ug of choriogonadotropin alfa in 0.5 mL.The following package combination is available:1 pre-filled syringe containing 250 ug Ovidrel(R) PreFilled Syringe NDC 44087-1150-1. pre-filled syringe containing 250 ug Ovidrel(R) PreFilled Syringe NDC 44087-1150-1. Storage. The Ovidrel(R) PreFilled Syringe must be stored refrigerated between 2-8C (36-46F) 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(R) PreFilled Syringe may be stored by the patient for no more than 30 days at room temperature (up to 25C (77F) but must be used within those 30 days.Protect from light.Store in original package. Discard unused material.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Ovidrel(R) 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(R) 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.. Selection of Patients. Before treatment with gonadotropins is instituted, thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Ovidrel(R) 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 greater predisposition to endometrial carcinoma as well as higher incidence of anovulatory disorders. 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(R) PreFilled Syringe therapy.Evaluation of the partners fertility potential should be included in the initial evaluation.. Before treatment with gonadotropins is instituted, thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Ovidrel(R) 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 greater predisposition to endometrial carcinoma as well as higher incidence of anovulatory disorders. 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(R) PreFilled Syringe therapy.. Evaluation of the partners fertility potential should be included in the initial evaluation.

INFORMATION FOR PATIENTS SECTION.

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 SECTION.

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:A rise in basal body temperatureIncrease in serum progesterone andMenstruation following shift in basal body temperatureWhen 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-sacOvarian stigmataCollapsed follicleSecretory endometriumAccurate interpretation of the indices of ovulation require physician who is experienced in the interpretation of these tests.. rise in basal body temperature. Increase in serum progesterone and. Menstruation following shift in basal body temperature. Fluid in the cul-de-sac. Ovarian stigmata. Collapsed follicle. Secretory endometrium.

NURSING MOTHERS SECTION.

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 nursing woman.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 250 ug/0.5 mL Syringe Carton. OVIDREL(R) PreFilledSyringe250 ug/0.5 mLchoriogonadotropin alfa injectionNDC 44087-1150-1For subcutaneous injectionRx Only1 Ovidrel(R) PreFilled SyringeEMDSERONO. PRINCIPAL DISPLAY PANEL 250 ug/0.5 mL Syringe Carton.

PEDIATRIC USE SECTION.

Pediatric Patients. Safety and effectiveness in pediatric patients has not been established.

PHARMACODYNAMICS SECTION.

Pharmacodynamics. In female subjects on oral contraception after an initial latency period, Ovidrel(R) induced clear increase in androstenedione serum levels by 24 hours after dosing. Pharmacodynamic studies in females determined that the relationship of Ovidrel(R) pharmacokinetics to pharmacologic effect of Ovidrel(R) 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 250 ug dose.

PHARMACOKINETICS SECTION.

Pharmacokinetics. When given by intravenous administration, the pharmacokinetic profile of Ovidrel(R) followed biexponential model and was linear over range of 25 ug to 1000 ug. Pharmacokinetic parameter estimates following SC administration of Ovidrel(R) 250 ug to females are presented in Table 1.Table 1: Pharmacokinetic Parameters (mean +- SD) of r-hCG after Single-Dose Administration of Ovidrel(R) in Healthy Female VolunteersOvidrel(R) 250 ug SCCmax: peak concentration (above baseline), tmax: time of Cmax, AUC: total area under the curve, 1/2 elimination half-life, F: bioavailabilityCmax (IU/L)121 +- 44tmax (h)median (range) 24 (12-24)AUC (hIU/L)7701 +- 2101t 1/2 (h)29 +- 6F0.4 +- 0.1. Absorption. Following subcutaneous administration of Ovidrel(R) 250 ug, maximum serum concentration (121 +- 44 IU/L) is reached after approximately 12 to 24 hours. The mean absolute bioavailability of Ovidrel(R) following single subcutaneous injection to healthy female volunteers is about 40%.. Distribution. Following intravenous administration of Ovidrel(R) 250 ug to healthy down-regulated female volunteers, the serum profile of hCG is described by 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 and the steady state volume of distribution is 5.9 +- 1.0 L.. Metabolism/Excretion. Following subcutaneous administration of Ovidrel(R), hCG is eliminated from the body with mean terminal half-life of about 29 +- hours. After intravenous administration of Ovidrel(R) 250 ug 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.

