Ovidrel

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 For Subcutaneous Use Only 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. Figure 1 Figure 2

CONTRAINDICATIONS 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.

WARNINGS Gonadotropins, including Ovidrel ® 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 ® PreFilled Syringe is a 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 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 and use of Ovidrel ® PreFilled Syringe in women requires monitoring of ovarian response with serum estradiol and transvaginal ultrasound on a 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 a medical event distinct from uncomplicated ovarian enlargement. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an apparent 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 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 4 of 236 (1.7 %) patients treated with Ovidrel ® 250 µg during clinical trials for ART and 3 of 99 (3.0%) patients treated in the OI trial. OHSS occurred in 8 of 89 (9.0%) patients who received Ovidrel ® 500 µg. Two patients treated with Ovidrel ® 500 µg 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 ® 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 ® 250 µg in the ART studies. In the ovulation induction clinical trial, 2 of 15 live deliveries (13.3%) were associated with multiple births in women receiving Ovidrel ® . The patient should be advised of the potential risk of multiple births before starting treatment. Pulmonary and Vascular Complications As with other hCG products, a potential for the occurrence of arterial thromboembolism exists.

ADVERSE REACTIONS (see WARNINGS ) The safety of Ovidrel ® was examined in four clinical studies that treated 752 patients of whom 335 received Ovidrel ® 250 µg 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 ® or an approved urinary-derived hCG, 14.6 % (49 of 335 patients) in the Ovidrel ® 250 µg group experienced application site disorders compared to 28% (92 of 328 patients) in the approved u-hCG group. Adverse events reported for Ovidrel ® 250 µg occurring in at least 2% of patients (regardless of causality) are listed in Table 9 for the 3 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 System Ovidrel ® 250 µg (n=236) Preferred Term Incidence Rate % (n) At Least One Adverse Event 33.1% (78) Application Site Disorders 14.0% (33) Injection Site Pain 7.6% (18) Injection Site Bruising 4.7% (11) Gastro-Intestinal System Disorders 8.5% (20) Abdominal Pain 4.2% (10) Nausea 3.4% ( 8) Vomiting 2.5% ( 6) Secondary Terms (Post-Operative Pain) 4.7% (11) Post-Operative Pain 4.7% (11) Adverse events not listed in Table 9 that occurred in less than 2% of patients treated with Ovidrel ® 250 µg whether or not considered causally related to Ovidrel ® , 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 System Ovidrel ® 250 µg (n=99) Preferred Term Incidence Rate % (n) At Least One Adverse Event 26.2% (26) Application Site Disorders 16.2% (16) Injection site pain 8.1% (8) Injection site inflammation 2.0% (2) Injection site bruising 3.0% (3) Injection site reaction 3.0% (3) Reproductive Disorders, Female 7.1% (7) Ovarian cyst 3.0% (3) Ovarian hyperstimulation 3.0% (3) Gastro-Intestinal System Disorders 4.0% (4) Abdominal pain 3.0% (3) Additional adverse events not listed in Table 10 that occurred in less than 2% of patients treated with Ovidrel ® 250 µg, whether or not considered causally related to Ovidrel ® , 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 Abortion Ectopic Pregnancy Premature Labor Postpartum Fever Congenital Abnormalities Of 125 clinical pregnancies reported following treatment with FSH and Ovidrel ® 250 µg or 500 µg, three were associated with a congenital anomaly of the fetus or newborn. Among patients receiving Ovidrel ® 250 µg, cranial malformation was detected in the fetus of one woman and a 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 a woman who received Ovidrel ® 500 µg, one birth in a set of triplets was associated with Down's 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 a complication of ovarian enlargement) Mild to moderate ovarian enlargement Hemoperitoneum There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship 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 ")

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.