chorionic gonadotropin 5000 UNT/ML Injectable Solution [Novarel]

INDICATIONS AND USAGE 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. Selection of Patients 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.

DOSAGE AND ADMINISTRATION: Intramuscular Use Only The dosage regimen employed in any particular case will depend upon the indication for use, the age and weight of the patient and the physician’s preference. The following regimens have been advocated by various authorities. Prepubertal Cryptorchidism Not Due To Anatomical Obstruction 4,000 USP units three times weekly for three weeks. 5,000 USP units every second day for four injections. 15 injections of 500 to 1,000 USP units over a period of six weeks. 500 USP units three times weekly for four to six weeks. If this course of treatment is not successful, another is begun one month later giving 1,000 USP units per injection. Selected Cases Of Hypogonadotropic Hypogonadism In Males 500 to 1,000 USP units three times a week for three weeks, followed by the same dose twice a week for three weeks. 4,000 USP units three times weekly for six to nine months, following which the dosage may be reduced to 2,000 USP units three times weekly for an additional three months. Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not due to primary ovarian failure and who has been appropriately pretreated with human menotropins (see prescribing information for menotropins for dosage and administration for that drug product). 5,000 to 10,000 USP units one day following the last dose of menotropins. (A dosage of 10,000 units is recommended in the labeling for menotropins.) IMPORTANT: USE COMPLETELY WITHIN 60 DAYS AFTER RECONSTITUTION. REFRIGERATE AFTER RECONSTITUTION. Intramuscular Use Only The dosage regimen employed in any particular case will depend upon the indication for use, the age and weight of the patient and the physician’s preference. The following regimens have been advocated by various authorities. Prepubertal Cryptorchidism Not Due To Anatomical Obstruction 4,000 USP units three times weekly for three weeks. 5,000 USP units every second day for four injections. 15 injections of 500 to 1,000 USP units over a period of six weeks. 500 USP units three times weekly for four to six weeks. If this course of treatment is not successful, another is begun one month later giving 1,000 USP units per injection. Selected Cases Of Hypogonadotropic Hypogonadism In Males 500 to 1,000 USP units three times a week for three weeks, followed by the same dose twice a week for three weeks. 4,000 USP units three times weekly for six to nine months, following which the dosage may be reduced to 2,000 USP units three times weekly for an additional three months. Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not due to primary ovarian failure and who has been appropriately pretreated with human menotropins (see prescribing information for menotropins for dosage and administration for that drug product). 5,000 to 10,000 USP units one day following the last dose of menotropins. (A dosage of 10,000 units is recommended in the labeling for menotropins.) IMPORTANT: USE COMPLETELY WITHIN 60 DAYS AFTER RECONSTITUTION. REFRIGERATE AFTER RECONSTITUTION.

WARNINGS Use hCG in conjunction with gonadotropin therapy only if the physician is experienced with infertility problems and is familiar with the criteria for patient selection, contraindications, warnings, precautions, and adverse reactions described in the package insert for gonadotropins. Gonadotropin therapy, including hCG, requires a 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 with use of PREGNYL requires monitoring of ovarian response with serum estradiol and transvaginal ultrasound on a regular basis. Anaphylaxis Anaphylaxis has been reported with urinary-derived hCG products. Ovarian Hyperstimulation Syndrome (OHSS) Ovarian Hyperstimulation Syndrome (OHSS) is a medical event distinct from uncomplicated ovarian enlargement and may progress rapidly to become a serious medical event. OHSS is characterized by a dramatic increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of the development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy, have been reported in association with OHSS. OHSS occurs after gonadotropin treatment has been discontinued and it can develop rapidly, reaching its maximum 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, withhold hCG. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, assess women for the development of OHSS for at least two weeks after hCG administration. Severe OHSS may be life-threatening. Monitor women undergoing ovarian stimulation for early signs and symptoms of OHSS. Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment with PREGNYL. Adherence to the recommended PREGNYL dose and treatment regimen and careful monitoring of ovarian response is important to reduce the risk of OHSS. If serious OHSS occurs, stop gonadotropins, including hCG, and consider whether the woman should be hospitalized. Treatment is primarily symptomatic and overall consists of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, avoid diuretics except in the late phase of resolution. Initiate early consultation with a physician experienced in the management of OHSS and fluid and electrolyte imbalances. Pulmonary and Vascular Complications Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic reactions both in association with, and separate from OHSS have been reported following gonadotropin therapy. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Women with generally recognized risk factors for thrombosis, such as a personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarction. In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of ovulation induction, in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment need to be weighed against the risks. Pregnancy itself also carries an increased risk of thrombosis. Ovarian Torsion Ovarian torsion has been reported after treatment with gonadotropins, including PREGNYL. Ovarian torsion may be related to other conditions, such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, and previous or current ovarian cysts. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion. Multi-Fetal Gestation and Birth Multi-fetal gestation and births have been reported with all gonadotropin therapy including hCG. Advise women of the potential risk of multiple births before starting treatment with gonadotropins including PREGNYL. Congenital Malformations The incidence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no indications that the use of gonadotropins during ART is associated with an increased risk of congenital malformations. Ectopic Pregnancy Infertile women undergoing Assisted Reproductive Technologies (ART) have an increased incidence of ectopic pregnancy. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important. Spontaneous Abortion The risk of spontaneous abortion (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be a factor of the underlying infertility. Ovarian Neoplasms There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug therapy for ovarian stimulation; however, a causal relationship has not been established.

CONTRAINDICATIONS Prior hypersensitivity reactions to human gonadotropins, including hCG, or any of the excipients (see ADVERSE REACTIONS ). High serum FSH, indicating primary gonadal failure in women. Presence of uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders). Tumors of the hypothalamus or pituitary gland and ovary, breast, or uterus in females and breast or prostate in males. Malformations of the reproductive organs incompatible with pregnancy. Fibroid tumors of the uterus incompatible with pregnancy. Abnormal vaginal bleeding of undetermined origin.

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 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 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 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) 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 .)