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warnings
WARNINGS Gonadotropins, including Luveris ® (lutropin alfa for injection), should only be used by physicians who are thoroughly familiar with infertility problems and their management. Like other gonadotropin products, Luveris ® is a potent gonadotropic substance capable of contributing to the development of Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications. The risks of gonadotropin treatment should be considered for women with risk factors of thromboembolic events such as prior medical or family history. 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 Luveris ® requires monitoring of ovarian response with serum estradiol and ovary ultrasound on a regular basis. Overstimulation of the Ovary Following Gonadotropin Therapy: Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain may occur in patients treated with gonadotropins (such as Luveris ® ). These conditions generally regress 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 therapy with Luveris ® and Gonal-f ® , hCG should not be administered in this course of therapy. This will reduce the risk 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 that are suggestive of hepatic dysfunction have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS). These liver function test abnormalities may be accompanied by morphological changes on liver biopsy. In hypogonadotropic hypogonadal women with profound LH and FSH deficiency from five clinical trials, four cases of OHSS were reported in 4 of 70 (5.7%) patients treated with 75 IU Luveris ® and Gonal-f ® and one case was reported in 1 of 31 (3.2%) patients treated with Gonal-f ® alone. Among women treated with any dose of Luveris ® in these studies, five of 96 (5.2%) patients reported 6 cases of OHSS after treatment with Luveris ® and Gonal-f ® . 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 severity at 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 ”), hCG must be withheld. If severe OHSS occurs, treatment with gonadotropins 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. Multiple Births: Patients should be advised of the potential risk of multiple births before starting treatment. Pulmonary and Vascular Complications: As with other gonadotropin products, a potential for the occurrence of arterial thromboembolism exists.
ADVERSE REACTIONS The safety of Luveris ® was examined in six clinical studies that treated 170 infertile women with hypogonadotropic hypogonadism of whom 152 received Luveris ® and Gonal-f ® in 283 treatment cycles. Adverse events reported by ≥ 2% of patients (regardless of causality) treated with any dose of Luveris ® (25, 75, 150, 225 IU) are listed in Table 7. Table 7: Adverse Events Reported in ≥ 2% Patients in All Cycles in All HH Patients in Studies 6253, 6905 (a) ,7798 (b) , 8297 (c) , 21008, and 21415 0 IU Luveris ® & Gonal-f ® 75 IU Luveris ® & Gonal-f ® All doses of Luveris ® & Gonal-f ® Patients (n=43) Patients (n=118) Patients (n=152) n (%) n (%) n (%) (a) Study 6905 was a randomized, open-label, dose-finding study to assess the efficacy and safety of Luveris ® administered with 150 IU Gonal-f ® for induction of follicular development in HH women. (b) Study 7798 was an uncontrolled, multicenter, dose-finding study to assess the efficacy and safety of Luveris ® administered with 150 IU Gonal-f ® for induction of follicular development in LH and FSH deficient anovulatory women in Germany. (c) Study 8297 was an uncontrolled, multicenter, dose-finding study to assess the efficacy and safety of Luveris ® administered with 150 IU Gonal-f ® for induction of follicular development in HH women in Spain. Patients With Events 20 (46.5) 50 (42.4) 72 (47.4) Headache 2 (4.7) 12 (10.2) 15 (9.9) Nausea 0 8 (6.8) 11 (7.2) Ovarian Hyperstimulation 1 (2.3) 7 (5.9) 9 (5.9) Breast Pain Female 4 (9.3) 6 (5.1) 9 (5.9) Abdominal Pain 5 (11.6) 6 (5.1) 13 (8.6) Ovarian Cyst 4 (9.3) 6 (5.1) 8 (5.3) Flatulence 3 (7.0) 5 (4.2) 6 (3.9) Injection Site Reaction 2 (4.7) 4 (3.4) 6 (3.9) Dysmenorrhoea 1 (2.3) 2 (1.7) 4 (2.6) Ovarian Disorder 0 2 (1.7) 3 (2.0) Diarrhoea 1 (2.3) 3 (2.5) 3 (2.0) Constipation 0 3 (2.5) 3 (2.0) Pain 3 (7.0) 3 (2.5) 6 (3.9) Fatigue 0 3 (2.5) 5 (3.3) Upper Resp Tract Infection 2 (4.7) 1 (0.8) 3 (2.0) The following medical events have been reported subsequent to pregnancies resulting from administration of gonadotropins for ovulation induction in controlled clinical studies: Spontaneous Abortion Ectopic Pregnancy Premature Labor Postpartum Fever Congenital Abnormalities 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 menotropin 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.