Follistim AQ (Page 3 of 6)

5.4 Ovarian Torsion

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

5.5 Multi-fetal Gestation and Birth

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 risk of multi-fetal gestation and births before starting treatment.

5.6 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 (e.g., maternal age, sperm characteristics) and to the higher incidence of multi-fetal 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.

5.7 Ectopic Pregnancy

Since infertile women undergoing IVF or ICSI often have tubal abnormalities, the incidence of ectopic pregnancies might be increased. Early confirmation of an intrauterine pregnancy should be determined by β-hCG testing and transvaginal ultrasound.

5.8 Spontaneous Abortion

The risk of spontaneous abortions (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be a factor of the underlying infertility.

5.9 Ovarian Neoplasms

There have been infrequent reports of ovarian 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.

5.10 Laboratory Tests

For Women:

In most instances, treatment with Follistim AQ Cartridge will result only in follicular growth and maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following the administration of Follistim AQ Cartridge or when clinical assessment indicates that sufficient follicular maturation has occurred. The degree of follicular maturation and the timing of hCG administration can both be determined with the use of sonographic visualization of the ovaries and endometrial lining in conjunction with measurement of serum estradiol levels. The combination of transvaginal ultrasonography and measurement of serum estradiol levels is also useful for minimizing the risk of OHSS and multi-fetal gestations.

The clinical confirmation of ovulation is obtained by the following direct or indirect indices of progesterone production as well as sonographic evidence of ovulation.

Direct or indirect indices of progesterone production are:

• Urinary or serum luteinizing hormone (LH) rise
• A rise in basal body temperature
• Increase in serum progesterone
• Menstruation following the shift in basal body temperature

The following provide sonographic evidence of ovulation:

• Collapsed follicle
• Fluid in the cul-de-sac
• Features consistent with corpus luteum formation

Sonographic evaluation of the early pregnancy is also important to rule out ectopic pregnancy.

For Men:

Clinical monitoring for spermatogenesis utilizes the following indirect or direct measures:

• Serum testosterone level
• Semen analysis

5.11 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

• Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2)]
• Atelectasis [see Warnings and Precautions (5.3)]
• Thromboembolism [see Warnings and Precautions (5.3)]
• Ovarian Torsion [see Warnings and Precautions (5.4)]
• Multi-fetal Gestation and Birth [see Warnings and Precautions (5.5)]
• Congenital Anomalies [see Warnings and Precautions (5.6)]
• Ectopic Pregnancy [see Warnings and Precautions (5.7)]
• Spontaneous Abortion [see Warnings and Precautions (5.8)]

6.1 Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Ovulation Induction

In a single cycle, multi-center, assessor-blind, parallel group, comparative study, a total of 172 chronic anovulatory women who had failed to ovulate and/or conceive with clomiphene citrate therapy, were randomized and treated with Follistim (105) or a urofollitropin comparator. Adverse reactions with an incidence of greater than 2% in either treatment group are listed in Table 2.

Table 2: Common Adverse Reactions Reported at a Frequency of ≥2% in an Assessor-Blind, Comparative Study of Anovulatory Women Receiving Ovulation Induction

System Organ Class/Adverse Reactions	TreatmentNumber (%) of Women
	FollistimN=105n (%)	ComparatorN=67n (%)
Gastrointestinal disorders
Abdominal discomfort	3 (2.9)	1 (1.5)
Abdominal pain	3 (2.9)	2 (3.0)
Abdominal pain lower	3 (2.9)	1 (1.5)
Reproductive system and breast disorders
Ovarian cyst	3 (2.9)	2 (3.0)
Ovarian hyperstimulation syndrome	8 (7.6)	3 (4.5)
General disorders and administration site conditions
Pyrexia	0 (0.0)	2 (3.0)

Adverse reactions reported commonly (greater than or equal to 2% of women treated with Follistim) in other ovulation induction clinical trials were headache, abdominal distension, constipation, diarrhea, nausea, pelvic pain, uterine enlargement, vaginal hemorrhage and injection site reaction.

In Vitro Fertilization/Intracytoplasmic Sperm Injection

In a single cycle, multi-center, double-blind, parallel group, comparative study, a total of 1509 women were randomized to receive controlled ovarian stimulation with either Follistim AQ Cartridge (751 women were treated with Follistim AQ Cartridge) or a comparator and pituitary suppression with a gonadotropin releasing hormone (GnRH) antagonist as part of an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle. Table 3 lists adverse reactions with an incidence of greater than 2% in the group of women treated with Follistim AQ Cartridge.

Table 3: 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 TreatmentN = 751n * (%)
* n = number of women with the adverse reaction
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%)

Induction of Spermatogenesis

In an open-label, non-comparative clinical trial, 49 men with hypogonadotropic hypogonadism were enrolled to receive pretreatment with hCG, followed by combination therapy with hCG and Follistim for induction of spermatogenesis. Of the 49 men, 30 received weekly Follistim doses of 450 international units; 24 of these 30 men received a total of 48 weeks of treatment with Follistim. Adverse reactions occurring with an incidence of greater than 2% in the 30 men treated with Follistim are listed in Table 4.

Table 4: Common Adverse Reactions Reported at a Frequency of ≥2% in an Open-Label Clinical Trial in Men with Hypogonadotropic Hypogonadism

System Organ Class/Adverse Reactions	Follistim TreatmentN=30n (%)
Nervous system disorders
Headache	2 (6.7)
General disorders and administration site disorders
Injection site reaction	2 (6.7)
Injection site pain	2 (6.7)
Skin and cutaneous tissue disorders
Acne	2 (6.7)
Rash	1 (3.3)
Reproductive system and breast disorders
Gynecomastia	1 (3.3)
Neoplasms benign, malignant and unspecified
Dermoid cyst	1 (3.3)