PRECAUTIONS SECTION.

PRECAUTIONS. 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(R) 250 ug, (10%) of 89 patients receiving Ovidrel(R) 500 ug 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:A rise in basal body temperatureIncrease in serum progesterone andMenstruation following shift in basal body temperatureWhen 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-sacOvarian stigmataCollapsed follicleSecretory endometriumAccurate interpretation of the indices of ovulation require physician who is experienced in the interpretation of these tests.. rise in basal body temperature. Increase in serum progesterone and. Menstruation following shift in basal body temperature. Fluid in the cul-de-sac. Ovarian stigmata. Collapsed follicle. Secretory endometrium. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies to evaluate the carcinogenic potential of Ovidrel(R) in animals have not been performed. In vitro genotoxicity testing of Ovidrel(R) 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 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 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.

PREGNANCY SECTION.

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

SPL UNCLASSIFIED SECTION.

FOR SUBCUTANEOUS USE.

STORAGE AND HANDLING SECTION.

Storage. The Ovidrel(R) PreFilled Syringe must be stored refrigerated between 2-8C (36-46F) 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(R) PreFilled Syringe may be stored by the patient for no more than 30 days at room temperature (up to 25C (77F) but must be used within those 30 days.Protect from light.Store in original package. Discard unused material.

WARNINGS SECTION.

WARNINGS. Gonadotropins, including Ovidrel(R) PreFilled Syringe (choriogonado-tropin alfa injection), should only be used by physicians who are thoroughly familiar with infertility problems and their management. Like other hCG products, Ovidrel(R) PreFilled Syringe is potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications. The risks of gonadoptropin treatment should be considered for women with risk factors of thromboembolic events such as prior medical or family history. Gonadotropin therapy requires certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see Precautions/ Laboratory Tests). Safe and effective induction of ovulation and use of Ovidrel(R) PreFilled Syringe in women requires monitoring of ovarian response with serum estradiol and transvaginal ultrasound on regular basis.. Overstimulation of the Ovary Following hCG Therapy. Ovarian Enlargement. Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain may occur in patients treated with FSH and hCG, and generally regresses without treatment within two or three weeks. Careful monitoring of ovarian response can further minimize the risk of overstimulation.If the ovaries are abnormally enlarged on the last day of FSH therapy, choriogonadotropin alfa should not be administered in this course of therapy. This will reduce the risk of development of Ovarian Hyperstimulation Syndrome.. Ovarian Hyperstimulation Syndrome (OHSS). OHSS is medical event distinct from uncomplicated ovarian enlargement. Severe OHSS may progress rapidly (within 24 hours to several days) to become serious medical event. It is characterized by an apparent dramatic increase in vascular permeability which can result in rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see Pulmonary and Vascular Complications). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).OHSS occurred in of 236 (1.7 %) patients treated with Ovidrel(R) 250 ug during clinical trials for ART and of 99 (3.0%) patients treated in the OI trial. OHSS occurred in of 89 (9.0%) patients who received Ovidrel(R) 500 ug. Two patients treated with Ovidrel(R) 500 ug developed severe OHSS.OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see Precautions/Laboratory Tests), the hCG must be withheld.If severe OHSS occurs, treatment with gonadotropins must be stopped and the patient should be hospitalized.A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.. Multiple Births. As with other hCG products, reports of multiple births have been associated with Ovidrel(R) treatment. In ART, the risk of multiple births correlates to the number of embryos transferred. Multiple births occurred in 17 of 55 live deliveries (30.9 %) experienced by women receiving Ovidrel(R) 250 ug in the ART studies. In the ovulation induction clinical trial, of 15 live deliveries (13.3%) were associated with multiple births in women receiving Ovidrel(R). The patient should be advised of the potential risk of multiple births before starting treatment.. Pulmonary and Vascular Complications. As with other hCG products, potential for the occurrence of arterial thromboembolism exists.