Gonal-f® RFF Pen (follitropin alfa injection) is indicated for the induction of ovulation and pregnancy in the oligo-anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure.  Gonal-f® RFF Pen is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program. Selection of Patients: Before treatment with Gonal-f® RFF Pen 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 Gonal-f® RFF Pen 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 Gonal-f® RFF Pen therapy. Evaluation of the partner’s fertility potential should be included in the initial evaluation.

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Infertility -- Inability to reproduce after a specified period of unprotected intercourse. Reproductive sterility is permanent infertility.

Fallopian tube obstruction --

Endometrial Carcinoma -- A malignant tumor arising from the epithelium that lines the cavity of the uterine body. The vast majority of endometrial carcinomas are adenocarcinomas; squamous cell and adenosquamous carcinomas represent a minority of the cases. Endometrioid adenocarcinoma is the most frequently seen variant of endometrial adenocarcinoma. Uterine bleeding is an initial clinical sign. The prognosis depends on the stage of the tumor, the depth of myometrial wall invasion, and the degree of differentiation. -- 2004

Disease -- A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.

Uterine hemorrhage -- Bleeding from blood vessels in the UTERUS, sometimes manifested as vaginal bleeding.

Physical findings -- Objective evidence of disease perceptible to the examining physician.

Gonal-f® RFF Pen (follitropin alfa injection) is contraindicated in women who exhibit: Prior hypersensitivity to recombinant FSH preparations or one of their excipients. High levels of FSH indicating primary gonadal failure. Uncontrolled thyroid or adrenal dysfunction. Sex hormone dependent tumors of the reproductive tract and accessory organs. An 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, not due to polycystic ovary syndrome (see "Selection of Patients"). Pregnancy.

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Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Primary testicular failure --

Neoplasms -- New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.

Pituitary Neoplasms -- Neoplasms which arise from or metastasize to the PITUITARY GLAND. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties (see ADENOMA, BASOPHIL; ADENOMA, ACIDOPHIL; and ADENOMA, CHROMOPHOBE). Pituitary tumors may compress adjacent structures, including the HYPOTHALAMUS, several CRANIAL NERVES, and the OPTIC CHIASM. Chiasmal compression may result in bitemporal HEMIANOPSIA.

Uterine hemorrhage -- Bleeding from blood vessels in the UTERUS, sometimes manifested as vaginal bleeding.

Ovarian Cysts -- General term for CYSTS and cystic diseases of the OVARY.

Hypertrophy -- General increase in bulk of a part or organ due to CELL ENLARGEMENT and accumulation of FLUIDS AND SECRETIONS, not due to tumor formation, nor to an increase in the number of cells (HYPERPLASIA).

Polycystic Ovary Syndrome -- A complex disorder characterized by infertility, HIRSUTISM; OBESITY; and various menstrual disturbances such as OLIGOMENORRHEA; AMENORRHEA; ANOVULATION. Polycystic ovary syndrome is usually associated with bilateral enlarged ovaries studded with atretic follicles, not with cysts. The term, polycystic ovary, is misleading.

Gonal-f® RFF Pen (follitropin alfa injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonal-f® RFF Pen is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications.  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 use of Gonal-f® RFF Pen in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis.  The lowest effective dose should be used. Overstimulation of the Ovary During FSH Therapy: Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain occurs in approximately 20% of those treated with urofollitropin 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 Gonal-f® RFF Pen therapy, hCG should not be administered in this course of therapy.  This will reduce the chances 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 6 of 83 (7.2%) Gonal-f® RFF treated women in Study 22240 (ovulation induction); none were classified as severe.  In Study 21884 (ART), OHSS occurred in 11 of 237 (4.6%) Gonal-f® RFF treated women and 1 (0.42%) was classified as severe.  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 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. Pulmonary and Vascular Complications: Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported.  In addition, thromboembolic events both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported.  Intravascular thrombosis and embolism can result in reduced blood flow to critical organs or the extremities.  Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb.  In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. Multiple Births:  Reports of multiple births have been associated with Gonal-f® RFF treatment.  In Study 22240 for women receiving Gonal-f® RFF over three treatment cycles, 20% of live births were multiple births.

In Study 21884, 35.1% of live births were multiple births in women receiving Gonal-f® RFF.  The rate of multiple births is dependent on the number of embryos transferred.  The patient should be advised of the potential risk of multiple births before starting treatment.