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Find Lowest Prices on Gonal-f® RFF (follitropin alfa) For Subcutaneous Injection *revised formulation female DESCRIPTION Gonal-f® RFF (follitropin alfa for injection) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the α- and β-subunits. The α- and β-subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structure are indistinguishable from those of human follicle stimulating hormone. Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors. Purification by immunochromatography using an antibody specifically binding FSH results in a highly purified preparation with a consistent FSH isoform profile, and a high specific activity. The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats. The in vivo biological activity of follitropin alfa has been calibrated against the first International Standard for recombinant human follicle stimulating hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization. Gonal-f® RFF (follitropin alfa injection) contains no luteinizing hormone (LH) activity. Based on available data derived from physico-chemical tests and bioassays, follitropin alfa and follitropin beta, another recombinant follicle stimulating hormone product, are indistinguishable. Gonal-f® RFF (follitropin alfa injection) is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution. Each Gonal-f® RFF single-dose vial is filled with 82 IU (6 µg)follitropin alfa to deliver 75 IU (5.5 µg) follitropin alfa and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate, 0.45 mg monobasic sodium phosphate monohydrate, 0.1 mg methionine, and 0.05 mg polysorbate 20. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials are reconstituted with Sterile Water for Injection, USP. Under current storage conditions, Gonal-f® RFF may contain up to 10% of oxidized follitropin alfa. Therapeutic Class: Infertility

INDICATIONS Gonal-f® RFF (follitropin alfa for 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 (follitropin alfa injection) 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 (follitropin alfa injection) 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 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 (follitropin alfa injection) therapy. Evaluation of the partner's fertility potential should be included in the initial evaluation. DOSAGE AND ADMINISTRATION Each Gonal-f® RFF Single-Dose vial delivers 75 IU follitropin alfa, respectively. Dosage Infertile Patients with oligo-anovulation The dose of Gonal-f® RFF (follitropin alfa for injection) to stimulate development of the follicle must be individualized for each patient. The lowest dose consistent with the expectation of good results should be used. Over the course of treatment, doses of Gonal-f® RFF (follitropin alfa injection) may range up to 300 IU per day depending on the individual patient response. Gonal-f® RFF (follitropin alfa injection) should be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5 to 7 days. Subsequent monitoring intervals should be based on individual patient response. It is recommended that the initial dose of the first cycle be 75 IU of Gonal-f® RFF (follitropin alfa injection) per day, ADMINISTERED SUBCUTANEOUSLY. An incremental adjustment in dose of up to 37.5 IU may be considered after 14 days. Further dose increases of the same magnitude could be made, if necessary, every seven days. Treatment duration should not exceed 35 days unless an E2 rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, chorionic gonadotropin, hCG,should be given after the last dose of Gonal-f® RFF (follitropin alfa injection) . Chorionic gonadotropin should be withheld if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, Gonal-f® RFF (follitropin alfa injection) treatment should be discontinued, hCG should not be administered, and the patient should be advised not to have intercourse; this may reduce the chance of development of the Ovarian Hyperstimulation Syndrome and, should spontaneous ovulation occur, reduce the chance of multiple gestation. A follow-up visit should be conducted in the luteal phase. The initial dose administered in the subsequent cycles should be individualized for each patient based on her response in the preceding cycle. Doses larger than 300 IU of FSH per day are not routinely recommended. As in the initial cycle, hCG must be given after the last dose of Gonal-f® RFF (follitropin alfa injection) to complete follicular development and induce ovulation. The precautions described above should be followed to minimize the chance of development of the Ovarian Hyperstimulation Syndrome. The couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity. Care should be taken to ensure insemination. In light of the indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct the necessary laboratory studies, he/she should not use Gonal-f® RFF (follitropin alfa injection) . Assisted Reproductive Technologies As in the treatment of patients with oligo-anovulatory infertility, the dose of Gonal-f® RFF (follitropin alfa injection) to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with Gonal-f® RFF should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day, until sufficient follicular development is attained. In most cases, therapy should not exceed ten days. In patients undergoing ART under 35 years old, whose endogenous gonadotropin levels are suppressed, Gonal-f® RFF (follitropin alfa injection) should be initiated at a dose of 150 IU per day. In patients 35 years old and older whose endogenous gonadotropin levels are suppressed, Gonal-f® RFF (follitropin