FIRMAGON

FIRMAGON is administered as a subcutaneous injection in the abdominal region only at the dosages in Table 1 below.

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 Each vial is to be reconstituted with a prefilled syringe containing 3 mL of Sterile Water for Injection. 3 mL is withdrawn to deliver 120 mg degarelix at a concentration of 40 mg/mL.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 Each vial is to be reconstituted with a prefilled syringe containing 4.2 mL of Sterile Water for Injection. 4 mL is withdrawn to deliver 80 mg degarelix at a concentration of 20 mg/mL.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.

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.

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.

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.

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.

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)].

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.

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

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.

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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.

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.

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

A single dose of 240 mg FIRMAGON causes a decrease in the plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and subsequently testosterone.

FIRMAGON is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL.

Figure 1: Plasma Testosterone Levels from Day 0 to 364 for Degarelix 240 mg/80 mg (Median with Interquartile Ranges)

Figure 1

Degarelix was administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg (about 9, 45 and 120% of the recommended human loading dose on a mg/m² basis). Long term treatment with degarelix at 25 mg/kg caused an increase in the combined incidence of benign hemangiomas plus malignant hemangiosarcomas in females.

Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg (about 5, 22 and 120% of the recommended human loading dose (240 mg) on a mg/m² basis). There was no statistically significant increase in tumor incidence associated with this treatment.

Degarelix did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration) nor in in vivo rodent bone marrow micronucleus tests.

Single degarelix doses of ≥ 1 mg/kg (about 5% of the clinical loading dose on a mg/m² basis) caused reversible infertility in male rats. Single doses of ≥ 0.1 mg/kg (about 0.5% of the clinical loading dose on a mg/m² basis) caused a decrease in fertility in female rats.

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].

Hypersensitivity

• Inform patients that if they have experienced severe hypersensitivity with degarelix or to any of the product components, FIRMAGON is contraindicated [see Contraindications (4)]. Instruct patients to immediately report signs of a severe hypersensitivity reaction [see Warnings and Precautions (5.1)].

QT Interval Prolongation

• Advise patients that androgen deprivation therapy treatment with FIRMAGON may prolong the QT interval. Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation [see Warnings and Precautions (5.2)].

Androgen Deprivation

• Inform patients about adverese reactions related to androgen deprivation therapy with FIRMAGON, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function [see Adverse Reactions (6.1)].

Injection Site Reactions

• Inform patients that FIRMAGON may cause redness, swelling, and itching at the injection site. Advise patients that these adverse reactions are usually mild, self limiting, and decrease within three days [see Adverse Reactions (6.1)].

Infertility

• Inform patients that FIRMAGON may cause infertility [see Use in Specific Populations (8.3)].