OVIDREL Solution for injection Ref.[10894] Active ingredients: Choriogonadotropin alpha

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.

(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):

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):

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”)

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.

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.