alfa injection) should be initiated at a dose of 225 IU per day. Treatment should be continued until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after five days based on the patient's response; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 75-150 IU additionally at each adjustment. Doses greater than 450 IU per day are not recommended. Once adequate follicular development is evident, hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of therapy. This should reduce the chance of developing OHSS. Administration Dissolve the contents of one or more single-dose vials of Gonal-f® RFF in 1.0 mL of Sterile Water for Injection, USP (concentration should not exceed 450 IU/mL) and ADMINISTER SUBCUTANEOUSLY immediately. Any unused reconstituted material should be discarded. HOW SUPPLIED Gonal-f® RFF (follitropin alfa for injection) is supplied in a sterile, lyophilized form in single-dose vials containing 82 IU with diluent (Sterile Water for Injection, USP) in a pre-filled syringe. Following reconstitution with the diluent as described, upon administration each vial will deliver a dose of 75 IU. Lyophilized vials may be stored refrigerated or at room temperature (2°-25°C/36°-77°F). Protect from light. Use immediately after reconstitution. Discard unused material. Sterile Water for Injection, USP is provided in a pre-filled syringe. Separate needles are provided for reconstitution (18 G) and administration (29 G). Note: No antimicrobial or other substance has been added to the Sterile Water for Injection for the Single-Dose Vials. Sterile Water for Injection is not suitable for intravascular injection without its first having been made approximately isotonic by the addition of a suitable solute. The following package combinations are available: 1 vial Gonal-f® RFF (follitropin alfa injection) 75 IU and 1 pre-filled syringe Sterile Water for Injection, USP, 1 mL, 1 reconstitution needle (18 gauge), 1 administration needle (29 gauge), NDC 44087-9005-1 10 vials Gonal-f® RFF (follitropin alfa injection) 75 IU and 10 pre-filled syringes Sterile Water for Injection, USP, 1 mL, 10 reconstitution needle (18 gauge), 10 administration needle (29 gauge), NDC 44087-9005-6 Manufactured for: SERONO, INC., Rockland, MA 02370 U.S.A. Revised: December 2006 FDA rev date:

PATIENT INFORMATION PATIENT INSTRUCTIONS FOR USE FOR GONAL-F® RFF (follitropin alfa injection) Step 1: Mixing (reconstituting) the vial containing Gonal-f® RFF (follitropin alfa injection) 1. Wash your hands with soap and water. 2. Prepare a clean, flat surface for mixing your Gonal-f® RFF vials. Place alcohol wipes on the surface within easy reach. 3. Using your thumb, flip off the plastic cap of the Gonal-f® RFF vial(s). 4. Wipe the top of the vial stopper with an alcohol wipe. 5. Remove the wrapping from the 18G 1-½" pink mixing needle. 6. Carefully remove the protective cap off the pre-filled syringe labeled "sterile water for injection, USP". Twist the mixing needle on the prefilled syringe until it is tightened and remove the needle cap. 7. Position the 18G 1-½" needle of the syringe of water in a straight, upright position over the marked center circle of the rubber stopper on the vial of Gonal-f® RFF powder. Keep the 18G 1-½" needle at a 90 degree angle to the rubber stopper as you insert it through the center circle, or it may be difficult to depress the plunger. Slowly inject the water into the vial by depressing the syringe plunger. 8. Leave the 18G 1-½" needle and syringe in the vial. Gently rotate the vial between your fingers until the powder is dissolved. Do not shake the vial. If bubbles appear, wait a few moments for the bubbles to settle. The liquid drug should be clear. 9. Draw the total contents of the vial into the syringe. If necessary, invert the vial and pull back the 18G 1-½" needle as far as needed to withdraw the entire contents of the vial. Remove the 18G 1-½" needle and syringe containing the solution from the vial. 10. If more than one vial of powder medication is to be dissolved repeat steps 3, 4 and 7 to 9. A new alcohol wipe should be used to clean each vial. Use the same 18G 1-½" needle and syringe now containing reconstituted solution to reconstitute the additional vial(s). (Discard any other unused syringes of water for injection.) 11. Gently pull the plunger back to allow a small air space. Carefully recap the needle. Twist off the mixing needle from the syringe and discard safely. Step 2: Determining your dose on the injection syringe Your doctor will instruct you to take a specific dose of Gonal-f® RFF (follitropin alfa injection) . Step 3: Preparing your dose 12. Remove the wrapping from the 29G ½" red injection needle. Twist the injection needle on the syringe and remove the need cap. 13. Invert the syringe with the 29G ½" needle for injection facing up toward the ceiling, gently tap the syringe, and push the plunger until all air bubbles have been expelled. This step may need to be repeated if all air bubbles are not expelled. Slightly depress the plunger until a drop of liquid is release from the tip of the needle. 14. Recap the 29G ½" needle for injection while preparing the injection site. Carefully lay the syringe on a flat, clean surface. Do not touch the needle or allow the needle to touch any surface. You should now be ready to prepare to receive the injection. Step 4: Injecting your dose Your doctor, nurse, or pharmacist should provide you with injection training. Inject the prescribed dose as directed. Usual injection sites include the skin on the stomach, upper arm, or upper leg. Change the injection location each day to minimize discomfort. 15. All needles should be disposed of in an appropriate needle disposal container as directed by the doctor. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

