FOLLISTIM^® AQ Cartridge

(follitropin beta injection)

FOLLISTIM^® AQ Cartridge(follitropin beta injection)

Safety

Adverse reactions

Common adverse reactions reported at a frequency of ≥2% in a randomized, double-blind, active-controlled, comparative study of normal ovulatory women undergoing controlled ovarian stimulation as part of an in vitro fertilization or intracytoplasmic sperm injection cycle

System organ class	Adverse reactions	FOLLISTIM AQ Cartridge treatment (N=751) n^a (%)
Nervous system disorders	Headache	55 (7.3%)
Gastrointestinal disorders	Nausea	29 (3.9%)
Reproductive system and breast disorders	Ovarian hyperstimulation syndrome	48 (6.4%)
	Pelvic discomfort	62 (8.3%)
	Pelvic pain	41 (5.5%)
General disorders and administration site conditions	Fatigue	17 (2.3%)

(a) n=number of women with the adverse reaction.

Indication

FOLLISTIM AQ Cartridge is indicated for the induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure.

FOLLISTIM AQ Cartridge is also indicated for pregnancy in normal ovulatory women undergoing controlled ovarian stimulation as part of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

Prior to initiation of treatment with FOLLISTIM AQ Cartridge for ovulation induction (OI) or IVF/ICSI:

Women should have a complete gynecologic and endocrinologic evaluation and diagnosis of the cause of infertility.
The possibility of pregnancy should be excluded.
The fertility status of the male partner should be evaluated.

Additionally, for women undergoing OI:

Primary ovarian failure should be excluded.
Tubal patency should be demonstrated.

Selected Safety Information

CONTRAINDICATIONS

FOLLISTIM AQ Cartridge is contraindicated in women who exhibit any of the following: prior hypersensitivity to recombinant human follicle-stimulating hormone (hFSH) products; high levels of FSH indicating primary gonadal failure; presence of uncontrolled non-gonadal endocrinopathies (eg, thyroid, adrenal, or pituitary disorders); hypersensitivity reactions to streptomycin or neomycin (FOLLISTIM AQ may contain traces of these antibiotics.); tumors of the ovary, breast, uterus, hypothalamus, or pituitary gland; pregnancy; heavy or irregular vaginal bleeding of undetermined origin; or ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS).

WARNINGS AND PRECAUTIONS

FOLLISTIM AQ Cartridge should be prescribed only by physicians who are experienced in infertility treatment. FOLLISTIM AQ Cartridge contains a potent gonadotropic substance capable of causing ovarian hyperstimulation syndrome (OHSS) with or without pulmonary or vascular complications and multiple births. Gonadotropin therapy requires the availability of appropriate monitoring facilities.

Abnormal Ovarian Enlargement

In order to reduce the risks associated with abnormal ovarian enlargement that may occur with FOLLISTIM AQ therapy, treatment should be individualized and the lowest effective dose should be used. Careful monitoring, including use of ultrasound monitoring of ovarian response, is important to reduce the risk of overstimulation. The concurrent determination of serum estradiol levels may also be useful.

Ovarian Hyperstimulation Syndrome

OHSS is a medical entity distinct from uncomplicated ovarian enlargement. Severe OHSS may be life-threatening. OHSS may be caused by administration of human Chorionic Gonadotropin (hCG) and by pregnancy (endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be associated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs more than 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration. Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment with FOLLISTIM AQ Cartridge. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended. Follow current clinical practice for reducing the risk of OHSS during IVF or ICSI. To monitor the risk of OHSS, ultrasound assessments of follicular development should be performed prior to treatment and at regular intervals during treatment. During clinical trials with FOLLISTIM or FOLLISTIM AQ Cartridge therapy, OHSS occurred in 7.6% of 105 women (OI) and 6.4% of 751 women (IVF or ICSI) treated with FOLLISTIM and FOLLISTIM AQ Cartridge, respectively.

Pulmonary and Vascular Complications

Serious pulmonary conditions, including acute respiratory distress syndrome, have been reported in women treated with gonadotropins. Thromboembolic events, both in association with and separate from OHSS, have been reported following therapy with gonadotropins, including FOLLISTIM AQ Cartridge. In women with generally recognized risk factors for thromboembolic events, such as a personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins, including FOLLISTIM AQ Cartridge. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb, and rarely, in myocardial infarction. In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of OI, IVF, or ICSI need to be weighed against the risks. It should be noted that pregnancy itself also carries an increased risk of thrombosis.

Ovarian Torsion

Ovarian torsion has been reported after treatment with gonadotropins including FOLLISTIM AQ Cartridge. Ovarian torsion may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cysts and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

Multi-fetal Gestation and Births

Multi-fetal gestation and births have been reported with all gonadotropin treatments including FOLLISTIM AQ Cartridge treatment. The woman and her partner should be advised of the potential risks for the mother (pregnancy and delivery complications) and the neonate (low birth weight) before starting treatment. For anovulatory women undergoing ovulation induction, monitoring follicular development with transvaginal ultrasonography may aid in determining whether or not to continue the cycle in order to reduce the risk of multi-fetal gestations. The concurrent determination of serum estradiol levels may also be useful. In women undergoing IVF or ICSI procedures, the risk of multiple pregnancy is mainly related to the number of embryos transferred.

Congenital Anomalies

The incidence of congenital malformations after IVF or ICSI may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (eg, maternal age, sperm characteristics) and to the higher incidence of multifetal gestations after IVF or ICSI. There are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations.

Ectopic Pregnancy

Infertile women undergoing IVF or ICSI have an increased incidence of ectopic pregnancies. Early confirmation of an intrauterine pregnancy should be determined by transvaginal ultrasound.

Spontaneous Abortion

Spontaneous abortions (miscarriage) have been reported for all gonadotropin products, including FOLLISTIM AQ Cartridge. However, causality has not been established, but may be related to a number of factors, including the underlying infertility.

Ovarian and Other Reproductive System Neoplasms

There have been infrequent reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for controlled ovarian stimulation; however, a causal relationship has not been established.

FOLLISTIM Pen

The FOLLISTIM Pen is intended only for use with FOLLISTIM AQ Cartridge. The FOLLISTIM Pen is not recommended for the blind or visually impaired without the assistance of an individual with good vision who is trained in the proper use of the injection device.