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 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 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

Gonal-F® (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy anovulatory infertile patients in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-F® is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.

Selection of Patients

1. Before treatment with Gonal-F® 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® only if enrolled in an in vitro fertilization program.

2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.

3. Appropriate evaluation should be performed to exclude pregnancy.

4. 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® therapy.

5. Evaluation of the partner's fertility potential should be included in the initial evaluation.

Dosage

Infertile Patients with oligo-anovulation: The dose of Gonal-F® (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® may range up to 300 IU per day depending on the individual patient response. Gonal-F® 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® 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, (5,000 USP units) should be given 1 day after the last dose of Gonal-F®. 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® 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, 5,000 USP units of hCG must be given 1 day after the last dose of Gonal-F® 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®.

Assisted Reproductive Technologies: In the treatment of patients with oligo-anovulatory infertility the dose of Gonal-F® to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with Gonal-F® 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, whose endogenous gonadotropin levels are suppressed, Gonal-F® 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 (5,000 to 10,000 USP units) 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 ampules of Gonal-F® in one-half to one mL of Sterile Water for Injection, USP (concentration should not exceed 225 IU/0.5 mL) and ADMINISTER SUBCUTANEOUSLY immediately. Any unused reconstituted material should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Gonal-F® (follitropin alfa for injection) is supplied in a sterile lyophilized form in single dose ampules containing 75 or 150 IU FSH activity. The following package combinations are available:

- 1 ampule 75 IU Gonal-F® and 1 ampule 1 mL Sterile Water for Injection, USP, NDC 44087-9075-1

- 10 ampules 75 IU Gonal-F® and 10 ampules 1 mL Sterile Water for Injection, USP, NDC 44087-9075-3

- 100 ampules 75 IU Gonal-F® and 100 ampules 1 mL Sterile Water for Injection, USP, NDC 44087-9075-4

- 1 ampule 150 IU Gonal-F® and 1 ampule 1 mL Sterile Water for Injection, USP, NDC 44087-9150-1

Lyophilized ampules may be stored refrigerated or at room temperature 2°-25° C (36°-77° F). Protect from light. Use immediately after reconstitution. Discard unused material.

Caution: Federal law prohibits dispensing without prescription.

The safety of Gonal-F® was examined in four clinical studies that enrolled 691 patients into two studies for ovulation induction (454 patients) and two studies for ART (237 patients).

Adverse events occurring in more than 10% of patients were headache, ovarian cyst, nausea, and upper respiratory tract infection in the US ovulation induction study and headache in the US ART study. Adverse events (without regard to causality assessment) occurring in at least 2% of patients are listed in Table 10 and Table 11.

* up to 3 cycles of therapy
** Severe = 0.8% of 118 patients in Study 5727

Additional adverse events not listed in Table 10 that occurred in 1 to 2% of Gonal-F® treated patients in the US ovulation induction study included the fol lowing: leukorrhea, vaginal hemorrhage, migraine, fatigue, asthma, nervousness, somnolence, and hypotension.

Additional adverse events not listed in Table 11 that occurred in 1 to 2% of Gonal-F® treated patients in the US Assisted Reproductive Technology (ART) study included the following: D&C following delivery or abortion, dysmenorrhea, vaginal hemorrhage, diarrhea, tooth disorder, vomiting, dizziness, paraesthesia, abdomen enlarged, chest pain, fatigue, dyspnea, anorexia, anxiety, somnolence, injection site inflammation, injection site reaction, pruritus, pruritus genital, myalgia, thirst, and palpitation.

Two additional clinical studies (for ovulation induction and ART, respectively) were conducted in Europe. The safety profiles from these two studies were comparable to that of the data presented above.

The following medical events have been reported subsequent to pregnancies resulting from Gonal-F® therapy in controlled clinical studies:

1. Spontaneous Abortion
2. Ectopic Pregnancy
3. Premature Labor
4. Postpartum Fever
5. Congenital abnormalities

TWO incidents of congenital cardiac malformations have been reported in children born following pregnancies resulting from treatment with Gonal-F® and hCG in Gonal-F® clinical studies 5642 and 5727. In addition, pregnancy occurring in study 5533 following treatment with Gonal-F® and hCG was complicated by apparent failure of intrauterine growth and terminated for a suspected syndrome of congenital abnormalities. No specific diagnosis was made. The incidence does not exceed that found in the general population.