SIDE EFFECTS The safety of Gonal-f® RFF (follitropin alfa injection) was examined in two clinical studies [(one ovulation induction study (n=83) and one study in ART (n=237)]. Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 22240 (ovulation induction) are listed in Table 4. Table 4: Safety Profile in Ovulation Induction Study 22240 Body System Preferred Term Gonal-f® RFF (follitropin alfa injection) Patients (%) Experiencing Events Treatment cycles = 176* n=83† Central and Peripheral Nervous System Headache 22 (26.5%) Dizziness 2 (2.4%) Migraine 3 (3.6%) Gastro-intestinal System Abdominal Pain 10 (12.0%) Nausea 3 (3.6%) Flatulence 3 (3.6%) Diarrhea 3 (3.6%) Toothache 3 (3.6%) Dyspepsia 2 (2.4%) Constipation 2 (2.4%) Stomatitis Ulcerative 2 (2.4%) Neoplasm Ovarian Cyst 3 (3.6%) Reproductive, Female Ovarian Hyperstimulation 6 (7.2%) Breast Pain Female 5 (6.0%) Vaginal Haemorrhage 5 (6.0%) Gynecological-related pain 2 (2.4%) Uterine haemorrhage 2 (2.4%) Respiratory System Sinusitis 5 (6.0%) Pharyngitis 6 (7.2%) Rhinitis 6 (7.2%) Coughing 2 (2.4%) Application Site Injection Site Pain 4 (4.8%) Injection Site Inflammation 2 (2.4%) Body as a Whole- General Back Pain 3 (3.6%) Pain 2 (2.4%) Fever 2 (2.4%) Hot Flushes 2 (2.4%) Malaise 2 (2.4%) Skin and Appendages Acne 3 (3.6%) Urinary System Micturition Frequency 2 (2.4%) Cystitis 2 (2.4%) Resistance Mechanism Infection viral 2 (2.4%) * up to 3 cycles of therapy † total patients treated with Gonal-f® RFF Headache occurred in greater than 20% of patients receiving Gonal-f® RFF (follitropin alfa injection) in this study. Adverse events (without regard to causality assessment) occurring in at least 2.0% of patients in Study 21884 (ART) are listed in Table 5. Table 5: Safety Profile in Assisted Reproductive Technologies Study 21884 Body System Preferred Term Gonal-f® RFF (follitropin alfa injection) Patients (%) Experiencing Events n=237† Gastro-intestinal System Abdominal Pain 55 (23.2%) Nausea 19 (8.0%) Body as a Whole- General Abdomen Enlarged 33 (13.9%) Pain 7 (3.0%) Central and Peripheral Nervous System Headache 44 (18.6%) Dizziness 5 (2.1)% Application Site Disorders Injection site bruising 23 (9.7%) Injection site pain 13 (5.5%) Injection site inflammation 10 (4.2%) Injection site reaction 10 (4.2%) Application site edema 6 (2.5%) Reproductive, Female Ovarian Hyperstimulation 11 (4.6%) Intermenstrual Bleeding 9 (3.8%) † total patients treated with Gonal-f® RFF Headache and abdomen enlargement occurred in more than 10% of patients and abdominal pain occurred in more than 20% of patients. The following medical events have been reported subsequent to pregnancies resulting from Gonal-f® RFF (follitropin alfa injection) therapy in controlled clinical studies: Spontaneous Abortion Ectopic Pregnancy Premature Labor Postpartum Fever There are no indications that use of gonadotropins during ART is associated with an increased risk of congenital malformations. The following adverse reactions have been previously reported during Gonal-f® RFF (follitropin alfa injection) 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 Reports During post-market surveillance, reports of hypersensitivity reactions including anaphylactoid reactions have been reported with the use of Gonal-f® RFF (follitropin alfa injection) . DRUG INTERACTIONS No drug/drug interaction studies have been performed.

WARNINGS Gonal-f® RFF (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonal-f® RFF (follitropin alfa injection) 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 (follitropin alfa injection) 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 (follitropin alfa injection) 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 (follitropin alfa injection) 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 (follitropin alfa injection) 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 (follitropin alfa injection) treatment. In Study 22240 for women receiving Gonal-f® RFF (follitropin alfa injection) 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 (follitropin alfa injection) . 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. PRECAUTIONS General Careful attention should be given to the diagnosis of infertility in candidates for Gonal-f® RFF (follitropin alfa for injection) therapy (see "Indications and Usage/ Selection of Patients"). Information for Patients Prior to therapy with Gonal-f® RFF (follitropin alfa injection) , 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. See "DOSAGE AND ADMINISTRATION" for "PATIENT INSTRUCTIONS FOR USE OF GONAL-F® RFF (follitropin alfa injection) ". Laboratory Tests In most instances, treatment of women with Gonal-f® RFF (follitropin alfa injection) 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 plasma estrogens do not give an indication of the size or number of follicles. 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; and Secretory endometrium. Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f® RFF. However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test. Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (≥40 IU/kg/day) for extended periods, through reduced fecundity. Pregnancy Pregnancy Category X. (See CONTRAINDICATIONS). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Gonal-f® RFF (follitropin alfa injection) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established.