FIRMAGON

Warnings and Precautions, Embryo-Fetal Toxicity ( 5.4 ) 02/2020

1 INDICATIONS AND USAGE FIRMAGON ® is indicated for treatment of patients with advanced prostate cancer. FIRMAGON is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer. ( 1 )

2 DOSAGE AND ADMINISTRATION FIRMAGON is for subcutaneous use only Starting Dosage: 240 mg given as two injections of 120 mg each ( 2.1 ) Maintenance Dosage: 80 mg administered as a single injection every 28 days ( 2.1 ) 2.1 Dosing information FIRMAGON is administered as a subcutaneous injection in the abdominal region only at the dosages in Table 1 below. Table 1: FIRMAGON Recommended Dosages Starting Dosage Maintenance Dosage – Administered once every 28 days 240 mg given as two subcutaneous injections of 120 mg at a concentration of 40 mg/mL The first maintenance dose should be given 28 days after the starting dose. 80 mg given as one subcutaneous injection at a concentration of 20 mg/mL 2.2 Reconstitution and Administration Instructions FIRMAGON is to be administered by a healthcare professional only . Before administering FIRMAGON read the Instructions for reconstitution and administration carefully. As with other drugs administered by subcutaneous injection, the injection site should vary periodically. Injections should be given only in areas of the abdomen that will not be exposed to pressure, e.g., not close to waistband or belt nor close to the ribs. FIRMAGON is supplied as a powder to be reconstituted with Sterile Water for Injection, USP. Starting dose (240 mg): Two single-dose vials each delivering 120 mg of degarelix in a white to off-white lyophilized powder for reconstitution supplied with diluent in two prefilled syringes. Each vial is to be reconstituted with a prefilled syringe containing 3 mL of Sterile Water for Injection. 3 mL is withdrawn to deliver 120 mg degarelix at a concentration of 40 mg/mL. Maintenance dose (80 mg): One single-dose vial delivering 80 mg of degarelix in a white to off-white lyophilized powder for reconstitution supplied with diluent in one prefilled syringe. Each vial is to be reconstituted with a prefilled syringe containing 4.2 mL of Sterile Water for Injection. 4 mL is withdrawn to deliver 80 mg degarelix at a concentration of 20 mg/mL. Follow the instructions for reconstitution closely and read the complete instructions before performing the subcutaneous injection. Reconstituted drug must be administered within one hour after addition of Sterile Water for Injection, USP. Do not shake the vials. Follow aseptic technique. FIRMAGON 240 mg Starting Dose Kit contains: 2 vials containing the 120 mg FIRMAGON powder (a) 2 syringes containing Sterile Water for Injection, USP (b) 2 vial adapters (c) 2 25 gauge × 1 inch injection needles (d) 2 plunger rods (e) FIRMAGON 80 mg Maintenance Dose Kit contains: 1 vial containing the 80 mg FIRMAGON powder (f) 1 syringe containing Sterile Water for Injection, USP (g) 1 vial adapter (h) 1 25 gauge × 1 inch injection needle (i) 1 plunger rod (j) In addition the healthcare professional will need: gloves (k) alcohol pads (l) a clean, flat surface (m) to work on, like a table a sharps disposal container (n) for throwing away your used needles and syringes. See " Disposing used needles and syringes " at the end of these instructions. The drug product must be prepared using the following instructions: NOTE: The mixing process must be repeated for the two injections of the Starting Dose prior to injecting the product into the patient's abdomen. Step 1: Attaching the vial adaptor to the vial Thoroughly wash your hands using soap and water and put on a pair of clean gloves. Place all the supplies required on a clean surface. Check that there is powder in the FIRMAGON vial and that the Sterile Water for Injection, USP is clear and free from particles. IMPORTANT: DO NOT USE if there is no powder in the vial or the Sterile Water for Injection, USP is discolored. Uncap the vial containing the FIRMAGON powder (o). Wipe the vial rubber stopper with an alcohol pad. IMPORTANT: Do not touch the top of the vial after wiping. Peel off the seal from the vial adaptor cover. IMPORTANT: Do not touch the vial adapter. Firmly press the vial adaptor (p) onto the vial containi …

3 DOSAGE FORMS AND STRENGTHS For injection: FIRMAGON (240 mg): Two single-dose vials each delivering 120 mg of degarelix in a white to off-white lyophilized powder for reconstitution supplied with diluent in two prefilled syringes. FIRMAGON (80 mg): One single-dose vial delivering 80 mg of degarelix in a white to off-white lyophilized powder for reconstitution supplied with diluent in one prefilled syringe. For injection: FIRMAGON (240 mg): Two single-dose vials each delivering 120 mg of degarelix in a lyophilized powder for reconstitution supplied with diluent in two prefilled syringes ( 3 ) FIRMAGON (80 mg): One single-dose vial delivering 80 mg of degarelix in a lyophilized powder for reconstitution supplied with diluent in one prefilled syringe ( 3 )

4 CONTRAINDICATIONS FIRMAGON is contraindicated in patients with history of severe hypersensitivity to degarelix or to any of the product components [see Warnings and Precautions (5.1) ] . Patients with history of severe hypersensitivity reactions to degarelix or to any of the product components ( 4 )

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 ex …

7 DRUG INTERACTIONS No drug-drug interaction studies were conducted. Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the CYP450 system in vitro . Therefore, clinically significant CYP450 pharmacokinetic drug-drug interactions are unlikely.

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 …

12.1 Mechanism of Action Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, thereby reducing the release of gonadotropins and consequently testosterone.

11 DESCRIPTION FIRMAGON is a sterile lyophilized powder for injection containing degarelix (as the acetate) and mannitol. Degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids. The acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilization. The chemical name of degarelix is D-Alaninamide, N -acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L-leucyl- N 6–(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formula of C 82 H 103 N 18 O 16 Cl and a molecular weight of 1632.3 Da. Degarelix acetate has the following structural formula: FIRMAGON is available in two packaging configurations: Starting Dose: Two vial carton with each vial delivering 120 mg of degarelix (equivalent to the median value of 126 mg degarelix acetate). Each 120 mg dose contains 150 mg mannitol. Maintenance Dose: One-vial carton delivering 80 mg of degarelix (equivalent to the median value of 84 mg degarelix acetate). Each 80 mg dose contains 200 mg mannitol. Chemical Structure

10 OVERDOSAGE There have been no reports of overdose with FIRMAGON. In the case of overdose, however, discontinue FIRMAGON, treat the patient symptomatically, and institute supportive measures.

16 HOW SUPPLIED/STORAGE AND HANDLING FIRMAGON is available as: NDC 55566-8403-1, Starting dose – One carton contains: Two single-dose vials each delivering 120 mg of degarelix in a white to off-white lyophilized powder for injection Two prefilled syringes each containing 3 mL of Sterile Water for Injection, USP Two vial adapters Two administration needles NDC 55566-8303-1, Maintenance dose – One carton contains: One single-dose vial delivering 80 mg of degarelix in a white to off-white lyophilized powder for injection One prefilled syringe containing 4.2 mL of Sterile Water for Injection, USP One vial adapter One administration needle Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [see USP Controlled Room Temperature].