The following adverse reactions have been previously reported during menotropin therapy:

1. Pulmonary and vascular complications (see WARNINGS),
2. Adnexal torsion (as a complication of ovarian enlargement),
3. Mild to moderate ovarian enlargement,
4. 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.

No drug/drug interaction studies have been performed.

Gonal-F® (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonal-F® is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) 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

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® 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 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, below). 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 9 of 228 (3.9%) Gonal-F® treated women during ovulation induction clinical trials and of this number, 1 of 228 (0.4%) was classified as severe. In ART clinical studies OHSS occurred in 0 of 116 (0.0%) Gonal-F® treated women. 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

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® treatment. In ovulation induction clinical trials, 12.3% of live births were multiple births in women receiving Gonal-F® and 14.5% of live births were multiple births in women receiving urofollitropin. In IVF/ET clinical trials, 44.0% of live births were multiple births in women receiving Gonal-F® and 41.0% of live births were multiple births in women receiving urofollitropin and is dependent on the number of embryos transferred. The patient should be advised of the potential risk of multiple births before starting treatment.

General

Careful attention should be given to the diagnosis of infertility in candidates for Gonal-F® (follitropin alfa for injection) therapy (see INDICATIONS AND USAGE: Selection of Patients).

Infrormation for Patients

See PATIENT INFORMATION section.

Laboratory Tests

In most instances, treatment with Gonal-F® 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:

1. A rise in basal body temperature;
2. Increase in serum progesterone; and
3. 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:

1. Fluid in the cul-de-sac;
2. Ovarian stigmata;
3. Collapsed follicle; and
4. 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®. However, r-hFSH 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 r-hFSH (³ 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®, 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.

Aside from possible ovarian hyperstimulation and multiple gestations (see WARNINGS), there is no information on the consequences of acute overdosage with Gonal-F® (follitropin alfa for injection).

Gonal-F® (follitropin alfa for injection) is contraindicated in women who exhibit:

1. Prior hypersensitivity to recombinant FSH preparations or one of their excipients.

2. High levels of FSH indicating primary ovarian failure.

3. Uncontrolled thyroid or adrenal dysfunction.

4. An organic intracranial lesion such as a pituitary tumor.

5. Abnormal uterine bleeding of undetermined origin (see INDICATIONS AND USAGE: Selection of Patients).

6. Ovarian cyst or enlargement of undetermined origin (see INDICATIONS AND USAGE: Selection of Patients).

7. Sex hormone dependent tumors of the reproductive tract and accessory organs.

8. Pregnancy.

Gonal-f®RFF (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH, the active component of Gonal-f® RFF is the primary hormone responsible for follicular recruitment and development. In order to effect final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Gonal-f® RFF when monitoring of the patient indicates that sufficient follicular development has occurred. There is interpatient variability in response to FSH administration.

Pharmacokinetics

Single-dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 300 IU Gonal-f® RFF to 21 pre-menopausal healthy female volunteers who were pituitary down-regulated with a GnRH agonist.

The descriptive statistics for the pharmacokinetic parameters are presented in Table 1.

Table 1: Pharmacokinetic parameters of FSH following administration of Gonal-f® RFF

Absorption

The absorption rate of Gonal-f® RFF following subcutaneous administration is slower than the elimination rate. Hence, the pharmacokinetics of Gonal-f® RFF are absorption rate-limited.

Distribution

Human tissue or organ distribution of FSH has not been determined for Gonal-f® RFF.

Metabolism/Excretion

FSH metabolism and excretion following administration of Gonal-f® RFF have not been studied in humans.

Special populations

Safety, efficacy, and pharmacokinetics of Gonal-f® RFF in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions

No drug-drug interaction studies have been conducted (see PRECAUTIONS).

Clinical Studies

The safety and efficacy of Gonal-f® RFF have been examined in two clinical studies: one study (Study 22240) for ovulation induction and one study (Study 21884) for assisted reproductive technologies (ART).

Ovulation Induction (OI)

Study 22240 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women undergoing ovulation induction. Patients were randomized to either Gonal-f® RFF (n=83), administered subcutaneously, or a comparator recombinant human FSH. The use of insulin-sensitizing agents was allowed during the study. Efficacy was assessed using the mean ovulation rate in the first cycle of treatment. The cycle 1 ovulation rate (primary outcome) for Gonal-f® RFF is presented in Table 2. Additionally, this table includes cumulative secondary outcome results from cycle 1 through 3. Study 22240 was not powered to demonstrate differences in these secondary outcomes.

