Degarelix

5 WARNINGS AND PRECAUTIONS Hypersensitivity: Anaphylaxis, urticaria and angioedema have been reported. Discontinue FIRMAGON if a severe hypersensitivity reaction occurs and manage as clinically indicated ( 5.1 ) QT Interval Prolongation: Androgen deprivation therapy treatment with FIRMAGON may prolong the QT interval. ( 5.2 ) Embryo-Fetal Toxicity: FIRMAGON can cause fetal harm. ( 5.4 , 8.1 ) 5.1 Hypersensitivity Reactions FIRMAGON is contraindicated in patients with history of severe hypersensitivity to degarelix or to any of the product components [see Contraindications (4) ]. Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported post-marketing with FIRMAGON. In case of a severe hypersensitivity reaction, discontinue FIRMAGON immediately if the injection has not been completed, and manage as clinically indicated. Patients with a known history of severe hypersensitivity reactions to FIRMAGON should not be re-challenged with FIRMAGON. 5.2 QT Interval Prolongation Androgen deprivation therapy may prolong the QT interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. In the randomized, active-controlled trial comparing FIRMAGON to leuprolide, periodic electro-cardiograms were performed. Seven patients, three (<1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study, the median change for FIRMAGON was 12.3 msec and for leuprolide was 16.7 msec. 5.3 Laboratory Testing FIRMAGON results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after FIRMAGON may be affected. The therapeutic effect of FIRMAGON should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured. 5.4 Embryo-Fetal Toxicity Based on findings in animal studies, FIRMAGON can cause fetal harm and loss of pregnancy when administered to a pregnant woman. In animal developmental and reproductive toxicity studies in rats and rabbits, oral administration of degarelix during organogenesis caused embryo-fetal lethality and abortion as well as increased post-implantation loss and decreased the number of live fetuses in animals at doses less than the clinical loading dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1) ].

6 ADVERSE REACTIONS Most common adverse reactions (≥10%) are injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring at 1-888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. FIRMAGON was studied in a randomized, open-label trial in which patients with prostate cancer were randomized to receive FIRMAGON (subcutaneous) or leuprolide (intramuscular) monthly for 12 months [see Clinical Studies (14) ] . The most common adverse reactions (≥10%) during FIRMAGON therapy are injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less. Adverse reactions reported in ≥ 5% of patients treated with FIRMAGON (subcutaneous) 240 mg starting dose and then 80 mg maintenance dose once every 28 days or who were treated with 7.5 mg of leuprolide (intramuscular) every 28 days are shown in Table 2. Table 2: Adverse Reactions Reported in ≥ 5% of Patients FIRMAGON 240/80 mg (subcutaneous) N = 207 Leuprolide 7.5 mg (intramuscular) N = 201 Any adverse reaction 79% 78% Body as a whole Injection site reactions Includes pain, erythema, swelling, induration, or nodule. 35% <1% Weight increase 9% 12% Chills 5% 0% Cardiovascular system Hot flash 26% 21% Hypertension 6% 4% Digestive system Increases in Transaminases and GGT 10% 5% Constipation 5% 5% Musculoskeletal system Back pain 6% 8% Arthralgia 5% 9% Urogenital system Urinary tract infection 5% 9% The following adverse reactions occurred in 1 to < 5% of patients treated with FIRMAGON: Body as a whole: Asthenia, fatigue, fever, night sweats Digestive system: Nausea Nervous system: Dizziness, headache, insomnia The following adverse reactions, not already listed, occurred in ≥ 1% of patients treated in any study with FIRMAGON: Reproductive System: Erectile dysfunction, testicular atrophy Endocrine Disorders: Gynecomastia General : Hyperhidrosis Gastrointestinal : Diarrhea Injection Site Reactions The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving FIRMAGON. Hepatic Laboratory Abnormalities Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients. FIRMAGON Extension Study The safety of FIRMAGON administered once every 28 days was evaluated further in an extension study (NCT00451958) in 385 patients who completed the above active-controlled trial. Of the 385 patients, 251 patients continued treatment with FIRMAGON and 135 patients crossed over treatment from leuprolide to FIRMAGON. The median treatment duration on the extension study was approximately 43 months (range 1 to 58 months). The most common adverse reactions reported in ≥10% of the patients were injection site reactions (e.g., pain, erythema, swelling, induration or inflammation), pyrexia, hot flush, weight loss or gain, fatigue, increases in serum levels of hepatic transaminases and GGT. One percent of patients had injection site infections including abscess. Hepatic laboratory abnormalities in the extension study included the following: Grade 1/2 elevations in hepatic transaminases occurred in 47% of patients and Grade 3 elevations occurred in 1% of patients. 6.2 Immunogenicity As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. Anti-Degarelix Antibodies Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for 1 year. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of FIRMAGON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Changes in bone density Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of medical castration in men will result in decreased bone density.

8 USE IN SPECIFIC POPULATIONS Females and males of reproductive potential: FIRMAGON may impair fertility ( 8.3 ) Patients with severe liver or kidney dysfunction have not been studied and caution is therefore warranted ( 8 ) 8.1 Pregnancy Risk Summary The safety and efficacy of FIRMAGON have not been established in women. Based on findings in animal studies and mechanism of action, FIRMAGON can cause fetal harm and loss of pregnancy when administered to a pregnant woman [ see Clinical Pharmacology (12.1) ]. There are no human data on the use of FIRMAGON in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicity studies in rats and rabbits, oral administration of degarelix during organogenesis caused embryo-fetal lethality and abortion as well as increased post-implantation loss and decreased the number of live fetuses in animals at doses less than the clinical loading dose based on body surface area ( see Data ). Advise pregnant patients and females of reproductive potential of the potential risk to the fetus. Data Animal Data When degarelix was given to rabbits during early organogenesis at doses of 0.002 mg/kg/day (about 0.02% of the clinical loading dose based on body surface area), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of 0.006 mg/kg/day (about 0.05% of the clinical loading dose based on body surface area) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of 0.0045 mg/kg/day (about 0.036% of the clinical loading dose based on body surface area), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of 0.045 mg/kg/day (about 0.36% of the clinical loading dose based on body surface area), there was an increase in the number of minor skeletal abnormalities and variants. 8.2 Lactation The safety and efficacy of FIRMAGON have not been established in females. There are no data on the presence of degarelix in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are present in human milk and because of the potential for serious adverse reactions in a breastfed child from degarelix, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. 8.3 Females and Males of Reproductive Potential Infertility Based on findings in animals and mechanism of action, degarelix may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of FIRMAGON, 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine. A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment [creatinine clearance (CrCL) 50-80 mL/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL < 50 mL/min. 8.7 Hepatic Impairment Patients with hepatic impairment were excluded from the randomized trial. A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 non-prostate cancer patients with either mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered. Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.