Table 2: Cumulative Ovulation and Clinical Pregnancy Rates in Ovulation Induction

Assisted Reproductive Technologies (ART)

Study 21884 was a phase III, assessor-blind, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for Assisted Reproductive Technologies (ART) after pituitary down-regulation with a GnRH agonist. Patients were randomized to either Gonal-f® RFF (n=237), administered subcutaneously, or a comparator recombinant human FSH. Randomization was stratified by insemination technique [conventional in-vitro fertilization (IVF) vs. intra-cytoplasmic sperm injection (ICSI)]. Efficacy was assessed using the mean number of fertilized oocytes the day after insemination. The initial doses of Gonal-f® RFF were 150 IU a day for patients < 35 years old and 225 IU for patients ≥ 35 years old. The maximal dose allowed for both age groups was 450 IU per day. Treatment outcomes for Gonal-f® RFF are summarized in Table 3.

Table 3: Treatment Outcomes in ART

Prior to therapy with Gonal-F®, 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 (see WARNINGS) and other possible adverse reactions (see ADVERSE REACTIONS) should also be discussed.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FOLLITROPIN ALFA - INJECTION

(foll-ih-TROH-pin)

COMMON BRAND NAME(S): Gonal-F

USES: This medication is used to treat certain fertility problems in women. It provides the hormone (FSH) that helps cause the ovaries to produce eggs. This medication is usually used in combination with another hormone (hCG) for the growth and release of a mature egg (ovulation).

This medication is not recommended for women whose ovaries no longer make eggs properly (primary ovarian failure).

HOW TO USE: This medicine comes with a Patient Information Leaflet. Read it carefully. Ask your doctor, nurse, or pharmacist any questions that you may have about this medicine.

Learn all preparation and usage instructions in the product package. If any of the information is unclear, consult your doctor or pharmacist.

Wash your hands with soap and water before using this medication. Before injecting each dose, clean the injection site with rubbing alcohol. It is important to change the location of the injection site daily to avoid discomfort or problem areas under the skin. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

Inject this medication under the skin or into a muscle, usually once a day or as directed by your doctor.

Dosage and length of treatment are based on your medical condition and response to treatment. Your doctor will do blood/medical tests (e.g., estradiol blood levels, ultrasound) to find the right dose for you and to decide when to inject the next medication (hCG).

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist.

SIDE EFFECTS: Headache, nausea, vomiting, mild stomach/abdominal pain, bloating, redness/pain at the injection site, or breast tenderness/pain may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual bleeding from the vagina/uterus, pain/redness/swelling of the calf muscles, cold/numb/pale skin of the arms/legs/hands/feet, swelling of ankles/hands/feet.

Seek immediate medical attention if any of these rare but very serious side effects occur: weakness on one side of the body, slurred speech, vision changes, sudden severe headache, chest pain, shortness of breath.

This medication may cause a condition known as ovarian hyperstimulation syndrome (OHSS). This condition may occur during treatment and after treatment has been stopped. Rarely, serious OHSS causes fluid to suddenly build up in the stomach, chest, and heart area. Seek immediate medical attention if you develop the following side effects: severe pain or swelling in the lower abdominal (pelvic) area, severe nausea/vomiting, sudden/rapid weight gain, difficult/painful breathing, change in the amount of urine.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: other fertility problems (e.g., primary ovarian failure), abnormal bleeding from the vagina/uterus, thyroid problems, adrenal gland problems, cancer of the reproductive organs (e.g., breast, uterus, ovary), tumor in the brain (e.g., pituitary tumor), ovarian cysts or enlarged ovaries (not due to polycystic ovary syndrome).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood clots, polycystic ovarian syndrome, stroke, certain heart diseases (e.g., angina, heart attack), lung problems (e.g., asthma).

Multiple births may occur as a result of this treatment. Discuss the risks and benefits of having such a pregnancy with your doctor.

Stop using this medication when you become pregnant. This medication must not be used during pregnancy. If you think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible harm to the nursing infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: clomiphene.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood hormone tests such as estradiol level, liver tests, ultrasound) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details.

It is important to keep all regular medical and laboratory appointments so your doctor can closely monitor your response to help reduce the risk of serious side effects and determine the timing of your hCG dose.

MISSED DOSE: If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store the unmixed medication in the refrigerator or at room temperature between 36-77 degrees F (2-25 degrees C). Protect from light and moisture. Do not freeze. Do not store in the bathroom. Use immediately after mixing. Discard any unused liquid. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised August 2008 Copyright(c) 2008 First DataBank, Inc.